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Philippine Obstetrical and

Gynecological Society (POGS), Foundation, Inc.

!
CLINICAL PRACTICE GUIDELINES
on
HYPERTENSIVE COMPLICATIONS
OF PREGNANCY
!

April 2010

Task Force on Clinical Practice Guideline

In the Diagnosis and Management of
Hypertensive Complications of Pregnancy
 Philippine Obstetrical and
Gynecological Society (POGS),
Foundation, Inc.

CLINICAL PRACTICE GUIDELINES

on
HYPERTENSIVE COMPLICATIONS OF
PREGNANCY

April 2010

Task Force on Clinical Practice Guidelines

In the Diagnosis and Management of
Hypertensive Complications of Pregnancy
 FOREWORD!

REGTA L. PITHAY, MD
President
Philippine Obstetrical and Gynecological Society (Foundation), Inc. (POGS), 2010

The 2nd Edition of the Clinical Practice Guideline (CPG) on Hypertensive

Complications of Pregnancy is a timely addition to our growing number of
must have reference books. The urgency and dispatch with which this
edition came to be, was in response to our resolve in reducing the
unacceptably high rate of attendant maternal and fetal morbidity and mortality.

In line with the thrust of this years centerpiece project, the Millennium
Development (MDG) Countdown Program, this CPG is a significant tool in
providing health workers & stakeholders with fresh, scientifically validated
data in the detection and management of one of the leading challenges of
obstetric practice. It is envisioned that with this book more of our colleagues
and partners will help the country reach its MDG 4 and 5 before 2015.

I commend the teamwork of the 2010 Committee on CPG and the Taskforce
on CPG - Hypertensive Complications of Pregnancy. Your unselfish
contribution to this body of work is a testimony of your unwavering
commitment and support to a major mission of POGS.

REGTA L. PICHAY, MD
 INTRODUCTION!

EFREN J. DOMINGO, MD, PhD

Chair, AdHoc Committee on the Clinical Practice Guidelines, 2010

The Clinical Practice Guidelines on Hypertensive Complications of Pregnancy

is the Second Edition of this Publication, 2010. The Philippine Obstetrical and
Gynecological Society, (Foundation), Inc. (POGS), through the Committee on Clinical
Practice Guidelines initiated and led to completion the publication of this manual in
plenary consultation with the Residency Accredited Training Hospitals Chairs and
Training Officers, The Regional Board of Directors, The Board of Trustees, The Task
Force on the Diagnosis and Management of Hypertensive Complications of
Pregnancy and the Committee on Continuing Medical Education.

This publication represents the collective effort of the POGS in updating the
clinical practice of Obstetrics and Gynecology, specifically on Hypertensive
Complications of Pregnancy, and making it responsive to the most current and
acceptable standard in this procedure. A greater part of the inputs incorporated in
this edition are the contributions originating from the day-to-day academic
interactions from the faculty of the different Residency-Accredited Hospitals in
Obstetrics and Gynecology in the country.

This Clinical Practice Guideline on Hypertensive Complications of Pregnancy

is envisioned to become the handy companion of the Obstetrician-Gynecologist in
his/her day-to-day rendition of quality care and decision making in managing the
Obstetric patient. This is also envisioned to provide the academic institutions in the
country and in Southeast Asia updated information on Hypertensive Complications of
Pregnancy treatments being practiced in the Philippines.

Profound gratitude is extended to all the members of the POGS, the Chairs
and Training Officers of the Residency-Training Accredited Institutions, the Regional
Directors, The Task Force Reviewers/Contributors, The CME Committee members,
and the 2010 POGS Board of Trustees.

EFREN J. DOMINGO, MD, PhD

BOARD OF TRUSTEES 2010

OFFICERS

Regta L. Pichay, MD
President

Sylvia delas Alas Carnero, MD

Vice President

Ditas Cristina D. Decena, MD

Secretary

Jericho Thaddeus P. Luna, MD

Treasurer

Gil S. Gonzales, MD
Public Relations Officer

BOARD OF TRUSTEES
Efren J. Domingo, MD, PhD
Virgilio B. Castro, MD
Blanca C. de Guia, MD
Raul M. Quillamor, MD
Rey H. delos Reyes, MD
Ma. Cynthia Fernandez-Tan, MD
 COMMITTEE ON CLINICAL PRACTICE GUIDELINES ON
HYPERTENSIVE COMPLICATIONS OF PREGNANCY

Efren J. Domingo, MD, PhD

Chair

MEMBERS
Ann Marie C. Trinidad, MD Ma. Victoria V. Torres, MD
Lisa T. Prodigalidad-Jabson, MD Christine D. Dizon, MD
Rommel Z. Duenas, MD

MANAGING EDITOR
Ana Victoria V. Dy Echo, MD

TECHNICAL STAFF ASSISTANTS

Ms. Emiliana C. Enriquez
Ms. Jhasmin G. De Guzman

TASK FORCE ON DIAGNOSIS AND MANAGEMENT

OF HYPERTENSIVE COMPLICATIONS OF PREGNANCY

Ernesto S. Uichanco, MD
Chair

Walfrido W. Sumpaico, MD
Virgilio B. Castro, MD
Ann Marie C. Trinidad, MD
Raul M Quillamor, MD
MDCarmencita B. Tiongco, MD
Joseph U. Olivar, MD
Members
Sol M. Pangan, MD
Milagros T. Jocson, MD
Ramon M. Gonzales, MD
Ronaldo R. Santos, MD
Diosdado M. Mariano, MD
Sherri Ann L. Suplido, MD
Pilar Lagman-Dy, MD
Mario A. Bernardino, MD
Ma. Luisa S. Acu, MD
Ma. Antonia E. Habana,
Ma. Cristina P. Crisologo, MD

TASK FORCE REVIEWERS AND PLENARY REVIEWERS

Regta L. Pichay, MD Lourdes B. Capito, MD Ma. Lorelli P. Parado, MD

Rogelio P. Mendiola, MD
Amaryllis Digna Yazon, MD
Zaida N. Gamilla, MD
Teresita Cardenas, MD
Rommel Z. Duenas, MD
Jennifer T. Co, MD
Sharon A. Capule, MD
Analyn Matignas, MD
Ma. Carmen H. Quevedo, MD
Marilyn D. Ruaro, MD
Nelinda Pangilinan, MD
Eugenia Mendoza, MD
Julieta Cadano, MD
Gilbert Reyes, MD
Aida San Jose, MD
Rainerio S. Abad, MD
Belen P. Rajagulgul, MD
Genara Manuel-Limson, MD
Carmelita Pasay-Recto, MD
Annelee B. Lojo, MD
Janette Tuquero, MD
Paz Leticia Anacta, MD
Mila Zaragoza-Ibay, MD
Lisa T. Prodigalidad-Jabson, MD
Rodante P. Galiza, MD
Grace delos Angeles, MD
Blanca C. de Guia, MD
Florentina A. Villanueva, MD
Rey H. delos Reyes, MD

Regional Directors
Betha Fe M. Castillo, MD (Region 1)
Concepcion P. Argonza, MD (Region 3)
Diosdado V. Mariano, MD (Region 4A NCR)
Evelyn R. Lacson, MD (Region 6)
Fe G. Merin, MD (Region 8)
Jana Joy R. Tusalem, MD (Region 10)
Noel C. de Leon, MD (Region 2)
Ernesto S. Naval, MD (Region 4)
Cecilia Valdes-Neptuno, MD (Region 5)
Belinda N. Paares, MD (Region 7)
Cynthia A. Dionio, MD (Region 9)
Ameila A. Vega, MD (Region 11)
 DISCLAIMER, RELEASE AND WAIVER OF RESPONSIBILITY

This is the Clinical Practice Guidelines (CPG) on Hypertensive Complications of

Pregnancy, Second Edition, April 2010.
This is the publication of the Philippine Obstetrical and Gynecological Society,
(Foundation), Inc. (POGS).
This is the ownership of the POGS, its officers, and its entire membership.
The obstetrician-gynecologist, the general practitioner, the patient, the student, the allied
medical practitioner, or for that matter, any capacity of the person or individual who may
read, quote, cite, refer to, or acknowledge, any, or part, or the entirety of any topic,
subject matter, diagnostic condition or idea/s willfully release and waive all the liabilities
and responsibilities of the POGS, its officers and general membership, as well as the
Commiittee on the Clinical Practice Guidelines and its Editorial Staff in any or all clinical
or other disputes, disagreements, conference audits/controversies, case
discussions/critiquing.
The reader is encouraged to deal with each clinical case as a distinct and unique clinical
condition which will never fit into an exact location if reference is made into any or all
part/s of this CPG.
The intention and objective of this CPG is to serve as a guide, to clarify, to make clear the
distinction. It is not the intention or objective of this CPG to serve as the exact and
precise answer, solution and treatment for clinical conditions and situations. It is always
encouraged to refer to the individual clinical case as the one and only answer to the case
in question, not this CPG.
It is hoped that with the CPG at hand, the clinician will find a handy guide that leads to a
clue, to a valauable pathway that leads to the discovery of clinical tests leading to clinical
treatments and eventually recovery.
In behalf of the POGS, its Board of Trustees, the Committee on The Clinical Practice
Guidelines, 2009, this CPG is meant to make each one of us a perfect image of Christ, the
Healer.

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!

CPG ON HYPERTENSIVE COMPLICATIONS OF PREGNANCY

TABLE OF CONTENTS / AUTHORS!

1. Epidemiology of Hypertensive Complications of Pregnancy .. .1

Ramon M. Gonzalez, M.D. and Ronaldo R. Santos, M.D.

2. The Classification of Hypertensive Complications of Pregnancy

Ernesto S. Uichanco, M.D. and Sherri Ann L. Suplido, M.D.

3. Predictive Tests for Hypertensive Complications of Pregnancy .

Ma. Antonia E. Habana, M.D and Ma. Cristina P. Crisologo, M.D.

4. Prevention of Pre-eclampsia .
Walfrido W. Sumpaico, M.D. and Milagros T. Jocson, M.D.

5. Gestational Hypertension and Mild Pre-eclampsia ..

Pilar Lagman-Dy, M.D. and Carmencita B. Tongco, M.D.

6. Severe Pre-eclampsia
Mario A. Bernardino, M.D. and Joseph Olivar, M.D.

7. Eclampsia ...
Raul M. Quillamor, M.D. and Diosdado V. Mariano, M.D.

8. Chronic Hypertension
Virgilio B. Castro, M.D. and Ann Marie C. Trinidad, M.D.

9. Complications of Pregnancy Induced Hypertension (HELLP, Abruptio Placenta) .

Ma. Luisa S. Acu, M.D. and Sol M. Pangan, M.D

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 Epidemiology of Hypertension in Pregnancy
Ramon M. Gonzalez MD, Ronaldo Santos MD and, Carelle Roux-Ong MD

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Preeclampsia is a life threatening complication of pregnancy characterized by
hypertension and proteinuria that contribute greatly to maternal morbidity and
mortality. This is primarily due to an abnormal implantation of trophoblasts in the
placenta as well as poor placental perfusion. It occurs in about 3% of all pregnancies.
This disease has long been recognized but the exact etiology of preeclampsia is still
obscure despite many attempts to identify possible causes. The etiology therefore, is
more likely to be multifactorial. Clues regarding the etiology may be derived from
the various risk factors that have been identified.

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Primiparity
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The only well accepted risk factor for preeclampsia is primiparity. Pregnancy-
induced hypertensive disorders, especially preeclampsia have been documented to
occur primarily in first pregnancies. The concept, therefore of primiparity is the
epidemiological cornerstone of this disease.1 In a population based study in Norway
covering all births since 1967 (about 1.5 million women), the risk of preeclampsia in
first pregnancies was 3%. It decreased to 1.7% in the second pregnancy.4

Immunologic Factors

There is circumstantial evidence to support the theory that preeclampsia is immune

mediated. Normal pregnancy is well known to be an immunological stimulation
towards the tolerance pathway and not an immunological depression of the mother. In
the past the theory was that this immunological tolerance could be due to blocking
antibodies, hiding the fathers antigens. More recently, it is now thought that this
tolerance rather involves cytokines through the tolerance network called T helper 2
(Th2) reaction. Preeclampsia caused by the failure of the trophoblast invasion can be
considered as a kind of rejection reaction by the mother towards the trophoblast
antigens through a failure of the tolerance system allowing the invasion. This may
arise in situations in which effective immunization by a previous pregnancy is
lacking, as in first pregnancies. The immunization concept is supported by
observations that preeclampsia develops less often in multiparas who had a prior term
pregnancy.1

Previous Pregnancy Complicated by Preeclampsia / Eclampsia / HELLP

Women who had previous pregnancies complicated by preeclampsia have an

increased risk for recurrence in subsequent pregnancies. Moreover, severe
preeclamptic women in an initial pregnancy have a recurrence rate of as high as 50%.
In a study by Campbell and coworkers, the rate of recurrence of preeclampsia was
7.5% and 65% when the previous pregnancy was complicated by severe
preeclampsia. Van Rijn and co-workers showed that there was a 25% chance of
recurrence in women with a history of early onset preeclampsia resulting in delivery
before 34 weeks of gestation. Those with pre-existing chronic hypertension had
higher rates of preeclampsia, about 75%. Sibai and Sullivan in separate studies
revealed a recurrence rate of preeclampsia with previous pregnancies with HELLP
syndrome to be 19% and 43% respectively. In a study by Sibai involving 366
eclamptic women, the rate of recurrence of eclampsia in subsequent pregnancies was
2% and the risk for developing preeclampsia was 22%.5

Family History of Preeclampsia

The predisposition to hereditary hypertension undoubtedly is linked to preeclampsia

and the tendency for preeclampsiaeclampsia is inherited. Women with preeclampsia
were 2.3 times more likely to have a sister who had preeclampsia. Those with
gestational hypertension on the other hand, were 1.6 times more likely to have a sister
with gestational hypertension. If two sisters have the same father but different
mothers the risk of preeclampsia is 1.8 (95% CI 1.01-2.9).4 The pathophysiologic
role for genetic and behavioural factors that cluster families is consistent with the
likelihood of preeclampsia among sisters of women with previous preeclamptic
pregnancies.10

Body Mass Index

The relationship between maternal weight and the risk of preeclampsia is progressive.
It increases from 4.3% for women with a body mass index (BMI) less than 19.8 kg/m2
to 13.3% in those with a BMI greater than 35 kg/m2. In a population based cohort
study in Missouri between 1989-1997 obese and overweight women had higher risks
of recurrent preeclampsia 19.3% and 14.2% respectively compared with women with
normal BMI which was 11.2%.8

Underlying Medical Conditions

Underlying medical conditions with vascular and connective tissue disorders or renal
implications are at risk for developing preeclampsia . In a study by Stamilio the odds
ratio was 6.9 (95% CI 1.1-42.3). Among 462 women with pregestational diabetes,
Sibai and co-workers demonstrated a 20% occurrence of preeclampsia.7 More so, the
frequency of preeclampsia rose with increasing severity of diabetes.

Pregnancy Related Conditions

Conditions with an increased trophoblast mass like hydrops fetalis and multifetal
gestation are at increased risk for preeclampsia. In women with twin gestations
compared with those with singletons, the incidence of gestational hypertension and
preeclampsia are both significantly increased, 13% in singletons and 5-6% in twins.
Although multiple gestations are considered at risk for preeclampsia, the risk for
recurrence in subsequent pregnancies is not clear. Trogstad and co-workers examined
a total of 550,218 women between 1967 and 1998. They found out that for women
with a previous singleton pregnancy complicated with preeclampsia, the recurrence
rate was 14.1% whereas the recurrence rate for twins was only 6.8%.5

Primipaternity

Recently, it has been suggested that primipaternity rather than primiparity is the
relevant risk factor. Immunogenetic factors explain the primipaternity phenomenon.
The role of the father has long been hypothesized to be central in the primipaternity
model which can be interpreted by an immunogenetic hypothesis. This may be
interpreted as an immunological habituation to paternal antigens through contact
between the sperm and the female genital tract. Having a new sexual partner will
expose the mother to new paternal antigens to which she may not be tolerant. Thus,
changing the father, for a woman with no history of preeclampsia may increase her
risk to the same level that she would have had as a primipara. This disease therefore,
may be a problem of primipaternity rather than primigravity. Moreover, if a woman
becomes pregnant by a man who has fathered a preeclamptic pregnancy in a different
woman, her risk of developing preeclampsia is 1.8 (95% CI 1.2-2.6).4 Paternal genes
in the fetus may therefore contribute substantially to a womans risk of preeclampsia.
In support of this theory, a higher risk for preeclampsia has also been observed in
women who had artificial insemination by an unknown donor.

Sexual Co-habitation

Robillard, et. al. suggested that preeclampsia is a disease of new couples and that
the longer the duration of co-habitation (without barrier contraceptives), the lower the
risk of preeclampsia. There is a linear decrease of the risk of preeclamsia with the
timing of conception within the first year of sexual co-habitation. Within the first four
months the risk is 40% compared to 3-5% over 12 months.1 Regardless of parity, the
length of sexual co-habitation was noted to be inversely related to the incidence of
pregnancy induced hypertension. A longer period of sexual co-habitation with the
father before conception reduces the risk of preeclampsia. One explanation is that the
mother adapts to the imprinted antigens from the father.

Maternal Infection

Systematic review and meta-analysis of observational studies were done to examine

the relationship between maternal infection and preeclampsia. The risk of
preeclampsia was increased in patients with urinary tract infection (OR 1.57, 95% CI
1.45-1.70) and periodontal disease (OR 1.76, 95% CI 1.43-2.18). Conclusion was that
urinary tract infection and periodontal diseases increased the risk of developing
preeclampsia.6
Gestational Age at Delivery in the First Pregnancy

The risk of recurrent preeclampsia is inversely related to the gestational age at the
first delivery: 38.6% for <28 weeks gestation, 29.1% between 29-32 weeks, 21.9%
for 33-36 weeks and 12.9% for >37 weeks age of gestation.8 A previous preterm
delivery and small for gestational age newborn increases the risk of preeclampsia in
subsequent pregnancies.9

Socioeconomic Status

Women from different socioeconomic status share the similar risk of developing
preeclampsia. This disease is the only major perinatal risk factor which is not
reported to be evidently associated with poor social status.

Smoking

Although smoking during pregnancy causes a variety of adverse pregnancy outcomes,

ironically, smoking has consistently been associated with a reduced risk of
hypertension during pregnancy.

References

1. Robillard P, Dekker G, Hulsey T. Revisiting the epidemiological standard of preeclampsia:

primigravidity or primipaternity? Eur J Obstet Gynecol Reprod Bio 1999;84(1):37-41.
2. Eskenazi B, Fenster L, Sidney S. Multivariate analysis of risk factors for preeclampsia. JAMA
1991;266(2):237-241.
3. Lie RT, Rasmussen S, Brunborg H, et. al. Fetal and maternal contributuions to risk of
preeclampsia: population based study BMJ 1998;316:1343-1347.
4. Dildy G, Belfort M, Smulian J. Preeclampsia recurrence and prevention. Sem Perinat
2007:31(3):135-141.
5. Agudelo AC, Villar J, Lindheimer M. Maternal infection and risk of preeclampsia: systematic
review and meta-analysis. Am J Obstet Gynecol 2008:198(1):7-22.
6. Sibai B, Caritis S, Hauth J, et. al. Risks of preeclampsia and adverse neonatal outcome among
women with pregestational diabetes mellitus. Am J Obstet Gynecol 2000:364-369.
7. Mostello D, Kallogjeri D, Tungsiripat R, Leet T. Recurrence of preeclamsia: Effects of
gestational age at delivery of the first pregnancy, body mass index, paternity, and interval
between births. Am J Obstet Gynecol 2008: 55.e1-55.e7.
8. Mostello D, Tegan C, Roman L, Holcomb W, Leet T. Preeclampsia in the parous woman:
who is at risk? Am J Obstet Gynecol 2002;187(2):425-429.
9. Darcy C, Epplein M, Johnson C, et. al. A sisters risk: family history as a predictor of
preeclampsia. Am J Obstet Gynecol 2005:193(3):965-972.
10. Eskanazi B, Harley K. Commentary: revisiting the primipaternity theory of preeclampsia. Int
J Obstet Gynecol 2001;30:1323-1324.
11. Cunningham F, Grant NF, et. al.Williams Obstetrics 22nd ed. New York NY:McGraw-
Hill;2005.
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Classification of Hypertensive Complications of Pregnancy

Ernesto S. Uichanco, MD and Sherri Ann L. Suplido, MD

Modern day obstetrics is still wanting of a classification of hypertensive

disorders of pregnancy that is simple, encompassing and meaningful in the clinical
situation. The various classification systems each have their own defects and
deficiencies. The confusions brought about by these numerous classification methods
may be one of the reasons why it is difficult to come up with researches on the topic
with significant results and conclusions.

Local medical centers are using a combination of the various definitions and
classification system of hypertensive disorders in pregnancy. Some terms are used
interchangeably, adding to the confusion when trying to give a diagnosis and in
labeling a patient. The committee is presenting this classification system for
uniformity and standardization in practice.

Recommendations of the Consensus Meeting

The committee recommends the following classification of hypertensive

complications of pregnancy, based on a review of three commonly-used classification
system used presently in the Philippines and several recommendations from different
societies and guidelines abroad.

Classification of Hypertensive Disorders in Pregnancy

A. Gestational hypertension / non- proteinuric hypertension of pregnancy /

transient hypertension
B. Pre-eclampsia
1. Mild
2. Severe
C. Eclampsia
D. Chronic Hypertension
E. Chronic Hypertension with Superimposed Pre-eclampsia

Definition of Terms

1. Hypertension

The National High Blood Pressure Education Program (NHBPEP)

Working Group defines hypertension in pregnant women as having a systolic
blood pressure (BP) of 140 mmHg or higher or a diastolic blood pressure of 90
mmHg or higher on more than 1 occasion1 (American College of Obstetrics and
 Gynecology (ACOG), Level III). In the past, it has been recommended that an
incremental increase of 30 mmHg systolic or 15 mmHg diastolic pressure be used
as a diagnostic criteria, regardless if absolute values were below 140/90 mmHg.
These criteria are no longer used because evidence reveals that these women are
unlikely to suffer adverse perinatal outcomes and because similar increases are
seen in uncomplicated pregnancies. Although this is the case, the Working Group
recommends close observation of these patients.
The diagnosis of hypertension should be based on office or in-hospital BP
measurement and is based on the average of at least two measurements, taken
using the same arm2 (National Guideline Clearinghouse (NGC), Level II-2, Grade
B). Korotkoff phase V is used to designate diastolic blood pressure2 (NGC, Level
I, Grade A).

2. Proteinuria

Proteinuria is defined as the presence of 0.3 grams or 300 mg or more of

protein in a 24- hour urine specimen, which usually correlates with a +1 (30
mg/dl) or greater, but should be confirmed with a random urine dipstick
evaluation or and a 24- hour or timed collection1 (ACOG, Level III). It may also be
defined as greater than 30 mg/mmol urinary creatinine in a spot (random) urine
sample2 (NGC, Level II, Grade A-B).

3. Edema

This is defined as swelling of the hands and the face or leg edema after an
overnight rest, and is no longer a criterion for the diagnosis of pre-eclampsia.

3. Pregnancy Induced Hypertension

This is defined as hypertension that develops as a consequence of

pregnancy and regresses post-partum however The term pregnancy-induced
hypertension should be abandoned, as its meaning in clinical practice is unclear 2
(NGC, Level III, Grade D).

4. Gestational Hypertension

The NHBPEP Working Group has recommended that the term gestational
hypertension replace the term pregnancy-induced hypertension to describe
cases in which elevated blood pressure without proteinuria develops in a woman
after 20 weeks of gestation and blood pressure levels return to normal 12 weeks
postpartum1 (ACOG, Level III).

5. Pre-eclampsia

Preeclampsia is a multiorgan disease process characterized by the presence

of hypertension and proteinuria occurring after 20 weeks of gestation in a woman
with a previously normal blood pressure.
6. Severe pre-eclampsia

Pre-eclampsia is characterized as severe if the patient manifests any of the

following3 (ACOG, Level III):
BP > or = 160 mm Hg systolic or > or = 110mm Hg diastolic taken at
least 6 hours apart on 2 occasions while the patient is on bed rest
Proteinuria > or = 5 g/24 hrs or >/= +3 in 2 random urine samples
collected at least 4 hours apart
Elevated serum creatinine
Pulmonary edema
Oliguria < 500 ml/24 hrs
Microangiopathic hemolysis
Thrombocytopenia
Hepatocellular dysfunction (elevated alanine transaminotransferase or
aspartase aminotransferase)
Intrauterine growth restriction or oligohydramnios
Symptoms suggesting end-organ involvement:
Headache
Visual disturbances
Epigastric or right upper quadrant abdominal pain

7. Mild pre-eclampsia

Pre-eclampsia is characterized as mild if the patient does not manifest any

of the signs and symptoms of severe pre-eclampsia.

8. Eclampsia

Eclampsia is defined as hypertension in pregnancy with proteinuria along

with convulsions or the occurrence of grand mal seizures in a patient with pre-
eclampsia.3

9. Chronic Hypertension

Chronic hypertension is characterized by elevation of blood pressure that

antecedes pregnancy or persists post-partum. It is defined by the NHBPEP
Working Group on High Blood Pressure in Pregnancy as hypertension present
before the 20th week of pregnancy or hypertension present before pregnancy1
(ACOG, Level III). The diagnosis is also made in a woman taking anti-
hypertensive medications before conception. It is classified as mild (BP > 140/90
mm Hg) or severe (BP > 180/110 mmHg, and is also present if the hypertension
persists longer than 12 weeks post delivery3.

10. Chronic Hypertension with Superimposed Pre-eclampsia

This is characterized by elevation of blood pressure that antecedes

pregnancy or persists post-partum with associated signs and symptoms of pre-
eclampsia. Diagnostic criteria include new-onset proteinura in a woman with
hypertension before 20 weeks gestation, sudden increase in proteinuria if already
present in early gestation, a sudden increase in hypertension, or the development
 of HELLP syndrome3. The acronym HELLP describes a variant of severe
preeclampsia characterized by hemolysis, elevated liver enzymes, and low platelet
count.

11. Unclassified Hypertension hypertension when essential clinical information is

lacking (This classification is put to insure that pregnancy induced and
chronic are not confused by the inclusion of equivocal cases and to enable all
patients to be placed in a definite category. Post-partum, patients may be
reclassified to amore definitive category.) This is now no longer encountered in
any of the recent guidelines and literature except for ICD-9 2101 which included
Unspecified Hypertension.

Should any other classification system is to be used, it is recommended that

the system of classification be mentioned and proper definitions presented for
clarification.
The measurement of blood pressure will follow the recommendations
presented by the Multi-sectoral Task Force on the Detection and Management of
Hypertension convened by the Philippine Society of Hypertension, 1997 (Table 2.1),
the NHBPEP Working Group on High Blood Pressure in Pregnancy, the ACOG, the
Royal College of Obstetricians and Gynecologists (RCOG) and the NGC.

Table 2.1 Method of Indirect Measurement of Blood Pressure

1. A mercury manometer is ideal for accurate measurement. Aneroid, digital or other

automated devices provide reasonable alternatives2 (NGC, Level II, Grade A),
provided that they satisfy technical requirements for accuracy, and are calibrated
and tested on a regular basis. Automated methods, however, need to be used with
caution, as they may give inaccurate blood pressure readings7 (RCOG, Level II-2,
Grade B). The manometer cuff should cover at least 2/3 of the length of the
patients arm, or the length 1.5 times upper arm circumference while the bladder
should cover at least 80% of the arm circumference.

2. The patient should be seated (or supine) or in the left lateral recumbent position
with arms bared, supported, and at heart level7 (RCOG, Level II-1, Grade A)2.
They should not have rested for at least 5 to 10 minutes, and should not have
smoked or ingested caffeine within 30 minutes before measurement.3. The edge
of the cuff should be placed 1 inch above the elbow crease, with the bladder
directly over brachial artery.

3. The bladder should be inflated to 30 mmHg above the point of radial pulse
extinction as determined by a preliminary palpatory determination. It should then
be deflated at a rate of 2 mmHg/beat, with the stethoscope bell placed directly
over the brachial artery.

4. Systolic pressure should be recorded at the appearance of the 1st clear tapping
sound (Korokoff phase 1). Diastolic blood pressure should be recorded at the
disappearance of these sounds (Korotkoff phase V)2 (NGC, Level I, Grade A),
unless these are still present near 0 mmHg in which case, softening of the sounds
should be used as diastolic pressure (Korotkoff phase IV).
5. For every visit, the mean of readings, taken at least 2 minutes apart, should be
regarded as the patients blood pressure. If the first 2 regarded differ by 5 mmHg
or more, a 3rd reading should included in the average.

6. If blood pressure is being taken for the first time, the procedure should be repeated
with the outer arm. Subsequent determination should then be performed on the
arm with a higher pressure reading.

7. If BP is consistently higher in one arm, the arm with the higher values should be
used for all BP measurements2 (NGC, Level III, Grade B).

8. Ambulatory BP monitoring (by 24-hour or home measurement) may be useful to

detect isolated office (white coat) hypertension2 (NGC, Level II, Grade B).

9. Patients should be instructed on proper BP measurement technique if they are to

perform home BP monitoring2 (NGC, Level III, Grade B)

Basis for the Recommendations

The above recommendations were based on a discussion on the classifications

used in the Philippines. A review of the classifications and definitions of hypertensive
disorders in pregnancy used in local hospitals and medical centers appeared to take
their origins from definitions and classifications used in the following sources,
namely:

A. Williams Textbook of Obstetrics, 22nd Edition

B. International Statistical Classification of Disease and Related Health Problems by
the World Health Organization
C. XIIth World Congress of Gynecology & Obstetrics in Rio De Janeiro
D. ACOG Practice Bulletin No. 33 on Diagnosis and Management of Pre-eclampsia
and Eclampsia and ACOG Practice Bulletin No. 29 on Chronic Hypertension in
Pregnancy
E. RCOG Evidence-based Clinical Guideline Number 10 A on The Management of
Severe Pre-eclampsia/ Eclampsia
F. NHBPEP Report on Hypertension in Pregnancy 2000
G. National Guideline Clearinghouse Guideline on Diagnosis, evaluation and
management of the hypertensive disorders of pregnancy
H. International Statistical Classification of Diseases and Related Health Problems
(ICD-10)

A summary and comparison of the above classifications and definitions are presented
in Tables 2.2 and 2.3.

A. Classification of Hypertensive Disorders Complicating Pregnancy from

Williams Textbook of Obstetrics
 This is perhaps the most popular definition and classification used in the
Philippines, our country most strongly influenced by teachings from the United
States.
In the past editions of Williams Obstetrics, the term pregnancy-induced
hypertension was utilized. The latest edition, which is the 22nd edition, also
adapts the current scheme of the Working Group of the NHBPEP in 2000.
The diagnosis of chronic underlying hypertension is suggested by the
following:
1. Hypertension (140/90 mm Hg or greater) antecedent to pregnancy
2. Hypertension detected before 20 weeks or
3. Persistent hypertension long after delivery
Additional factors that support the diagnosis are multiparity, hypertension
complicating a previous pregnancy and a strong family history of hypertension.

Diagnosis of Pregnancy aggravated hypertension or superimposed

preeclampsia) is given when a pre-existing chronic hypertension worsen and is
usually accompanied by proteinuria or pathologic edema.

B. International Statistical Classification of Disease and Related Health Problems

by the World Health Organization (ICD-10)

In this comprehensive classification of diseases, there is a section on

Oedema, proteinuria and hypertensive disorders in pregnancy, childbirth and the
puerperium. This classification may be easily compared to the ACOG
classification and the NHBPEP Working Group presented above and
corresponding classes may be matched. Without a corresponding category though
is the class Gestational edema and proteinuria without hypertension (ICD 10
code 012.2). Perhaps this may be indicative on broader outlook at the possible
complications of pregnancy with regards to this topic possibly initially starting
as to involve other organ systems even prior to the clinical manifestation of overt
elevation in blood pressure. Another difference in the classification is ICD 10
code 013, where Gestational Hypertension without significant proteinuria, or
Gestational Hypertension not otherwise specified are also known as Mild Pre-
eclampsia. According to the 22nd edition of Williams Obstetrics and the Working
Group, to make the diagnosis of gestational hypertension, there should be no
proteinuria. The ICD 10 also included the term Moderate Pre-eclampsia (ICD
10 code 014).
This is the classification system used mainly by the group of the Fetal As
A Patient but the term EPH Gestosis (Edema, Proteinuria, Hypertension is used to
correspond to the term pre-eclampsia.

C. XIIth World Congress of Gynecology & Obstetrics

This is a classification based solely on the physical signs of hypertension

and proteinuria with the intention of defining clinical categories without
necessarily implying a particular etiology or pathology. Edema is not included
because it was noted not to have prognostic significance.
 In this classification, Gestational hypertension, proteinuria and
proteinuric hypertension are further subdivided into antepartum, intrapartum or
postpartum types because of possible differences in clinical, pathologic and
prognostic significance.

The Unclassified hypertension and/or proteinuria in pregnancy is used

for cases when essential clinical information is lacking which happens quite
often. This is important to insure that chronic or gestational categories are not
confused by the inclusion of equivocal cases and enable patients to be placed in a
definite category. This classification however, is no longer encountered in any of
the recent guidelines and latest literature.
In this proposal, complications are to be classified separately. For
example, severe hypertension and severe proteinuria should be defined separately.
Suggested criteria for severe hypertension are as follows:
A. DBP of 120 mmHg or more on any one occasion, or
B. DBP of 110 mmHg or more on two or more consecutive occasions 4 or
more hours apart

D. ACOG Practice Bulletin No. 33 on Diagnosis and Management of Pre-

eclampsia, Eclampsia and ACOG Practice Bulletin No. 29 on Chronic
Hypertension in Pregnancy and National High Blood Pressure Education
Program Working Group on High Blood Pressure in Pregnancy

The National High Blood Pressure Education Programs (NHBPEP)

Working Group on High Blood Pressure in Pregnancy recently issued a report
identifying four hypertensive disorders of pregnancy namely: chronic
hypertension that predates pregnancy; preeclampsia-eclampsia, a serious, systemic
syndrome of elevated blood pressure, proteinuria and other findings; chronic
hypertension with superimposed preeclampsia; and gestational hypertension, or
nonproteinuric hypertension of pregnancy. This scheme and the criteria for each
category differ from former diagnostic schemes and the current schemes of other
groups. Important features of the preeclampsia elimination of a change in blood
pressure as a diagnostic criterion wherein the group recommends using cut-off of
140/90 mm Hg, elimination of edema as a criterion, because this finding is so
common in healthy pregnant women and absolute requirement of proteinuria of
more than 300 mg per 24 hours for the diagnosis. The gestational hypertension
category is used in women with nonproteinuric hypertension of pregnancy, in
which the pathophysiologic perturbations of the preeclampsia syndrome do not
occur before delivery. The American College of Obstetricians and Gyneocologists
adapt the present scheme of the NHBPEP Working Group, as reported in the
ACOG Practice Bulletin No. 29 and 33.
For a more detailed breakdown of the three classification systems, please
see Table 2.2.
Table 2.2: Classification of Hypertensive Disorders in Pregnancy
WHO (ICD-10) XIIth World Congress Williams Obstetrics 22nd
Ed/NHBPEP Working
Group/ACOG
Gestational hypertension Gestational hypertension The term pregnancy-
w/o sig. proteinuria (w/o proteinuria) induced hypertension is
now replaced by gestational
hypertension

Same 5 Types of Hypertensive

Gestational hypertension Disease in Pregnancy:
with sig. Proteinuria A. Gestational
Hypertension/
Transient
Hypertension
B. Pre-eclamsia
Mild
Severe
Eclampsia Eclampsia C. Eclampsia

Pre-existing hypertension Chronic hypertension w/o D. Chronic Hypertension

proteinuria
Pre-existing hypertension Chronic hypertension w/ E. Pre-eclampsia
w/ superimposed pre- superimposed pre- superimposed on
eclampsia eclampsia Chronic Hypertension

Unspecified hypertension Unspecified hypertension Used interchangeably with

w/o proteinuria gestational hypertension

Gestational edema & Gestational proteinuria (w/o

proteinuria w/o hypertension)
hypertension Chronic renal dis. (w/ or
w/o hypertension)
Unclassified proteinuria
(wo hypertension)
 Table 2.3: Definitions
Williams Obstetrics 22nd WHO (ICD 10) XIIth World Congress
Ed/NHBPEP Working
Group/ACOG
>/=140/90 mm Hg 140/90 DBP 110 mmHg
Incremental increase in BP is no !30mmHg systolic or DBP 90 mmHg
Hypertension longer included. !15 mmHg diastolic (4 hours apart)
Korotkoff phase V is used to (6 hours apart)
define diastolic BP (Korotkoff Ph.IV) (Korotkoff Ph.IV)

> 300 mg per 24 hours 0.3 g/L in 24 hr collection 300 mg in 24 hours

30 mg/dl (+1) dipstick in random 0.1 g/L or 2+ in 2 random 1 g/L or 2+ in 2 random 4
Proteinuria urine samples 6 hours apart hours apart
0.3 g/L or 1+ on reagent
(SG >1.030 & pH < 8)
Abandoned as diagnostic criterion Swelling of hands & face
Edema Weight gain of 5 lbs
(2.27 kg) in a week
References

1. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in
Pregnancy. Am J Obstet Gynecol 2000;183(1):S1-S22.
2. Diagnosis, evaluation and management of the hypertensive disorders of pregnancy. National Guideline
Clearinghouse. http://www.guideline.gov/about/inclusion.aspx.
3. American College of Obstetricians and Gynecologists. ACOG Committee on Practice Bulletins
Obstetrics. ACOG Practice Bulletin No. 33, January 2002. Diagnosis and management of preeclampsia and
eclampsia. Obstet Gynecol 2002;99(1):159-167.
4. Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver
enzymes, and low platelet count. Obstet Gynecol 2004;103(5 pt 1):981-991.
5. Barton JR, Sibai BM. Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets
syndrome. Clin Perinatol 2004;31(4):807-833.
6. Magann EF, Martin JN Jr. Twelve steps to optimal management of HELLP syndrome. Clin Obstet Gynecol
1999;42(3):532-550.
7. Royal College of Obstetricians and Gynaecologists. The Management of Severe Pre-eclampsia/ Eclampsia:
Evidence-based Clinical Guideline Number 10 A, 2006, March.
8. American College of Obstetricians and Gynecologists. ACOG Committee on Practice Bulletins
Obstetrics. ACOG Practice Bulletin No. 29, July 2001. Chronic Hypertension in Pregnancy. Obstet
Gynecol 2001; 98: 177-185.
9. Cunningham, et.al, Williams Obstetrics. 22 ed.2005.

!
 Predictive Tests for Hypertensive Complications of Pregnancy
Ma. Antonia E. Habana, MD and Ma. Cristina P. Crisologo, MD

Hypertensive Complications of Pregnancy are more likely to develop in a woman who

(1) is exposed to abnormal chronic villi for the first time

(2) is exposed to super abundance of chorionic villi, or with twins or hydatidiform mole
(3) has preexisting vascular disease, or
(4) is genetically predisposed to hypertension developing during pregnancy

The tendency to develop pre-eclampsia is said to be heritable. Cooper and Siston (1971)
examined the possibility that susceptibility to pre-eclampsia is dependent upon a single recessive
gene. Chesley and Cooper (1986) reanalyzed Chesleys extensive data and concluded that the
single gene hypothesis fits well, but multifactorial inheritance cannot be excluded. Risk factors
for hypertensive complications of pregnancy are found in Table 3.1.17

Table 3.1. Risk Factors for Hypertension in Pregnancy

Factor! Risk Ratio
Diabetes Mellitus 2:1
Hypertension in previous pregnancy 2-3:1
Nulliparity 3:1
Change of partner for second or subsequent 3:1
pregnancy
Age > 40 years 3:1
Twin gestation 4:1
Family History of PIH 5:1
Chronic Hypertension 10:1
Chronic renal disease 20.1
Anti-phospholipid syndrome 10:1
Angiotensinogen gene
Homozygous 20:1
Heterzygous 4:1

Regardless of the lack of existing prophylactic and therapeutic means to address

preeclampsia, the search for non-invasive markers that could predict the development or assist in
the detection of this life-threatening pregnancy disorder is still of utmost importance. The
availability of such markers could have decisive impact not only on the medical management of
pregnant women and their child, such as referral to a tertiary centre, but also on the health costs
associated with this prevalent medical condition. There are many proposed strategies on the
detection or prediction of hypertensive complication of pregnancy.
 The following are suggested predictive tests for pre-eclampsia:

1. Case Finding as part of General Physical Examination

Opportunities for case finding are common in general practice. Health service providers are
encouraged to measure the blood pressure at each patient visit and consultation (either on
outpatient or on emergency basis) even if the patient complains for unrelated symptoms.
Reviewing maternal history for potential risk factors, coupled with uterine artery Doppler
assessment showed that these seem to select two different populations - early and late-onset
preeclampsia, which might suggest a different pathogenesis for these - hypertensive states7.
(Level II, Grade A)

2. Screening Maneuvers
a. Mean Arterial Pressure
The mean arterial pressure (MAP) is defined as diastolic blood pressure (DBP) + 1/3 the
pulse pressure [MAP = DBP + 1/3 (systolic blood pressure (SBP)-DBP)]. A MAP value
in the second trimester (MAP -2) > 90 mmHg (sensitivity of 61-71% and specificity of
62-74%) or a MAP value in the third trimester (MAP -3) > 105 mmHg has resulted in an
increased incidence of pre-eclampsia.18 The lower critical cut off in the second trimester
represents the mid-trimester drop in blood pressure (BP) which strengthens the belief that
throphoblastic proliferation at this time has resulted in dilatation of the spiral arterioles.
Therefore, the absence of a mid-trimester drop in BP despite MAP -2 values < 90 mmHg
may predict future pregnancy induced hypertension (PIH) based on the absence of
arteriolar vasodilatation and should alert the physician for closer follow-up. Several
authors suggest that the MAP -2 value may be more predictive for chronic hypertension
or essential or transient hypertension.19,20 Recent reports suggest the sensitivity of this
test may be much lower (22-35%) any may be of little value in predicting preeclampsia.21
In a systematic review looking at MAP and BP measurements in predicting preeclampsia,
second trimester MAP of 90 mm Hg or more showed a positive likelihood ratio of 3.5
(95% CI 2.0-5.0) and a negative likelihood ratio of 0.46 (95% CI 0.16-0.75). In women
deemed to be at high risk, a DBP of 75 mm Hg or more at 13 to 20 weeks' gestation best
predicted pre-eclampsia: positive likelihood ratio 2.8 (95% CI 1.8-3.6), negative
likelihood ratio 0.39 (95% CI 0.18-0.71). Thus, When BP is measured in the first or
second trimester of pregnancy, the MAP is a better predictor for pre-eclampsia than SBP,
DBP, or an increase of BP.9 (Level I, Grade B)

b. Supine Pressure Test or Roll Over Test

Originally described by Gant, et. al. in 1974, women were seen between 28-32 weeks of
pregnancy when their DBP in the superior arm were first stabilized in the left lateral
recumbent position. The women were then rolled over to the supine position and BP
readings were taken immediately and after 5 minutes. An increase of at least 20 mmHg
in the diastolic pressure constituted a positive roll over test. A positive roll over test is
associated with a 3-fold increase of developing pre-eclampsia, similar to the results of the
angiotensin sensitivity test. Gant, et. al. (1973) and Oney and Kaulhausen (1982) infused
angiotensin II and demonstrated increased pressor response in primigravidas, with 20
mmHg as the positive response. However, the positive predictive value of this test in
predicting preeclampsia is only 33 percent. (Level I, Grade B)
 c. Combination of the MAP-2 and Roll Over Test
Performed singly, the MAP -2 test or the roll over test predicted a 60% risk hypertension
or pre-eclampsia later in pregnancy but when a MAP -2 value >90 mmHg and a positive
roll over test are combined, the prediction rate increased to 78%.22 (Grade B)

d. 48-hour BP Monitoring
In the first trimester, the test accurately diagnosed 93% of the 60 women who later
developed pregnancy induced hypertension or pre-eclampsia. This rose to 99% by the
third trimester. The test does not require monthly monitoring during pregnancy which
was done during the study to validate the test. It is additionally examines lower blood
pressure in women and fluctuations between activity and the rest during different
trimesters. This allows diagnosis before blood pressure becomes elevated.23 (Grade C)

e. 24 hours Ambulatory BP and Heart Rate

The sensitivity in predicting pre-eclampsia for MAP of ! 85 mmHg at 20 weeks was
65%, with a positive predictive value for a test combining MAP ! 85 mmHg and a heart
rate ! 90 bpm were 53% and 45% respectively. The efficiency of the test is increased by
combining the awake ambulatory heart rate and blood pressure measurement together.23
(Grade C)

f. Hyperbaric Index (HBI) The HBI was calculated as a time-specified BP excess over a
pre-set tolerance limit for SBP, DBP and MAP. In a study comparing its predictive
efficacy with standard sphygmomanometry and 48-hour ambulatory BP monitoring, the
predictive value was low for all three methods, sensitivity between 54 and 77%,
specificity between 41 and 78%.24 (Level II-2)

3. Laboratory Tests
When evaluating new screening strategies, not only sensitivity, specificity and predictive
values should be taken into account, but also costs, patient's acceptability and quality control

a. Doppler Velocimetry
Diminished blood flow may be reflected as an increased systolic/diastolic ratio (Stuart
Index) or the more ominous absence or reversed end diastolic (ARED) blood flow.24
Bilateral notching of uterine arteries at 12-14 weeks is a useful tool in predicting the
development of hypertensive disorders in high-risk pregnancies. The sensitivity of
bilateral notching in predicting hypertensive disorders of pregnancy decreased with
advancing pregnancy from 91 to 35%, and the specificity and the positive predictive
values increased from 41 to 94% and from 7 to 70%, respectively. The negative
predictive values ranged from 86 to 97%.4 (Level II-1) Doppler velocimetry of the
uterine and uteroplacental arteries at 24 weeks is an effective test to predict PIH.
Persistence of the early diastolic notch in both uterine arteries strongly correlates with
severe PIH requiring delivery before 34 weeks with a sensitivity of 81% and specificity
of 87%. In contrast, women without a notch constitute a very low risk group with < 1%
having delivery before 34 weeks.25 When used to predict hypertension in twin
pregnancies, the sensitivity of abnormal uterine artery Doppler results defined by twin
nomograms vs. singleton nomograms was 36.4% vs. 18.2% for pre-eclampsia. Despite
 using specially constructed twin nomograms, uterine artery Doppler studies in twin
gestations had an overall low sensitivity in predicting adverse obstetric outcome.
Negative predictive values of uterine Doppler studies in twin gestations are lower
compared to those reported in unselected singleton pregnancies, i.e. maternal and fetal
complications occur more frequently despite normal uterine artery waveforms. This
suggests that there is an additional pathomechanism, causing pre-eclampsia and
consequent growth restriction in twin gestations, that is unrelated to uteroplacental
insufficiency.10 (Level II-2)

b. Fibronectin
This glycoprotein are derived principally from the liver and endothelial cells, and its
release into plasma is a marker of vascular disruption and endothelial cell activation.
Increased levels have been found to predict pre-eclampsia but not in chronic
hypertension. In a study among 125 pregnant women, the elevated maternal plasma
fibronectin level over 40 mg/dL is capable of predicting preeclampsia in the third
trimester with a sensitivity of 73% and a specificity of 92%. These results suggest that
serial plasma fibronectin measurements before 24 weeks' of gestation may be helpful in
the early detection of preeclampsia in normotensive gravid women who are destined to
become clinically preeclamptic.12 (Level II-2)

c. Hematocrit
Pre-eclampsia represents a state of hemoconcentration and increased hematocrit levels. A
fall in repeat hematocrit values may denotes clinical improvements.26

c. Proteinuria
Amounts greater than 300mg/24 hr urine sample or dipsticks values of +1 or more have
been said to denote poor prognosis, however, a systematic review concluded that even
increasing levels of protenuria are not predictive of poor maternal nor fetal outcomes.13
Deemed more important than the proteinuria values is the urinary protein/creatinine ratio
in its ability to predict hypertensive complications during pregnancy. For
protein/creatinine ratio 130-150 mg/g, sensitivity ranged from 90-99%, and specificity
ranged from 33-65%; for protein/creatinine ratio 300 mg/g, sensitivity ranged from 81-
98% and specificity ranged from 52-99%; for protein/creatinine ratio 600-700 mg/g,
sensitivity ranged from 85-87%, and specificity ranged from 96-97%. Random
protein/creatinine ratio determinations are helpful primarily when they are below 130-150
mg/g, in that 300 mg or more proteinuria is unlikely below this threshold. Midrange
protein/creatinine ratio (300 mg/g) has poor sensitivity and specificity, requiring a full
24-hour urine for accurate results.14

d. Serum uric acid

Uric acid values correlate with the development of pre-eclampsia, its severity and
increased perinatal mortality.26

e. Hemoglobinuria, elevated SGPT and thrombocytopenia comprise the diagnosis of the

HELLP syndrome.
 f. Maternal serum alpha fetoprotein (MSAFP) levels > 2 multiples of median (MOM) were
associated with a higher incidence of pre-eclampsia compared to controls. This elevation
also correlated with a higher likelihood of developing adverse perinatal outcomes such as
growth restriction, preterm delivery and intrauterine fetal demise.15

g. Hypocalciuria and the calcium/creatinine ratio are tests to predict pre-eclampsia from
chronic hypertension.26,27

h. Glucose Intolerance
Insulin resistance is associated with and may be causal in essential hypertension, but the
relation between insulin resistance and hypertension arising de novo in pregnancy is
unclear. In a retrospective case-control study, women who developed hypertension in
pregnancy had significantly higher glucose levels on 50-g oral glucose loading test and a
significantly higher frequency of abnormal glucose loading tests (> or = 7.8 mmol/L) than
women who remained normotensive. Relative glucose intolerance was particularly
common in women who developed nonproteinuric hypertension. Women who developed
hypertension also had greater prepregnancy body mass index and baseline systolic and
diastolic blood pressures, although all subjects were normotensive at baseline by study
design. However, after adjustment for these and other potential confounders, an abnormal
glucose loading test remained a significant predictor of development of hypertension and,
specifically, nonproteinuric hypertension in pregnancy.17

i. Inhibin A and circulating angiogenic factors levels obtained at 12 to 19 weeks age of

gestation have significant associations with onset of preeclampsia at less than 27 weeks,
as do levels obtained at 24-28 weeks with onset of preeclampsia at less than 37 weeks.
However, because the corresponding sensitivities and/or positive predictive values were
low, these markers might not be clinically useful to predict preeclampsia in women with
previous previous preeclamspia and/or chronic hypertension.5

4. In the recent years, other biochemical markers have been proposed as potential predictors for
preeclampsia. To be effective, a screening test need to be sufficiently sensitive and specific
and must provide an adequate positive predictive value. Several promising markers have
been described, alone or in combination, that might fulfill these criteria. However, these data
came often from small case studies with selected populations. Therefore, there is a need for
worldwide large scale prospective studies to confirm the sensitivity and specificity of these
promising markers and assess their utility in different subtypes of preeclampsia before they
could serve in clinically useful screening tests.2 The following table summarizes the
potential predictive biochemical markers for preeclampsia. (Level III, Grade C)

Biochemical Plasma Concentrations Reported Altered levels are

Marker 1st 2nd Manifest combinations also correlated
trimester trimester preeclampsia for prediction with:
sflt-1 -- ! ! sEng, PlGF
VEGF
Ultrasound
sEng -- ! ! sflt-1, PlGF IUGR
Ultrasound HELLP
 SGA
PlGF ! ! ! sEng, sflt-1 SGA
PP-13 ! " " Ultrasound IUGR
Preterm delivery
P-Selectin " " " Activin A
sflt-1
Other adhesion
molecules
Cell-free fetal " " " Inhibin A IUGR
DNA Polyhydramnios
Trisomy 21
Preterm labor
Cell free DNA -- -- "
ADAM12 ! -- -- -- Trisomy 21
Trisomy 18
SGA
PTX3 " " " -- IUGR
PAPP-A ! ! ! -- birthweight
Visfatin -- "! "! -- Type-2 diabetes
mellitus
Gestational
diabetes mellitus
Obesity
IUGR
Adrenomedullin " " " -- Vascular
disorders
Summary of potential biochemical markers for the prediction (1. trimester, 2. trimester) or the detection (Manifest
preeclampsia) of preeclampsia in maternal peripheral blood.
sflt-1: soluble fms-like tyrosine kinase 1; sEng: soluble Endoglin; PlGF: placental growth factor; PP-13: Placental
protein 13; ADAM12: A disintegrin and metalloprotease 12; PTX3: Pentraxin 3; PAPP-A: pregnancy-associated
plasma protein A; IUGR: Intrauterine growth retardation; SGA: Small for gestational age; HELLP: Hemolysis
elevated liver enzymes; low platelets

Because of the abundance of tests evaluating the predictive value of different parameters
in predicting preeclampsia, a systematic review of these reviews were conducted. Where
multiple studies were available, only a body mass index of > 34, alpha-fetoprotein, fibronectin
(cellular and total), and uterine artery Doppler (bilateral notching) measurements reached
specificity above 90%. Only Doppler (any/unilateral notching, resistance index, and
combinations) measurements were over 60% sensitive. Further research should focus on tests
which offer much higher levels of sensitivity than tests currently available. High sensitivity is a
more useful attribute in early detection of pre-eclampsia than specificity because consideration of
benefits, harms and costs indicates a much greater preference for minimizing false negatives than
false positives, although the ideal would be to avoid both.11

References

1. Brown MA, Mackenzie C, Dunsmuir W, Roberts L, Ikin K, Matthews J, Mangos G, Davis G. Can we
predict recurrence of pre-eclampsia or gestational hypertension? BJOG 2007;114(8):984-93.
2. Grill S, Rusterholz C, Zanetti-Dllenbach R, Tercanli S, Holzgreve W, Hahn S, Lapaire O. Potential
 markers of preeclampsia a review. Reprod Biol Endocrinol 2009;7:70.
3. Caritis S, Sibai B, Hauth J, Lindheimer M, VanDorsten P, Klebanoff M, Thom E, Landon M, Paul R,
Miodovnik M, Meis P, Thurnau G, Dombrowski M, McNellis D, Roberts J. Predictors of pre-eclampsia in
women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal
Medicine Units. AJOG 1998;179:4,946-51.
4. Vainio M, Kujansuu E, Koivisto AM, Menp J. Bilateral notching of uterine arteries at 12--14 weeks of
gestation for prediction of hypertensive disorders of pregnancy. Acta obstetr et gynecol Scan 2005;84:11,
1062-7.
5. Sibai BM, Koch MA, Freire S, Pinto e Silva JL, Rudge MV, Martins-Costa S, Bartz J, de Barros Santos C,
Cecatti JG, Costa R, Ramos JG, Spinnato JA. Serum inhibin A and angiogenic factor levels in pregnancies
with previous preeclampsia and/or chronic hypertension: are they useful markers for prediction of
subsequent preeclampsia? AJOG 2008;199:3,268.e1-9.
6. Odegrd RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R. Risk factors and clinical manifestations of
pre-eclampsia. BJOG 2000 Nov;107(11):1410-6.
7. Llurba E, Carreras E, Gratacs E, Juan M, Astor J, Vives A, Hermosilla E, Calero I, Milln P, Garca-
Valdecasas B, Cabero L. Maternal history and uterine artery Doppler in the assessment of risk for
development of early- and late-onset preeclampsia and intrauterine growth restriction. Obstet Gynecol Int
2009:275613. Epub 2009 May 27.
8. Vollebregt KC, Gisolf J, Guelen I, Boer K, van Montfrans G, Wolf H. Limited accuracy of the hyperbaric
index, ambulatory blood pressure and sphygmomanometry measurements in predicting gestational
hypertension and preeclampsia J Hypertens 2010;28(1):127-34.
9. Cnossen JS, Vollebregt KC, de Vrieze N, ter Riet G, Mol BW, Franx A, Khan KS, van der Post JA.
Accuracy of mean arterial pressure and blood pressure measurements in predicting pre-eclampsia:
systematic review and meta-analysis. BMJ 2000;336(7653):1117-20.
10. Geipel A, Berg C, Germer U, Katalinic A, Krapp M, Smrcek J, Gembruch U. Doppler assessment of the
uterine circulation in the second trimester in twin pregnancies: prediction of pre-eclampsia, fetal growth
restriction and birth weight discordance. Ultrasound Obstet Gynecol 2002;20(6):541-5.
11. Cnossen JS, ter Riet G, Mol BW, van der Post JA, Leeflang MM, Meads CA, Hyde C, Khan KS. Are tests
for predicting pre-eclampsia good enough to make screening viable? A review of reviews and critical
appraisal. Acta Obstet Gynecol Scand 2009;88(7):758-65.
12. Aydin T, Varol FG, Sayin NC. Third trimester maternal plasma total fibronectin levels in pregnancy-
induced hypertension: results of a tertiary center. Clin Appl Thromb Hemost. 2006;12(1):33-9.
13. Thangaratinam S, Coomarasamy A, O'Mahony F, Sharp S, Zamora J, Khan KS, Ismail KM. Estimation of
proteinuria as a predictor of complications of pre-eclampsia: a systematic review. BMC Med. 2009;24;7-10.
14. Papanna R, Mann LK, Kouides RW, Glantz JC. Protein/creatinine ratio in preeclampsia: a systematic
review. Obstet Gynecol. 2008;112(1):135-44.
15. Toal M, Chaddha V, Windrim R, Kingdom J. Ultrasound detection of placental insufficiency in women
with elevated second trimester serum alpha-fetoprotein or human chorionic gonadotropin. J Obstet
Gynaecol Can. 2008;30(3):198-206.
16. Solomon CG, Graves SW, Greene MF and Seely EW. Glucose intolerance as a predictor of hypertension in
pregnancy. Hypertension. 1994;23:717-721
17. ACOG Technical Bulletin, Jan 1996
18. Page and Christianson, 1976
19. Chesley and Sibai, 1974
20. Chesley and Sibai, 1988
21. Chesley and Sibai, 1987
22. Sumpaico and Santillan, 1982
23. Kyle and Clark, 1993
24. Vollebregt, 2010
25. Pangan, 1997
26. Sumpaico, 1995
27. Lim and Cardenas, 1996
 Prevention of Pre-eclampsia
Milagros J. Tia-Jocson, MD and Walfrido W. Sumpaico, MD

Strategies to effectively prevent pre-eclampsia have been the subject of investigations for
decades. In fact, the latest issue of the Cochrane Database of Systematic Reviews revealed a
number of meta-analyses on various interventions aimed at preventing preeclampsia. However,
the only strategies found to significantly reduce the risk of this complication are calcium
supplementation and use of antiplatelet agents.
The meta-analysis by Hofmeyr, et. al.,1 which included 12 randomized controlled trials
(RCTs) of good quality, showed that pregnant women who were given calcium supplementation
at dose of 1.5 to 2g per day before 32 weeks age of gestation (AOG) until delivery, had
significantly reduced incidence of hypertension (RR 0.70, 95% CI 0.57-0.86) and pre-eclampsia
(RR 0.48, 95% CI 0.33-0.69) when compared to those taking placebo. There was no overall
effect on the risk of preterm birth (RR 0.81, 95% CI 0.64-1.03) nor on stillbirth or neonatal death
prior to discharge (RR 0.89, 95% CI 0.73-1.09)1.
The meta-analysis by Duley, et. al. on use of antiplatelet agents for preventing pre-eclampsia
and its complications,2 which included 59 RCTs comparing antiplatelet agents with either
placebo or no antiplatelet agent, also showed a significant reduction (by 17%) in the risk of pre-
eclampsia among those given antiplatelet agents (RR 0.83, 95% CI 0.77-0.89). There was no
overall difference in the risk of placental abruption between the comparison groups (RR 1.10,
95% CI 0.89-1.37). Women included in the studies were either at moderate to high risk in
developing pre-eclampsia. Interventions varied as to the doses of aspirin (ASA), (ranging from
60 mg to 150 mg/day) and dipyridamole (200 mg to 400 mg/day in combination with ASA
except in one study), although conclusion of the authors was that doses of ASA up to 75 mg
appear to be safer.2

Recommendations

1. Calcium supplementation to pregnant women (both low risk and those at risk for developing
pre-eclampsia), given at a dose of 1.5 to 2g per day before 32 weeks AOG until delivery,
appears to decrease the risk of developing hypertension by around a third and pre-eclampsia
by half. (Level I, Grade A)

2. Use of antiplatelet agents, either ASA or dipyridamole, has also been shown to reduce the
risk of pre-eclampsia by 17% among moderate to high risk women. This intervention has not
been shown to increase the risk of placental abruption. (Level I, Grade A)

3. There are insufficient evidence to support the use of anti-oxidants (vitamin C, vitamin E,
lycopene, red palm oil, selenium)3, nitric oxide4, rest during pregnancy5, exercise6, diuretics7,
reduced salt intake8, marine oil or other prostaglandin precursor9 and garlic10 in the
prevention of pre-eclampsia. (Level I-II, Grade A-B).
References

1. Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing
hypertensive disorders and related problems. Cochrane Database Syst Rev 2006, Issue 3.
2. Duley I, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its
complications. Cochrane Database Syst Rev 2007, Issue 2.
3. Rumbold A, Duley I, Crowther CA, Haslam RR. Antioxidants for preventing pre-eclampsia. Cochrane
Database Syst Rev 2008, Issue 1.
4. Meher S, Duley I. Nitric oxide for preventing pre-eclampsia and its complications. Cochrane Database Syst
Rev 2007, Issue 2.
5. Meher S, Duley I. Rest during pregnancy for preventing pre-eclampsia and its complications in women
with normal blood pressure. Cochrane Database Syst Rev 2006, Issue 2.
6. Meher S, Duley L. Exercise or other physical activity for preventing pre-eclampsia and its complications.
Cochrane Database Syst Reviews 2006, Issue 2.
7. Churchill D, Beevers GCG, Meher S, Rhodes C. Diuretics for preventing pre-eclampsia. Cochrane
Database Syst Rev 2007, Issue 1.
8. Duley L, Henderson-Smart D. Reduced salt intake compared to normal dietary salt, or high intake, in
pregnancy. Cochrane Database Syst Rev 1999, Issue 3.
9. Makrides M, Duley, Olsen S. Marine oil, and other prostaglandin precursor, supplementation for pregnancy
uncomplicated by pre-eclampsia or intrauterine growth restriction. Cochrane Database Syst Rev 2006,
Issue 3.
10. Meher S, Duley L. Garlic for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev
2006, Issue 3.
!
 Gestational Hypertension and Mild Pre-eclampsia
Pilar Lagman-Dy, M.D. and Carmencita B. Tongco, M.D.

Gestational Hypertension

Definition: Blood pressure elevation of 140/90 unaccompanied by proteinuria after 20 weeks

gestational age and usually resolves by six weeks postpartum.

Mild Preeclampsia

Definition:
1. Blood pressure of 140 mmHg systolic or higher, or 90 mmHg diastolic or higher, in an
upright sitting blood pressure after a 10-minute rest, that occurs after 20 weeks of gestation in
a woman with previously normal blood pressure.
2. Proteinuria, defined as urinary excretion of 300 g protein or higher in a 24-hour urine
specimen.

Approximately 35% of women with gestational hypertension with onset at < 34 weeks develop
preeclampsia, and the associated risks of serious maternal (2%) and perinatal complications
(16%) are high. These women should receive heightened maternal and fetal surveillance, the
nature and frequency of which has not been established.

The following should be part of the management of Gestational Hypertension/Mild

Preeclampsia:

1. Home Health Care

As long as the criteria for severe pre-eclampsia are excluded, this may be recommended
for women with mild hypertension without heavy proteinuria. This may continue as long as the
disease does not worsen and if fetal growth restriction is not suspected. Sedentary activity
throughout the greater part of the day is essential. Home blood pressure and urine protein
monitoring or frequent evaluation visits by a visiting nurse or training midwife are acceptable.
These women should be instructed in detail about reporting symptoms. During such home
management, they are allowed a regular diet, without salt restriction, and they are allowed to be
up and about as desired. She should also be instructed about recording fetal kick counts and
about immediate reporting of symptoms.7 (Grade B)

Patients having all of the following criteria can be managed at home: (Grade B)
1. Ability to comply with recommendation
2. Diastolic pressure ! 100 mm Hg
3. Systolic pressure ! 140 mm Hg
4. Proteinuria < 1,000 mg 24 hr or < 2+ on dipstick
5. Platelet count > 120,000/mm
6. Normal fetal growth and testing
 7. No indications for delivery

Summary of Evidence

The management of gestational hypertension/mild preeclampsia during pregnancy was

based largely on clinical experience rather than the result of randomized controlled trials. In
theory, hospital admission for bed rest could delay or prevent progression of hypertension to
severe preeclampsia and might reduce the frequency of eclampsia or abruption placentae, with
improvement in fetal survival.8 This practice was challenged in 1971 by a British team who
showed a reduction in perinatal mortality in patients with nonproteinuric hypertension despite
ambulatory management. As a result of this policy, they reduced hospital admissions by 72%
when only patients with proteinuric hypertension were hospitalized. In a subsequent study, they
reported on 135 patients with gestational hypertension entered on a randomized trial. They
showed that complete bed rest in hospital appeared to have no advantage over ambulation as
desired in controlling the severity of maternal disease.9 Hospitalization was not associated with
an overall improvement in fetal growth or reduction in the neonatal morbidity.10 Several other
studies supported the idea of out-patient management of gestational hypertension and mild pre-
eclampsia.11-13
Recently, obstetricians were increasingly using outpatient management of gestational
hypertension, especially with the increasing pressure to curb medical expenses. Outpatient
ambulatory management was endorsed by American College of Obstetricians and Gynecologists
(ACOG) provided the patient had a thorough initial evaluation.14
Ambulatory management was also recommended for a select group of patients in the
1993 issue of Williams Obstetrics.4 In an attempt to reduce hospitalization, improved patient
satisfaction and reduce costs, several programs were introduced during the past decade to
manage such patients at home. All such programs involved some form of maternal and fetal
evaluation.15
The success rate of outpatient management depends mostly on maternal status (presence
or absence of proteinuria, diastolic blood pressure, and gestational age) at time of enrolment.
Pregnancies complicated by mild preeclampsia with proteinuria are associated with a lower
gestational age at delivery, shorter pregnancy prolongation, and an increased requirement for
antepartum hospitalization as compared with pregnancies with gestational hypertension.8
Women who develop gestational hypertension/preeclampsia at an earlier age tend to have an
earlier gestational age at delivery, a worsening of the disease status, and worse fetal outcome
when compared with those who develop the disease at term.16

2. Timing of Delivery

The delivery of patients with gestational hypertension-mild preeclampsia will depend on

fetal gestational age and fetal testing as well as maternal blood pressure, amount of proteinuria,
and maternal symptoms. Patients having any of the following should be hospitalized and
considered for delivery: (Grade A)
Gestational age ! 40 weeks
Gestational age ! 37 weeks if there is:
 Bishop score > 5
Fetal weight <10th percentile
Non-reactive NST
Gestational age 34 weeks and above with the presence of:
Labor
Rupture of Membranes
Vaginal bleeding
Abnormal biophysical profile
Criteria for severe preeclampsia
Expectant management should be considered for women remote from term who have
mild preeclampsia. (Grade C)

3. Monitoring of Fetal Well-Being

The patient should be evaluated by a physician for maternal and fetal well-being at least
once weekly. This weekly check-up should include the following:
a. Blood pressure at each visit (Grade A)
b. Platelet count and liver enzymes at regular intervals (Grade B)
c. Non-stress tests at regular intervals (Grade B)
d. Fetal growth every 2 to 3 weeks (Grade B)

In contrast, patients with gestational age < 37 weeks who do not satisfy the criteria for
home management should be immediately hospitalized. Subsequently management should
depend on results of maternal and fetal conditions. (Grade A)

4. Medications:

Magnesium sulfate and other anti-convulsants are not recommended and should be
withheld in cases of gestational hypertension/mild preeclampsia. (Grade B)
Patients with mild preeclampsia and gestational hypertension will be given anti-
hypertension medications only if there is an increase in blood pressure readings from baseline.17
Please refer to the recommendations for medications in the section on severe pre-eclampsia.
Low dose aspirin and high dose calcium are not recommended for the prevention of the
progression to severe preeclampsia. (Grade B)

Summary

Management of women with gestational hypertension/mild preeclampsia must always

consider maternal safety first and then the delivery of a newborn who will not require intensive
and prolonged neonatal care. Outpatient management of patients with gestational
hypertension/mild preeclampsia has been documented to be more cost- effective than similar in-
patient therapy. Therefore, out-patient management must provide evaluation of maternal and
fetal status similar to that of in-patient management.
References

1. ACOG Practice Bulletin No. 33. American College of Obstetricians and Gynecologists. Diagnosis and
management of preeclampsia and eclampsia. Obstet Gynecol 2002;99:159-167 (Level III)
<http://www.acog.com/publications/educational_bulletins/pb033.htm>
2. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in
Pregnancy. Am J Obstet Gynecol 2000;183:S1-S22. (Level III) http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?cmd=Retrieve&db=PubMed&list_uids=10920346&dopt=Abstract
3. Gabbe SG, Neibyl JR, Simpson JL (Eds). Obstetrics: Normal and Problem Pregnancies. 4th Ed.
Hypertension, Chapter 28. Churchill Livingstone, New York, 2002. 945-1004. (Level III)
4. Cunningham GF, et. al. (Eds) Williams Obstetrics, 21st Edition. Hypertensive Disorders in Pregnancy,
Section 7. McGraw-Hill, 2001. 24:567-618. (Level III)
5. Chobanian AV, et. al. The seventh report of the joint national committee on prevention, detection,
evaluation, and treatment of high blood pressure. JAMA 2003;289:2560-2571. (Level III) http://jama.ama-
assn.org/cgi/content/full/289/19/2560
!"## Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing
hypertensive disorders and related problems. Cochraine Library Syst Revs.
http://www.ihs.gov/generalweb/webapps/sitelink/ site.asp?link=http://www.cochranelibrary.com/enter/#
7. Frangieh AY, Sibai BM. Outpatient management of gestational hypertension and mild preeclampsia.
Contemporary OB-Gyn 1996:67.
8. Crowther CA, Bouwmeester AM, Ashurst HM. Does admission to hospital for bed rest prevent disease
progression or improve fetal outcome in pregnancy complicated by non-proteinuric hypertension? Br J
Obstet Gynecol 1992;99:13.
9. Matthews DD, Agarwal V, Shuttleworth TP. The effect of rest and ambulation on plasma urea levels in
pregnant women with proteinuric hypertension. Br J Obstet Gynecol 1980;87:1095.
10. Barton JR, Stanzino GJ, Sibai BM. Monitored outpatient management of mild gestational hypertension
remote from term. Am J Obstet Gynecol 1994;170:765.
11. Matthews DD, Patel IR, Sengupta SM. Outpatient management of toxemia. Br J Obstet Gynecol
1971;78:610.
12. Feeney JE. Hypertension in pregnancy managed by community midwives. BMJ 1984;288:1046.
13. Tuffnell DJ, Lilford RJ, Buchan PC, et. al. Randomized controlled trial of day care for hypertension in
pregnancy. Lancet 1992;339:224.
14. American College of Obstetricians and Gynecologists. Technical Bulletin: Hypertension in pregnancy.
Washington DC, 219, January 1996.
15. Dawson AJ, Middlemiss C, Coles EC. A randomized study of a domiciliary antenatal care scheme: The
effect on hospital admissions. Br J Obstet Gynecol 1989;96:1319.
16. Hamlin RHJ. The prevention of eclampsia-preeclampsia. Lancet 1982;1:64.
17. Sibai BM, Barton JR, Aki S. A randomized prospective comparison of nifedipine and bed rest versus bed
rest alone in the management of preeclampsia remote from term. Am J Obstet Gynecol 1992;167:879.
 Severe Pre-eclampsia
Mario A. Bernardino, M.D. and Joseph U. Olivar, M.D.

The objectives in the management of severe preeclampsia include the following:

1. To reduce its severity or prevent progression of the disease process.
2. To prevent convulsions.
3. To control severe hypertension.
4. To deliver the mother of a fetus at the optimum time and with the least trauma.
5. To detect and appropriately treat end-organ damage.
6. To completely restore the health of the mother.

Background

Incidence

As the most common medical disorder of pregnancy, hypertension is reported to

complicate 5 6% of all pregnancies worldwide,1 with 5- 10 % being severe.2 It is the 2nd most
common cause of maternal death in the US.1,3 Locally, the incidence of severe preeclampsia is 2-
5% and is the 2nd most common cause of maternal death.4 It is also associated with a high
perinatal mortality and morbidity rate, which is primarily due to iatrogenic prematurity.5 The
development of preeclampsia cannot be accurately predicted nor effectively prevented. Delivery
of the fetus and placenta remains the only definitive treatment.6! For all these reasons, the timing
of delivery is critical to optimize maternal and perinatal outcome.

Classification of Preeclampsia

Preeclampsia is classified as mild and severe. Mild preeclampsia refers to disease that
meets the criteria for the diagnosis of preeclampsia but is not severe disease. A diagnosis of
severe preeclampsia requires evidence of new-onset proteinuric hypertension occurring at > 20
weeks age of gestation with > 1 of a series of complications (see Table 1). It is emphasized that
only 1 of the listed criteria in Table 1 is required for the diagnosis of severe preeclampsia. The
distinction between mild and severe preeclampsia is important because it dictates management,5
and one must not be complacent with mild preeclampsia6 because apparently mild disease may
progress rapidly to severe disease.6
 !"#$%&"'()*+',*)-.%/0'12$&3%#4%'+#4#5&+&4%'*('6&7&)&'$)&&38#+$6.#')&+*%&'()*+'%&)+0'!+'9':;6%&%'<=4&3*8'>??@'0'

Management

The main objective in the management of severe preeclampsia must always be the safety
of the mother and the fetus.5 The initial management of preeclampsia includes stabilization of the
mothers condition, confirmation of gestational age and assessment of fetal well-being. Once the
diagnosis of severe preeclampsia is established, traditional management has focused on maternal
safety with expedited delivery. Because these pregnancies are associated with high rates of
maternal morbidity and mortality and with potential risks for the fetus, there is general
agreement that such patients should be delivered if the disease develops > 34 weeks of
gestation.7,8 Although delivery is always appropriate for the mother, it may not be optimal for
the premature fetus (< 34 weeks).9 Complications of prematurity include respiratory distress
syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis and even death. In the
past, it was believed that infants born prematurely to severely preeclamptic women had lower
rates of neonatal morbidity and mortality than infants of similar gestational age born to non-
preeclamptic women. In contrast, several recent case-control studies have demonstrated that
premature infants born after severe preeclampsia have neonatal complications and mortality
similar to those of other premature infants of similar gestational age and have higher rates of
admission to NICU.10 In addition, case-control studies have revealed that fetuses of
preeclamptic women do not exhibit accelerated lung or neurological maturation.10
There are 3 circumstances in which expectant management of severe preeclampsia
remote from term (< 34 weeks) is clearly acceptable. The first is severe preeclampsia by
proteinuria.5 Neither the amount of protein spilled in the urine nor the rate of increase correlates
with maternal or perinatal outcome.11,12 As such, proteinuria > 5 grams per 24 hours is not, of
itself, an indication for delivery.5 The second is severe preeclampsia on the basis of IUGR alone
with good fetal testing. Although not candidates for immediate delivery, such patients should be
treated as in-patients5 with at least daily fetal well-being studies. Third, there is precedent in the
literature to support the expectant management of women with severe preeclampsia by blood
pressure criterion. This approach, although potentially dangerous for the mother, has been
substantiated in a number of clinical trials.7,8 There are only 2 published randomized trials on
the expectant management of severe preeclampsia. In 1990, Odendaal, et. al. studied 38 patients
with severe preeclampsia at 28-34 weeks of gestation. 20 patients underwent aggressive
treatment (steroid therapy followed by delivery in 48 hours), and 18 patients were treated
expectantly (steroid therapy followed by delivery only for maternal and fetal indications). In the
conservative group, the authors reported no increase in maternal complications but with
statistically significant prolongation of pregnancy (mean, 7.1 days), a reduction in neonates that
required ventilation (11% vs 35%), and a reduction in total neonatal complications (33 vs 75%).7
Sibai, et. al. studied 95 patients with severe preeclampsia at 28-32 weeks of gestation: 46 patients
underwent aggressive treatment and 49 were assigned to expectant management. In women who
were treated conservatively, there was no increase in maternal complications, but there was a
statistically significant prolongation of pregnancy (mean 15.4 vs 2.6 days), less time in neonatal
intensive care unit (NICU) (20.2 vs 36.6 days), and a reduce incidence of respiratory distress
syndrome (22.4% vs 50.5%).8 These 2 trails7,8, demonstrated improved perinatal benefit with
reasonable maternal safety when expectant management was conducted in a select group of
patients with severe preeclampsia at 28-34 weeks of gestation.13!
Recently, the results of several retrospective and observational studies that described
expectant management of severe preeclampsia at 24-34 weeks of gestation have suggested that
such management improves perinatal outcome without increasing maternal morbidity.14-23
In 2005, Sibai published an algorithm in the expectant management of preeclampsia < 34 weeks.

!"#$%&%'&()*'+&),"&"-($.-+/&01$%-&

Maternal-fetal evaluation for 24 hours

Magnesium sulfate for 24 hours
Antihypertensives if systolic blood pressure >160
mmHg, diastolic blood pressure > 110 mmHg, or
mean arterial pressure >125 mmHg

!,/&'2&%3-&2'(('4$,5&6+-0-,%7&

Eclampsia
Pulmonary edema
Magnesium sulfate
Acute renal failure
and delivery
Disseminated intravascular coagulation Yes
Suspected abruptio placenta
Non-reassuring fetal status
Labor or rupture of membranes >34 weeks
gestation

No
HELLP syndrome (Hemolysis, Elevated Liver
enzymes, and Low Platelets) Steroids
Persistent symptoms Yes

No

< 23 weeks 2332 weeks 33 34 weeks

Steroids Steroids
Terminate Antihypertensives if needed Delivery after 48
pregnancy Daily evaluation of maternal- hours
fetal condition
Delivery if: with indications
(see Table 2)
Delivery at 32-34 weeks

DD
8$51+-&9:&&;),)5-#-,%&'2&0-.-+-&6+--<()#60$)&=&>?&4--@0:&&A!")6%-"&2+'#&B$*)$:C &
Table 2. Indications for Delivery During Expectant

45
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'
+*:%')&$*)%:1'%?&'+#C-+;+'"*:&'*('?9")#=#E-/&'-:'23'+B'FGH'6-(&"-$-/&'I3'+B'@J'#/"'6-<#)"-$-/&'")-$'K3'+BL?*;)D'
'

'

Perinatal Complications

Though the main aim of expectant management is to improve perinatal outcome by

prolonging gestation and reducing neonatal morbidities (acute and long term)13 due to
prematurity, expectant treatment has potential complications.
During expectant management of patients with severe preeclampsia at 24-34 weeks of
gestation, the rate of perinatal death ranged from 0 to 16.6 %.7,8 Abruptio placenta is also a
reported complication and it ranged from 4.1% to 22.9%.8,22 In addition, delivery for non-
reassuring fetal status ranged from 26-75%.18,20 In all the reported studies, intensive fetal
monitoring for early detection of fetal compromise is recommended. The most common
indication for delivery was deterioration in fetal status underscoring the need that these
pregnancies managed expectantly should be observed in centers that are capable of rapid
intervention for fetal reasons.

Maternal Complications

The main aim of the expectant management of severe preeclampsia remote from term is
prolonging gestation without jeopardizing maternal safety. Progressive deterioration in maternal
condition during the clinical course of severe preeclampsia may occur. Thus, any protocol for
management of severe preeclampsia has potential for maternal complications.5 During expectant
management, maternal complications in reported studies include: HELLP syndrome (4.1-27.1%),
pulmonary edema (0-8.5%), eclampsia and acute renal failure (<1%).8,16,20
Expectant management must provide heightened surveillance to ensure adequate
maternal oxygenation, provide prompt intervention for symptoms of hepatic dysfunction
(HELLP syndrome or subcapsular hematoma of the liver), and particularly provide evaluation of
the fetal status and maternal presentation given the risks of placental abruption.5

Severe Preeclampsia < 25 weeks

Only few literatures are published regarding maternal and perinatal outcomes during
expectant treatment of patients with severe preeclampsia at <25 weeks of gestation. Severe
preeclampsia that develops in the mid-trimester of pregnancy is associated with high perinatal
mortality and morbidity rates. 14-16,23 Aggressive treatment in the form of immediate delivery will
usually result in high neonatal mortality rate.14,26 If the fetus survives, significant neonatal
complications are expected and these will require prolonged hospitalization in the
NICU.4,23,24,25,28 On the other hand, attempts to prolong pregnancy may result in fetal death and
may expose the mother to severe morbidity.14,16,24,25,27 Overall, in these studies, the perinatal
death rate ranged from 71% to 100%, with few newborn infant surviving without handicap.14,27,28
There was one reported maternal death in a patient who had eclampsia and HELLP syndrome
who underwent expectant treatment at 23 weeks age of gestation.27 Furthermore, maternal
morbidities were very high.5
Bombrys and colleagues29 found small studies that focused on expectant management of
severe preeclampsia before 28 weeks. In pregnancies before 23 weeks, maternal complications
were common and there were no infant survivors. Thus, the authors recommended pregnancy
termination for these women. For those at 23 weeks, the perinatal survival rate was 18%, but
long term perinatal morbidity is yet unknown. For women with pregnancies at 24 to 26 weeks,
perinatal survival approached 60%, and it averaged 90% for those at 26 weeks.

Preeclampsia with HELLP

The clinical course of women with HELLP syndrome is characterized by progressive and
sudden deterioration in the maternal condition.29 Because this syndrome is associated with
increased rates of maternal morbidity and mortality, some authors consider its presence an
indication for immediate delivery, except for the benefit of steroid for fetal lung maturity in
gestation at 24-34 weeks.5
There are 3 studies30-32 published regarding expectant management in patients with
HELLP syndrome at < 34 weeks of gestation. Their results suggest that expectant treatment is
possible in a select group of women with alleged HELLP syndrome at < 34 weeks of gestation.
However, despite pregnancy prolongation in some of these cases, the overall perinatal outcome
was not improved, compared with cases of similar gestational age who were delivered within 48
hours after steroid therapy. Since the sample size in these studies is inadequate, such approach is
currently experimental.5

Clinical Considerations and Recommendations

A. What are the clinical features of severe preeclampsia?

A diagnosis of severe preeclampsia requires evidence of new onset proteinuric
hypertension along with ! of a series of complications (summarized in Table 1). (Level
III, Grade C)

Although the classification of severity of preeclampsia is primarily based on the level

of blood pressure and the degree of proteinuria, other organ may be potentially involved and
clinicians should be vigilant when assessing the maternal risk.34 It is emphasized that only 1
of the listed clinical features in addition to hypertension (! 140/90 mmHg) and proteinuria
(!300 mg/24 hours) is required for the diagnosis of severe disease.5 Ultimately as many
clinical criteria are subjective, women should be managed according to a careful clinical
assessment rather than relying overly on precise criteria.34

B. Assessment of the Woman

B1. What is the initial management in a woman with severe preeclampsia?
In a woman with severe preeclampsia, immediate admission preferably in a high
risk unit is mandatory. (Level I, Grade A)

Hospitalization is considered in women with severe preeclampsia.6

Hospitalization is indicated in cases in which the woman is unreliable, ! 2 systolic blood
pressure (SBP) >150 mmHg or diastolic blood pressure (DBP) > 100 mmHg, heavy
proteinuria or persistent maternal symptoms.35,36

B2. How should the BP be taken?

When taking the blood pressure, the woman should be rested sitting at 45-degree
angle. The cuff should be of the appropriate size and should be placed at the level
of the heart. Multiple readings should be used to confirm the diagnosis. Korotkoff
phase 5 is the appropriate measurement of diastolic blood pressure. (Level I, Grade
A)

Automated methods should be used with caution. (Level II-2, Grade B)

 The blood pressure should be checked every 15 minutes until the woman is
stabilized and then every 30 minutes in the initial phase of the assessment. The
blood pressure should be checked every 4 hours except between midnight and
morning if a conservative management plan is in place and the woman is stable and
asymptomatic. (Level III, Grade C)

When taking the blood pressure the woman should be appropriately positioned
and the cuff should be of an appropriate size placed at the level of the heart. Multiple
readings are required to accurately assess the blood pressure because of natural
variations. Korotkoff phase 5 is the appropriate method for diastolic blood pressure.37
Automated methods can systematically underestimate particularly the systolic
blood pressure. 38 It has been suggested that mercury sphygmomanometers should be
used to establish baseline blood pressure as a reference.39 However, many units no longer
have mercury sphygmomanometers and a baseline check with another validated device
would be an alternative.
Initial assessment of the woman with severe preeclampsia requires more frequent
monitoring of the blood pressure until the woman is stabilized.13

B3. How should proteinuria be measured?

The usual screening test is visual dipstick assessment. A (+)1 dipstick measurement
can be taken as evidence of proteinuria but a negative (-) dipstick may not be
accurate. Ideally, a more accurate test (24 hour urine protein collection) is required
to confirm this. (Level III, Grade C)

While it has to be acknowledged that there is poor predictive value from urine
dipstick testing,40 approximate equivalence is +1 = 0.3 g/L, +2 = 1g/L and +3 = 3g/L.
False negative as well as false positive results are possible with the use of dipstick
assessment 40 because the degree of proteinuria may fluctuate widely over the 24 hour
period, even in severe cases.6 In view of this, laboratory testing usually by a 24 hour
urine collection is recommended to confirm significant proteinuria unless the clinical
urgency dictates immediate delivery.41

B4. What other laboratory exams should be requested?

The following laboratory exams should be requested in cases of severe
preeclampsia: CBC with platelet count, peripheral blood smear, liver enzymes
(AST, ALT), creatinine, uric acid, LDH, and total bilirubin. (Level III, Grade C)

A falling platelet count is associated with worsening disease and is itself a risk to
the mother.45 A platelet count persistently less than 100 x 106/L should be a consideration
for delivery. On the other hand, it is not until the count is less than 100 x 106/L that there
may be an associated coagulation abnormality.46 Clotting studies are not required if the
platelet count is over 100 x 106/L.
A diagnosis of HELLP syndrome needs confirmation of hemolysis, either by
LDH levels (! 600U/L), blood film to look for fragmented red cells or total bilirubin >1.2
 mg/dL; elevated liver enzymes (AST or ALT >70 U/L) and low platelet (< 100 x 106/L).5
If only 1 or 2 of the 3 criteria are met, the diagnosis is partial HELLP syndrome.6
In preeclampsia, there can be a rise in uric acid that correlates with poorer
outcome for both mother and the fetus.47 This rise confirms the diagnosis of preeclampsia
but the levels should not be used for clinical decision-making. Renal function is generally
maintained in preeclampsia until the late stage unless HELLP syndrome develops.48 If
creatinine is found to be elevated early in the disease process, underlying renal disease
should be suspected. In severe disease, serum creatinine can be seen to rise and is
associated with a worsening outcome 48 but renal failure is not uncommon in
preeclampsia and when it does occur, it is usually associated with hemorrhage, HELLP
syndrome or sepsis.34

C. Anti-Seizure Prophylaxis
C1. How should seizure be prevented?
Magnesium sulfate (MgSO4) is the drug of choice for the prevention of convulsions.
This drug should be considered for women with preeclampsia for whom there is
concern about the risk of eclampsia. This is usually in the context of moderate to
severe preeclampsia (at least 150-160/100-110 mmHg), once a delivery decision is
made and in the immediate postpartum period. In women with mild disease, the
decision is less clear and will depend on individual case assessment. (Level I, Grade
A)

The MagPie Trial (Magnesium sulfate for Prevention of Preeclampsia) has

demonstrated that administration of MgSO4 to women with preeclampsia reduces the risk
of an eclamptic seizure.42 Women allocated MgSO4 had a 58% lower risk of an eclamptic
seizure (95% CI 40-71%). The relative risk reduction was similar regardless of the
severity of preeclampsia. More women need to be treated when preeclampsia is not
severe (109) to prevent one seizure when compared with severe preeclampsia (63).
When MgSO4 is given, regular assessment of the urine output, maternal reflexes,
respiratory rate and oxygen saturation is important.34

MgSO4 can be given in 2 ways: continuous intravenous infusion and intermittent

intramuscular injections (see Table 3).

C2. How should seizure be controlled?

The principles of management should follow the basic principles of airway,
breathing, and circulation. (Level III, Grade C)

MgSO4 is the therapy of choice to control seizures. A loading dose of 4 grams should
be given over 5-10 minutes, followed by a further infusion of 1 gram / hour
maintained for 24 hours after the last seizure. (Level I, Grade A)
Recurrent seizures should be treated with either a further bolus of 2 grams MgSO4,
or an increase in the infusion rate to 1.5 grams or 2 grams/hour. (Level I, Grade A)

Do not leave the woman alone but call for help. Ensure that it is safe to approach
the woman and do effort to prevent maternal injury during the convulsion. Place the
woman in left lateral recumbent position and administer oxygen. Assess the airway and
breathing and check the pulse and blood pressure. The use of the pulse oximeter is
helpful.43 Once stabilized, plans should be made to deliver the woman but there is no
particular hurry and a delay of several hours to make sure the correct care is in hand is
acceptable, assuming that there is no acute fetal concern such as fetal bradycardia.34
MgSO4 is the therapy of choice and diazepam and phenytoin should no longer be
used as first-line drugs.44 The intravenous route is has few side effects. Magnesium
toxicity is unlikely with the recommended regimens and the levels do not need to be
routinely measured. MgSO4 is mostly excreted in the urine. Urine output should be
closely observed and if it becomes reduced below 20 ml/hour, the magnesium infusion
should be halted.34 Because magnesium is cleared almost exclusively by renal excretion,
plasma magnesium concentration is excessive if glomerular filtration is decreased
substantively. The initial standard dose of MgSO4 can be safely administered without
knowledge of renal function. Renal function is thereafter estimated by measuring
plasma creatinine, and whenever it is 1.3 mg/dL or higher, only half of the maintenance
MgSO4 dose is given.6 Magnesium toxicity can also be assessed by clinical assessment
of the maternal deep tendon reflexes and respiratory rate. If there is loss of the deep
 tendon reflexes (DTRs) and the respiratory rate falls below 12 cpm, the MgSO4 infusion
should be halted. Calcium gluconate 1 gram (10 ml) over 10 minutes can be given if
there is concern of MgSO4 toxicity.34
In the collaborative eclampsia trial,44 a further bolus of 2 gram MgSO4 was
administered for recurrent seizures. An alternative is to increase the infusion rate to 1.5
grams or 2 grams/hour. If there are repeated seizures, then alternative agents such as
diazepam or thiopentone may be used, but only as a single dose, since prolonged use of
diazepam is associated with an increase in maternal death.44 If convulsions persist,
intubation is likely to be necessary to protect the airway and maintain oxygenation.
Transfer to intensive care facilities with intermittent positive pressure ventilation is
appropriate in these circumstances.34
Patients with severe preeclampsia who are expectantly managed should receive
MgS04 for 24 hours. If blood pressure is controlled adequately and fetal testing is
reassuring, MgS04 is discontinued. MgS04 is cleared by the kidneys 4 hours after the last
dose. After this time, the risk of convulsion is again present. MgS04 should be given
once the blood pressure rises again and remains in the severe range, or when delivery is
planned. This should be continued up to 24 hours postpartum.

D. How should fluid balance be managed?

Fluid restriction is advisable to reduce the risk of fluid overload in the intrapartum
and postpartum periods. In usual circumstances, total fluids should be limited to 80
ml/hour or 1 ml/kg/hour. (Level III, Grade C)

Close fluid balance with charting of input and output is essential. A catheter is
advisable in the acute situation, especially in the immediate postpartum period.
(Level III, Grade C)

Pulmonary edema is a significant cause of maternal death.38 This has often been
associated with inappropriate fluid management. There is no evidence of the benefit of
fluid expansion49 and a fluid restriction regimen is associated with good maternal
outcome.43 There is no evidence that maintenance of a specific urine output is important
to prevent renal failure, which is rare.34 Fluid restriction should be maintained until there
is postpartum diuresis, as oliguria is common with severe preeclampsia. If there is
associated hemorrhage, fluid balance is more difficult and fluid restriction is
inappropriate.34

E. How should the fetus be assessed?

A baseline cardiotocography (CTG) should be undertaken. This gives information
about fetal well-being at that time but does not give any predictive information.
(Level II-2, Grade B)

Women in labor with severe preeclampsia should have continuous electronic fetal
monitoring (EFM). (Level II-2, Grade B)
 If conservative management is planned, then further assessment of the fetus with
ultrasound measurements of fetal size every 2 weeks, biophysical screening (BPS)
and amniotic fluid index (AFI) measurement at least twice weekly, umbilical artery
Doppler once a week and daily nonstress test (NST) should be undertaken. Serial
assessment will allow timing of delivery to be optimized. (Level I, Grade A)

CTG is the mainstay of fetal monitoring. It gives information concerning fetal

well-being at that time but has little predictive value. If the woman is in labor, then
continuous EFM is appropriate.50
The main pathology affecting the fetus, apart from prematurity is placental
insufficiency leading to intrauterine growth restriction (IUGR). Ultrasound assessment
of fetal size, at the time of the initial presentation with hypertension, is a valuable
measurement to assess fetal growth. Measurement of the abdominal circumference is the
best method of assessment since IUGR in this case is usually asymmetrical. Reduced
amniotic fluid volume is also associated with placental insufficiency and fetal growth
restriction. Serial estimations of amniotic fluid volume can detect fetal compromise.
Randomized trials have shown that investigation with umbilical artery Doppler using
absent or reversed-end diastolic flow, improves neonatal outcome52 and serial
investigations of this and other fetal vessels can be used to follow pregnancies under
treatment and optimize delivery.51

F. How should we control the blood pressure?

F1. Antihypertensive treatment should be started in woman with BP ! 160/110 mmHg.
In woman with other markers of potentially severe disease, treatment can be
considered at lower degrees of hypertension. (Level III, Grade C)

There is consensus that severe hypertension in pregnancy, defined as ! 160/110

mmHg requires treatment because these women are at increased risk of intracerebral
hemorrhage, and that treatment decreases the risk of maternal death.53 There is also a
consensus that, if the blood pressure is below 160/110 mmHg, there is no immediate
need for antihypertensive therapy. An exception may be if there are markers of
potentially more severe disease, such as heavy proteinuria or disordered or
haematological test results. Since, in this situation, alarming rise in blood pressure may
be anticipated, anti-hypertensive treatment at lower blood pressure levels may be
justified.38

F2. What blood pressure is the aim of anti-hypertensive therapy?

The aim of anti-hypertensive therapy is to keep systolic blood pressure between 140
and 155 mmHg and diastolic blood pressure between 90 and 105 mmHg. (Level III,
Grade C)

In treating severe hypertension, it is important to avoid hypotension, because the

degree to which placental blood flow is autoregulated is not established, and aggressive
 lowering may cause fetal distress. Consideration should be given to initiating agents for
treatment of acute severe hypertension at lower doses, because these patients may be
intravascularly volume depleted and may be at increased risk for hypotension.53

F3. Labetalol given orally or intravenously, intravenous hydralazine, or oral nifedipine

can be used for the acute management of severe hypertension. (Level I, Grade A)

The preferred therapeutic agents are labetalol, nifedipine or hydralazine.

Labetalol has the advantage that it can be given initially by mouth in severe hypertension
and then, if needed, intravenously. A review has suggested that hydralazine may be less
preferable, although the evidence is not strong enough to preclude its use.54
The National High Blood Pressure Education Program (NHBEP) Working Group
Report on High Blood Pressure in Pregnancy published in the journal of American Heart
Association the recommended drugs for urgent control of severe hypertension in
pregnancy.

Drugs for Urgent Control of Severe Hypertension in Pregnancy

Drug (FDA Risk*) Dose and Route Precaution & Adverse Effect
Labetalol ( C ) 10 to 20 mg IV, then 20 to 80 mg every Because of a lower incidence of
20 to 30 minutes, maximum of 300 mg; maternal hypotension and other
for infusion: 1 to 2 mg/min adverse effects, its use now
supplants that of hydralazine; avoid
in women with asthma or
congestive heart failure. Not
available locally.

Hydralazine ( C ) 5 mg, IV or IM, then 5 to 10 mg every A drug of choice according to

20 to 40 minutes; once BP controlled NHBEP; long experience of safety
repeat every 3 hours; for infusion: 0.5 to and efficacy
10.0 mg/hr; If no success with 20 mg IV
or 30 mg IM, consider another drug

Nifedipine ( C ) Tablets recommended only: 10 to 30 mg Should be used with caution if

PO, repeat in 45 minutes if needed concomitantly used with MgSO4

IV Nicardipine D5W 90 mL + Nicardipine 10 mg in Should be used with caution if

soluset concomitantly used with MgSO4
Concentration = 0.1 mg/ mL
Start drip at 10 ugtts/min (equivalent to 1
mg/hr)
Titrate every hour (increments of 1
mg/hr).
Maximum dose 10 mg/hr
Note: The IV infusion site must be
changed every 12 hours
 Note: Since Labetalol is not locally available, hydralazine is the first line drug in the
urgent control of severe hypertension in pregnancy. If no success with 20 mg IV, another
drug should be considered, and this is usually a calcium channel blocker (oral nifedipine
or IV nicardipine). The maximum dose of oral nifedipine is 50 mg PO and 10mg/hour for
IV nicardipine. Maternal adverse effects include tachycardia, palpitation, peripheral
edema, headache and facial flushing. Patients with resistant severe hypertension after
maximum doses of these drugs should be delivered.

F4.Treatment of moderate hypertension may assist in the prolongation of

pregnancy. (Level III, Grade C)

There is continuing debate concerning women with blood pressure between 150
160 systolic and 100 110 diastolic. Maternal treatment is associated with a reduction of
severe hypertensive crises and a reduction in the need for further antihypertensive
therapy. With treatment, a prolongation of pregnancy of an average of 15 days is
possible as long as there is no other reason to deliver.55
Methyldopa and labetalol were the most commonly used therapies. Methyldopa
has been proven safe in long term follow-up of the delivered babies.56
The NHBEP Working Group Report on High Blood Pressure in Pregnancy
published in the journal of American Heart Association the recommended drugs for the
treatment of gestational hypertension and chronic hypertension (Table 4).
Doctors should use the drugs with which they are familiar. A recent meta-
analysis of 24 trials concluded that there is insufficient data to favour one agent over
another.57 Although others have concluded that agents other than parenteral hydralazine
(eg labetalol or nifedipine) are preferable because of reduced maternal and fetal adverse
effects.54

F5. Atenolol, angiotensin converting-enzyme (ACE) inhibitors, angiotensin receptor

blocking drugs (ARB) and diuretics should be avoided during pregnancy. (Level II-
2, Grade B)

Atenolol is associated with an increase in fetal growth restriction. ACE inhibitors

and ARBs would appear contraindicated because of unacceptable fetal adverse effects.
Diuretics are relatively contraindicated for hypertension and should be reserved for
pulmonary edema.34

F6. Nifedipine (10mg or 30 mg XR) should be given orally not sublingually and should
be used with caution if concomitantly used with magnesium sulfate. (Level III, Grade
C)

Calcium antagonists given sublingually are now not recommended for the
treatment of hypertension in nonpregnant patients because of reports of myocardial
infarction and death in hypertensive patients with coronary artery disease.58 One study
has shown efficacy and safety of long-acting oral nifedipine in pregnant patients with
Table 4. Drugs for Gestational or Chronic Hypertension in Pregnancy

severe hypertension in pregnancy.59 A concern with the use of calcium antagonists for BP
control in preeclampsia has been the concomitant use of magnesium sulfate to prevent
seizures; drug interactions between nifedipine and magnesium sulfate were reported to
cause neuromuscular blockade, myocardial depression, or circulatory collapse in some
cases.60 In a recent evaluation,61 these medications are commonly use together without
increased risk.

F7. How is postpartum hypertension managed?

Anti-hypertensive drugs should be given if the BP exceed 150 mmHg systolic or 100
mmHg diastolic during the postpartum. (Level III, Grade C)

Agents commonly used in the antepartum period may be used or continued

postpartum. (Level III, Grade C)

Diuretics can be used during the postpartum period. (Level I, Grade A)

 It is prudent to avoid non-steroidal anti-inflammatories in postpartum women who
are hypertensive. (Level III, Grade C)

Postpartum, no guidelines currently exist with regard to antihypertensive

medications but Tan and de Swiet62 have suggested that antihypertensive drugs should be
given if the BP exceeds 150 mmHg systolic or 100 mmHg diastolic in the first 4 days of
the puerperium.
Choice of antihypertensive agent in the postpartum period is often influenced by
breast feeding,63 but in general, the agents commonly used in the antepartum period may
be continued postpartum.
The medication may be discontinued when the blood pressure normalizes. Home
blood pressure monitoring by the patient is helpful in this regard.53
In select cases of women with severe preeclampsia, there seems to be some
benefit to a brief course of furosemide diuresis in the days postpartum.64
A few case reports have suggested that nonsteroidal anti-inflammatories may
contribute to blood pressure elevation postpartum,65 and the effects on blood pressure in
non-pregnant individuals are well documented. Thus, in postpartum patients who are
already hypertensive, these drugs should be used cautiously or should perhaps be
avoided.

G. Use of Corticosteroids
G1. Is corticosteroid therapy indicated for fetal lung maturity?
Between 24-34 weeks, corticosteroids should be given to enhance fetal lung
maturity. The recommended regimens are the following:
Betamethasone 12 mg IM every 24 hours for 2 doses
Dexamethasone 6mg IM every 12 hours for 4 doses (Level I, Grade A)

In pregnancies less than 34 weeks and the pregnancy can be prolonged in excess
of 24 hours, steroids help to reduce fetal respiratory mortality.66-67 There is probable
benefit from steroid therapy even if delivery is less than 24 hours after administration.68-69

G2. Does steroid therapy have a role in the treatment of HELLP syndrome?
The use of dexamethasone or other steroids for therapy specific for HELLP
syndrome is not recommended and this approach should be considered
experimental. (Level I, Grade A)

Two trials70-71 compared treatment with dexamethasone vs. placebo in women

with HELLP syndrome. Both studies revealed outcomes that were not significantly
different between 2 groups. One study72 suggests that corticosteroids use lead to a more
rapid resolution of the biochemical and hematological abnormalities but there is no
evidence that they reduce morbidity.
H. Delivery
H1. When is the woman with severe preeclampsia delivered?
Pregnancies ! 34 weeks of gestation complicated by severe preeclampsia is best
managed by delivery after maternal stabilization. (Level I, Grade A)

If the fetus is less than 34 weeks of gestation and delivery can be deferred,
corticosteroids should be given, although after 24 hours, the benefits of conservative
management should be reassessed. (Level I, Grade A)

If the gestation is greater than 34 weeks and complicated by severe preeclampsia,

delivery after stabilization is recommended.34 As the gestational age approaches 34
weeks, short and long term neonatal outcomes are excellent, fetal survival is already
similar to that of term gestations, and the potential benefits of expectant management
becomes less compelling.
Prolonging the pregnancy at very early gestation may improve the outcome for
the premature infant but can only be considered if the mother remains stable.68,69 Two
small randomized controlled trials73,74 have reported a reduction in neonatal
complications with an expectant approach to management of severe early-onset
preeclampsia with no increase in maternal complications. Several case series have also
reported similar outcomes in different settings with gestations as early as 24 weeks.7,8,68,69

H2. What is the mode of delivery?

The mode of delivery should be determined after considering the presentation of the
fetus and the fetal condition, together with the likelihood of success of induction of
labor after assessment of the cervix. (Grade C)

In all situations, a carefully planned delivery is appropriate. Vaginal delivery is

generally preferable but, if gestation is below 32 weeks, caesarean section is more likely
as the success of induction is reduced. After 34 weeks with cephalic presentation,
vaginal delivery should be considered.5,34 The obstetrician should discuss the mode of
delivery with the mother. Vaginal prostaglandins will increase the chance of success.
Anti-hypertensive treatment should be continued throughout assessment and labor.34

I. How should the woman be managed following delivery?

I1. Clinicians should be aware of the risk of late seizures and ensure that women have a
careful review before discharge form the hospital. (Level III, Grade C)

I2. Anti-hypertensive medication should be continued after delivery as dictated by the

blood pressure. It may be necessary to maintain treatment for up to 3 months.
(Level III, Grade C)

I3. Women with persisting hypertension and proteinuria at 6 weeks may have renal
disease and should be considered for further investigation. (Level III, Grade C)
 Severe preeclampsia can occur postpartum. Women who develop hypertension or
symptoms of preeclampsia postnatally (headaches, visual disturbances, nausea and
vomiting or epigastric pain) should be assessed.75 As eclampsia has been reported up to 4
weeks postnatally, the optimum length of inpatient postnatal stay is unclear but the
incidence of eclampsia and severe preeclampsia falls after the 4th postpartum day.76 The
decision about discharge from hospital needs to consider the risk of late seizures. Most
women with severe preeclampsia or eclampsia will need inpatient care for 4 days or more
following delivery. Careful assessment of the woman to ensure improving clinical signs
is needed before disacharge.34
Antihypertensive therapy should be continued after delivery. Although, initially,
blood pressure may fall, it usually rises again at around 24 hours postpartum. A
reduction in anti-hypertensive therapy should be made in a stepwise fashion. There is no
reason why the woman cannot go home on treatment, to be weaned off therapy as an
outpatient. After preeclampsia, blood pressure can take up to 3 months to return to
normal. During this time, blood pressure should not be allowed to exceed 160/100
mmHg. There is insufficient evidence to recommend any particular drug, however, it is
good practice to avoid the use of methydopa in the postnatal period because of its adverse
effect profile, particularly depression. Atenolol and metoprolol are also found to be
concentrated in the breastmilk.34,53

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61. Magee LA, et. al. Therapy with both magnesium sulfate and nifedipine does not increase the risk of serious
magnesium related maternal side effects in women with preeclampsia. Am J Obstet Gynecol 2005:193:153-
163.
62. Tan LK, de Swiet M. The management of postpartum hypertension. BJOG 2002.109:733-736.
63. Beardmore KS, et, al. Excretion of anti-hypertensive medication into human breastmilk: a systematic
review. Hypertens Pregnancy 2002;21:85-95.
64. Ascarelli MH, et. al. Postpartum preeclampsia management with Furosemide: A randomized clinical trial.
Obstet Gynecol 2005;105:29-33.
65. Makris A, et. al. Postpartum hypertension and non-steriodal analgesia. Am J Obstet Gynecol 2004;190:577-
578.
66. Crowley P. Prophylactic corticosteroids for preterm birth. Cochrane Database Syst Rev 2000 (2):
CD000065.
67. Leveno KJ, Cunningham FG, Lindheimer MD, Roberts JM, Cunningham FG (eds): Chesleys
Hypertensive Disorder of Pregnancy 3rd ed. New York, In Press, 2009, p.395.
68. Magan EF, et. al. Neonatal salvage by weeks gestation in pregnancies complicated by HELLP syndrome. J
Soc Gynecol Investig 1994;1:206-9.
69. Bramovici D, et. al. Neonatal outcome in severe preeclampsia at 24-36 weeks gestation: Does the HELLP
Syndrome matter? Am J Obstet Gynecol 1999;180:221-5.
70. Fonseca JE, et. al. Dexamethasone treatment does not improve the outcome of women with HELLP
syndrome. A Double blind placebo-controlled, randomized clinical trial. Am J Obstet Gynecol
193:1591,2005.
71. Katz L, et. al. Postpartum dexamethasone for women with. HELLP Syndrome. A double blind, placebo-
controlled, randomized clinical trial. Am J Obstet Gynecol 198.283. el, 2008.
72. Clenny TL, Viera AJ. Corticosteroid for HELLP syndrome. BMJ 2004;329;270-2.
73. Murphy DJ, Stirrat GM. Mortality and morbidity associated with early onset preeclampsia. Hypertens
Pregnancy 2000;19:221-31.
74. Haddad B, Deis S. Goffinet F, Paniel BJ, Cabral D, Sabai BM. Maternal and perinatal outcome during
expectant management of 239 severe preeclampsia women between 24-33 weeks gestation. Am J Obstet
Gynecol 2004;190-1590-7.
75. Atterburry JL, et. al. Clinical presentation of women readmitted with postpartum severe preeclampsia or
eclampsia. J Obstet Gynecol Neonatal Nurs 1998;27:134-41.
76. Lubarsky SL, Sibai BM. Late postpartum eclampsia revisited. Obstet Gynecol1994;83:502-5.
77. Sibai BM. Expectant management of preeclampsia. OBG Management 2005;3:18-36.
78. Sibai BM, Bartom JR. Expectant management of severe preeclampsia remote from term: patient selection
treatment, and delivery Indications. Am J Obstet Gynecol 2007;514:E1-E9.
 Eclampsia
Raul M. Quillamor, MD and Diosdado V. Mariano, MD

The aims in the treatment of eclampsia are:

control of seizure
correction of hypoxia and acidosis
control of blood pressure
delivery after control of seizure

The protocol of active management of eclampsia consists of:

A. Hospitalization - required for all patients with eclampsia. (Level I, Grade A)

B. Control of seizures and prevention of recurrence

Magnesium sulfate (MgSO4) is currently considered the drug of choice in the prevention
of eclamptic seizures as well as the reduction of recurrent seizures. The Eclampsia Collaborative
Trial Group in 1995 has established the superiority of magnesium sulfate over diazepam and
phenytoin in the treatment of convulsions. Significantly fewer recurrences of seizures were noted
among patients given magnesium sulfate than those given diazepam or phenytoin, although no
significant reduction in maternal and perinatal mortalities was noted among the three groups.
The recommended MgSO4 dosage schedules for severe preeclampsia and eclampsia have
been previously mentioned in the chapter on management of severe pre-eclampsia (Section Six)
but they are restated here for emphasis:

1. Loading doses of 4 g IV slowly over 5-10 minutes and 10 g deep IM (5 g to each

buttock), then 5 g IM every 4 hours until 24 hours after delivery. (Pritchard 1984).
2. Loading dose of 4 g IV followed immediately by IV infusion of 2 g per hour.
Incorporate 20 g MgSO4 (four 10-ml ampules of 50% MgSO4) to 1000 ml D5W or
Normosol-M, and infuse IV at a rate of 100 ml/hour (2 g/hr), via infusion pump or
soluset (Anderson 1986). One may reduce the drip to 1 g/hr after 24 hours.

The following precautions must be observed prior to administration of succeeding doses:

1. Urine output of at least 30 ml for the past hour or 100 ml for the past 4 hours
2. Presence of patellar reflex
3. Respiratory rate of not less than 12/min.
4. IV Calcium gluconate (10 ml of 10% solution) available at bedside for MgSO4
overdose.
5. Serum magnesium levels may be taken at certain intervals to monitor for magnesium
toxicity (Level III, Grade C). Maintenance of plasma magnesium levels at 4-7 meq/L
almost always prevents eclamptic convulsions.2 Patellar reflexes disappear with
plasma levels of 8-10 meq/L. This sign warns of impending magnesium toxicity since
respiratory depression develops at 12 meq/L, followed by respiratory and cardiac
paralysis and arrest.
 6. If a patient is to be transferred to another hospital, the full loading dose must have
been given and the patient should be accompanied by a responsible health personnel,
with provisions for control of seizures and other complications, if they occur. (Level
II-2, Grade B)

If MgSO4 is not available, other anti-seizure options that may be used are:

Diazepam
A loading dose of 10 mg IV over 2 minutes, repeated if convulsions recurred, followed by an
intravenous infusion of 40 mg in 500ml normal saline for 24 hours. The rate of infusion is
titrated based on the level of consciousness, with the aim of overcoming restlessness and keeping
the patient sedated but rousable. During the next 24 hours, an infusion of 20 mg diazepam in 500
ml normal saline is given and slowly reduced. It may be used with Phenytoin in the management
of convulsions in the absence of magnesium sulfate. (Level II-2, Grade B)

Phenytoin
There is no consensus about an ideal phenytoin regimen, although the dose may be varied
according to the patients weight. Since phenytoin is only recommended for the prevention of
seizures, 10mg diazepam IV should be given to control the seizures. Thereafter, an initial
phenytoin loading dose of 1 gm slow IV (over 20 min) is given with continuous cardiac
monitoring, and followed by succeeding doses of 100 mg every 6 hours for the next 24 hours.
(Level II-2, Grade B)

C. Anti-hypertensive therapy

Patients with severe hypertension should be started on IV therapy. The drugs that may be
used are hydralazine (drug of choice); clonidine and nifedipine (Level II-2, Grade B); and
labetalol7 (Level I, Grade A)
Give Hydralazine by IV boluses of 5 or 10 mg at 20 to 30 min intervals until the desired
BP is attained. Administering hydralazine via an IV drip is not recommended because of the
instability of the preparation. (Level II-1, Grade B)
a. Clonidine IM 75-150 mcg is the next recommended drug.
b. Nifedipine 5 or 10 mg can be given orally and takes effect within 15-50 minutes. The
sublingual route is not recommended for pregnant patients because of the acute
fluctuations in blood pressure levels and the absence of good studies on fetal effects
of calcium antagonists. (Level II-2, Grade C)
c. Labetalol can be given with an initial dose of 20 mg IV bolus. If the desired BP is not
attained within 10 minutes, give 40 mg, then 80 mg every 10 minutes but not to
exceed a total of 220 mg per episode treated.7,8 This drug should be avoided in
women with asthma or congestive heart failure.
D. Delivery after control of seizures

It is generally accepted that continuation of pregnancy in eclamptic patients constitutes a

significant threat to maternal and fetal well being such that pregnancy should be terminated.
It is recommended to induce labor or to perform a cesarean section as soon as the patient
becomes conscious and oriented, since temporization to gain fetal maturity in the presence of
eclampsia is always risky. (Level II-3, Grade B)
It has been observed that the uterus is sensitive to oxytocin so that labor can be induced
even with an unfavorable cervix and assisted vaginal delivery can be performed if labor
progresses.

Cesarean section is reserved if:

1. vaginal delivery does not appear easy and imminent
2. there is failure of progress after induction, or
3. there is fetal compromise.

Anticonvulsant therapy should be continued for at least 24 hours after delivery. In

comatose patients, a neurologic evaluation with possibly a CT scan should be performed.

References

1. Creasy RK, Resnik R. Creasy & Resniks Maternal-Fetal Medicine Principles and Practice, Sixth Edition.
2009, Saunders Elsevier.
2. Cunningham FG, Leveno K, et. al. Williams Obstetrics 23rd Edition 2010, The McGraw-Hill Companies,
Inc.
3. Duley L, Henderson-Smart D. Magnesium Sulfate versus diazepam for eclampsia. Cochrane Database Syst
Rev (4):CD000127, 2003.
4. Greer I, Walker J, et. al. Second line therapy with nifedipine in severe pregnancy induced hypertension.
Clin Exp Hypertens B8:277,1989.
5. RCOG Guideline Number 10, March 2006: The Management of Severe Preeclampsia/Eclampsia.
6. Sibai BM. Diagnosis, Prevention, and Management of Eclampsia. Obstetr Gynecol 2005; 105:402-10.
7. ACOG 2002.
8. National High Blood Pressure Education Program 2000
!

!
 Chronic Hypertension
Virgilio B. Castro, MD and Ann Marie C. Trinidad, MD

Definition

Chronic hypertension, defined as BP 140/90 mm Hg either predating pregnancy or

developing before 20 weeks gestation and hypertension that persists 12 weeks postpartum. This
complication may result in significant maternal, fetal and neonatal mortality and morbidity.
Hypertensive disorders during pregnancy occur in women with pre-existing primary or
secondary chronic hypertension, and in women who develop new-onset hypertension in the
second half of pregnancy.
Antihypertensive agents are mainly used to prevent and treat severe hypertension; to
prolong pregnancy for as long as safely possible, thereby maximizing the gestational age of the
infant and to minimize fetal exposure to medications that may have adverse effects. The goal of
treatment is to maintain BP at a level that minimizes maternal cardiovascular and
cerebrovascular risk. Prevention of preeclampsia is desirable; however, current evidence has not
shown that either specific BP targets in pregnancy or specific antihypertensive agents modify the
risk of superimposed preeclampsia in women with pre-existing hypertension. The challenge is in
deciding when to use antihypertensive medications and what level of BP to target. The choice of
antihypertensive agents is less complex, because only a small proportion of currently available
drugs have been adequately evaluated in pregnant women, and many others are contraindicated.

Recommendations

1. Low dose Aspirin (65-85 mg PO) at bedtime everyday from 12 weeks until birth should be
considered in women with historical risk factors to decrease superimposed preeclampsia (e.g.
hypertensive disease during a previous pregnancy, chronic renal disease, autoimmune disease
such as systemic lupus erythematosis or antiphospholipid syndrome, type 1 or type 2
diabetes, chronic hypertension) (Grade A)
Some women are more resistant than others to the effects of aspirin, a dose of at least 75
mg/d may be necessary to inhibit both platelet and placental thromboxane. However, a dose
of 100 mg/d may affect fetal prostacyclin synthesis.

2. Angiotensin converting enzyme (ACE inhibitors) and Angiotensin II receptor blockers

(ARBs) are contraindicated during pregnancy. (Level II-2, Grade A)

3. The beta blocker atenolol may be associated with growth restriction and is not recommended
for use in pregnancy. (Grade B)

4. Antihypertensive therapy should be reinstituted if BP exceeds 150-160 systolic or 100-110

diastolic. Initial antihypertensive therapy include the following:
a. Methyldopa 250500mg PO BID-QID (max 2g/day)
b. Labetalol 100400mg PO BID-TID (max 1200 mg/day)
 c. Nifedipine PA (intermediate release) tablets (1020 mg PO BID-TID, max 180
mg/day) or XL (slow release) preparation (2060 mg PO OD, max 120 mg/day)

Methyldopa and labetalol are the first line antihypertensive therapies. (Level I, Grade A)

Obstetric Management

1. Baseline ultrasound at 18-20 weeks and repeat scan at 28-32 weeks to monitor fetal growth
and to check amniotic fluid volume.
2. If with growth restriction or superimposed preeclampsia, Antenatal fetal surveillance should
include umbilial artery Doppler velocimetry. (Grade A)
3. For women with pre-existing hypertension laboratory exams at initial visit include complete
blood count (CBC), serum creatinine, serum potassium and urinalysis. (Grade B)
4. If with suspicion of preeclampsia, creatinine clearance and 24 hour urine protein are
encouraged. (Grade A)
5. Vaginal delivery should be considered unless a cesarean section is required for the usual
obstetric indication. (Grade B)
6. If vaginal delivery is planned and the cervix is unfavourable, then cervical ripening should be
used to increase the chance a successful vaginal delivery. (Grade A)
7. Women with long standing hypertension should be evaluated for end-organ disease including
cardiomegaly, renal insufficiency and retinopathy. (Grade C)
 Complications of Pregnancy Induced Hypertension (HELLP,
Abruptio Placnta)
Ma. Luisa S. Acu, MD and Sol M. Pangan, MD

HELLP Syndrome

Definition

The acronym HELLP was created by Louis Weinstein in 1982 to describe a subset of
severe preeclampsia/eclampsia with microangiopathic hemolytic anemia, moderate to
severe thrombocytopenia, disrupted or destroyed erythrocytes on peripheral smear, and
abnormal liver function tests presenting with right upper quadrant/epigastric pain, nausea
and vomiting. (H = hemolysis, EL = elevated liver enzymes, and LP = low platelets)1
Two classification systems have been created to stratify patients risks for significant
maternal morbidity, to guide therapeutic intervention and assess outcomes.
The Tennessee Classification (Sibai 1986)2 defines complete HELLP syndrome if all
the following criteria are met: (1) moderate to severe thrombocytopenia with platelets
100,000/ml or less; (2) hepatic dysfunction with AST 70 IU/L or greater; (3) evidence of
hemolysis with an abnormal peripheral smear in addition to either total serum LDH 600
IU/L or greater, or bilirubin 1.2 mg/dL or greater. When some but not all these
parameters are present, the term partial or incomplete HELLP is used.
The Mississippi Triple Class System (Martin 1999)3 divides patients into 3 classes based
on their platelet counts: class 1 requires severe thrombocytopenia (platelets < 50,000/ml,
evidence of hepatic dysfunction (AST and/or ALT > 70 IU/L), and evidence of hemolysis
(total serum LDH > 600 IU/L); class 2 requires similar criteria except thrombocytopenia
is moderate ( >50,000 to < 100,000/ml ); and class 3 includes patients with mild
thrombocytopenia (platelets >100,000 but < 150,000/ml), mild hepatic dysfunction (AST
and/or ALT > 40 IU/L), and hemolysis (total serum LDH > 600 IU/L).

Pathophysiology

The pathophysiology of HELLP remains unclear. Strand et al4 postulated that placenta-
derived proteins are shed into the maternal circulation which damage hepatic cells,
suggesting that HELLP syndrome is a placenta-instigated, liver-targetted acute
inflammatory condition and disordered immunologic process.5
Clinical Presentation

Usually develops suddenly in the third trimester or immediate postpartum. Progression is

usually rapid with 35-50 % decrease in platelets per day and rise in AST and ALT until
24 48 hours postpartum when levels begin to recover.6,7,8
Onset of disease occurs antepartum in 70 %, and postpartum in 30 % of cases.15
Hypertension and proteinuria may be mild and may not directly correlate with laboratory
parameters. Patients are usually seen complaining of malaise (90%), epigastric or right
upper quadrant pain (90%), or nausea or vomiting (50%), and some with non-specific
viral-like symptoms.13
The most important symptom is severe epigastric/right upper quadrant pain, found in
100% of Weinsteins original series of 29 advanced cases, often heralds rapidly
progressive disease.1,3,9
A patient with severe preeclampsia who suddenly develops severe writhing
epigastric/upper abdominal pain, may have hepatic hematoma or rupture, and constitutes
an obstetric emergency. Rupture of a subcapsular liver hematoma is one of the most
dreaded, life-threatening complication of the HELLP syndrome. If suspected, hepatic
imaging with transabdominal ultrasound, computed tomography (CT), or magnetic
resonance imaging (MRI), can be performed.14
Significant maternal morbidity occurs with worsening thrombocytopenia, very high
LDH, AST and/or uric acid levels.3,11
HELLP usually resolves within a week postpartum.5,6,25
60 % of maternal mortalities occur with class 1 disease and the most common cause is
cerebral hemorrhage/stroke. Other causes of death are cardiac arrest, DIC, ARDS, renal
failure, sepsis, hepatic rupture and hypoxic encephalopathy.10

Management

Liver function tests and platelet counts should be done in all preeclamptic women,
especially with suspected HELLP. (Level II, Grade B)
Best managed in a center with intensive care facilities for hepatologic, hematologic and
obstetric emergencies. (Grade B)
There is a consensus of opinion that prompt delivery is indicated if the syndrome
develops beyond 34 weeks gestation, or earlier if there is multiorgan dysfunction,
disseminated intravascular coagulopathy, liver infarction or hermorrhage, renal failure,
suspected abruption placentae, or nonreassuring fetal status. In these situations, treatment
consists of prophylaxis against convulsions with magnesium sulfate, control of
hypertension, stabilization of maternal condition, and then delivery.16 (Level III, Grade
B)
There is no general agreement, however, on the management of women with HELLP
syndrome before 34 weeks gestation when the maternal condition is stable except for
mild to moderate abnormalities in blood tests with a reassuring fetal condition.29,16
(Grade C)
Aggressive high dose corticosteroid therapy has been advocated to improve maternal and
neonatal outcome in HELLP. Intravenous dexamethasone 10-12 mg every 12 hours, or
 intramuscular betamethasone 10-12 mg every 12 hours, until delivery, and additional 3
more doses after delivery, were given with reported improvement in laboratory values,
improvement in blood pressure, shorter hospital stay and an increased use of regional
anesthesia.16-23,27 Most of these studies are retrospective and have critical design flaws,
mainly in inclusion criteria, choice of historical controls and/or clinical outcome
reported.29 The 4 randomized trials were not placebo controlled. Although improved
laboratory values and urine output were obtained in the patients given dexamethasone, no
differences in serious maternal morbidity such as need for transfusion, pulmonary edema,
renal failure, or serous hepatic complications were shown.29 Hence a Cochrane review
(2004) concluded that there is insufficient evidence to determine whether corticosteroid
use in HELLP syndrome decreases major maternal and perinatal morbidity.24
The results of two recent studies, Fonseca25 and Katz26, both randomized, double-blind,
placebo-controlled clinical trials, with the largest sample sizes to date, on the use of high
dose dexamethasone to improve maternal outcome in patients with HELLP syndrome, do
not support routine use of this regimen for all HELLP cases. However, a subgroup
analysis according to severity of disease, of the Fonseca cases, showed that among the
patients with Class 1 HELLP (platelet counts less than 50,000/mm3 ), there was a shorter
average platelet count recovery and less duration of hospitalization in those who received
dexamethasone (4.6 versus 10.4 days).
Replacement of clotting factors with frozen plasma and factor concentrates, and platelet
transfusion for counts below 50,000/mm3 should be given as needed. (Level III, Grade
B)
Epidural or spinal anesthesia is the preferred anesthesia for patients with preeclampsia.
Aggressive high dose corticosteroids can increase the platelet count to 75,000/mm3 , the
threshold deemed adequate to undertake regional anesthesia (from 0% to 42%), and to
enable cervical ripening, induction of labor, and possible vaginal delivery.27,28 (Level II,
Grade B)
Most of the patients could be discharged after 4-8 days hospitalization, if the platelet
count is greater than 100,000/mm3 and no evidence of end-organ damage.25

References

1. Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe
consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982;142:159-67.
2. Sibai BM, Taslimi MM, el-Nazer A, Amon E, Mabie BC, Ryan GM. Maternal-perinatal outcome
associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe
preeclampsia-eclampsia. Am J Obstet Gynecol 1986;155:501-9.
3. Martin JN Jr, Rinehart K, May WL, Magann EF, Terrone DA, Blake PG. The spectrum of severe
preeclampsia: comparative analysis by HELLP sybdrome classification. Am J Obstet Gynecol
1999;180:1373-84.
4. Strand S, Strand D, Seufert R, Mann A, Lotz J, Blessing M, et. al. Placenta-derived CD95 ligand
causes liver damage in HELLP syndrome. Gastroenterology 2004;126:849-58.
5. Martin JN Jr, Magann EF, Isler CM. HELLP sybdrome: the scope of disease and treatment. In: Belfort
MA, Thornton S, Saade GR, editors. Hypertension in pregnancy. Chap 7. Oxford: Marcel Dekker;
2003.p.141-88.
6. Martin JN Jr, Blake PG, Perry KG, McCaul JF, Hess LW, Martin RW. The natural history of HELLP
syndrome: patterns of disease progression and regression. Am J Obstet Gynecol 1991;164:1500-13.
7. Katz VL, Thorp JM, Rozas L, Bowes WA Jr. The natural history of thrombocytopenia associated with
preeclampsia. Am J Obstet Gynecol 1990;163:1142-3.
8. Makkonen N, Harju M, Kirkinen P. Postpartum recovery after severe preeclampsia and HELLP
sybdrome. J Perinat Med 1996;24:641-9.
9. Faridi A, Rath W. Differential HELLP syndrome diagnosis. Z Gerburstschilfe 1996;200:88-95.
10. Isler CM, Rinehart BK, Terrone DA, Martin RW, Magann EF, Martin JN Jr. Maternal mortality
associated with HELLP syndrome. Am J Obstet Gynecol 1998;181:924-8.
11. Catanzarite VA, Steinberg SM, Mosley CA, Lauders CF, Cousins LM, Sneider JM. Severe
preeclampsia with fulminant and extreme elevationof aspartate aminotransferase and lactate
dehydrogenase levels: high risk for maternal death. Am J Perinatol 1995;12:310-3.
12. Martin JN Jr, Rose CH, Briery CM. Understanding and managing HELLP syndrome: the integral role of
aggressive glucocorticoids for mother and child. Am J Obstet Gynecol 2006;195:914-34.
13. Sibai BM. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about
nothing? Am J Obstet Gynecol 1990;162:311-6.
14. Wicke C, Pereira PL, Neeser E, Flesch I, Rodegerdts EA, Becker HD. Subcapsular liver hematoma in
HELLP syndrome: evaluation of diagnostic and therapeutic options A unicenter study. Am J Obstet
Gynecol 2004;190:106-112.
15. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA. Maternal morbidity and
mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP
syndrome). Am J Obstet Gynecol 1993;169:1000-6.
16. Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver
enzymes and low platelet count. Obstet Gynecol 2004;103:981-91.
17. Martin JN Jr, Magann EF. High-dose dexamethasone:a promising therapeutic option for HELLP.
Contemp Ob Gyn 1999;44:55-65.
18. Magann EF, Bass D, Chouhan SP, Sullivan DL, Martin RW, Martin JN Jr. Antepartum corticosteroids:
disease stabilization in patients with HELLP syndrome. Am J Obstet Gynecol 1994;171:1148-53.
19. Magann EF, Perry KG Jr, Meydrech EF, Harris RL, Chouhan SP, Martin JN Jr. Postpartum
corticosteroids: accelerated recovery fom HELLP syndrome. Am J Obstet Gynecol 1994;171:1154-8.
20. van Runnard Heimel PH, Juisjes AJM, Franx A, Koopman C, Bots ML, Bruinse HW. A randomized
placebo controlled trial of prolonged prednisolone administration to patients with HELLP syndrome
remote from term: maternal and neonatal complications. Am J Obstet Gynecol 2004;191:S41.
21. Isler CM, Barrilleaux PS, Magann EF, Bass JD, Martin JN Jr. A prospective randomized trial
comparing the efficacy of dexamethasone and betamethasone for the treatment of antepartum HELLP
syndrome. Am J Obstet Gynecol 2001;184:1332-7.
22. Vigil-DeGracia P, Garcia-Caceres E. Dexamethasone in the postpartum treatment of HELLP syndrome.
Int J Gynaecol Obstet 1997;59:217-21.
23. Yalcin OT, Sener T, Hass H, Ozalp S, Okur A. Effects of postpartum corticosteroids in patients with
HELLP syndrome. Int J Gynaecol Obstet 1997;61:141-8.
24. Matchaba P, Moodley J. Corticosteroids for HELLP syndrome in pregnancy. (Cochrane Review) In: The
Cochrane Library, Issue 4, 2004:CD002076 Oxford: Updates Software.
25. Fonseca JE, Mendez F, Catano C, Arias F. Dexamethasone treatment does not improve the outcome of
women with HELLP syndrome: a double blind, placebo-controlled, randomized clinical trial. Am J Obstet
Gynecol 2005;193:1591-8.
26. Katz L, de Amorin MMR, Figueroa JN, Pinto eSilva JL. Postpartum dexamethasone for women with
hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome: a double-blind, placebo-
controlled, randomized clinical trial. Am J Obstet Gynecol 2008;198:283.e1-283.e8.
27. Obrien JM, Shumate SA, Satchwell SL, Milligan DA, Barton JR. Maternal benefit of corticosteroid
therapy in patients with HELLP (hemolysis, levated liver enzymes, and low platelet count) syndrome:
impact on the rate of regional anesthesia. Am J Obstet Gynecol 2002;186:457-9.
28. Rose CH, Thigpen BD, Bofill JA, Cushman J, May WL, Martin JN Jr. Obstet implications of
antepartum corticosteroid therapy for HELLP syndrome. Obstet Gynecol 2004;104:1011-4.
29. Sibai BM, Barton JR. Dexamethasone to improve maternal outcome in women with hemolysis, elevated
liver enzymes, and low platelets syndrome. Am J Obstet Gynecol 2005;193:1587-90.
 Abruptio Placenta

Definition

Placental abruption is defined as premature separation of a normally implanted placenta.

Approximately 0.5 1% of all pregnancies are complicated by placental abruption. Abruption
may be revealed, in which case blood tracks between the membranes and the decidua, and
escapes through the cervix into the vagina. The less common concealed abruption occurs when
blood accumulates behind the placenta, with no obvious external bleeding. Total abruption
involves the entire placenta, in which case it typically leads to fetal death, while in partial
abruption, only a portion of the placenta is detached from the uterine wall.
There are no randomized controlled studies that have specifically studied abruption,
Majority of the studies published in English are observational (i.e. cohort, case-control, or case
series). Most large studies with abruption have examined the risk factors for this condition.
Studies dealing on management strategies for abruptio are usually limited by small sample size.
The levels of available evidence for the diagnosis and management of abruptio placenta are
mostly II-1, II-2, and III. There are no trials to assess any intervention for prevention of
abruption or its complications.

Clinical Importance

Placental abruption has a wide spectrum of clinical significance, varying from cases with
minor bleeding and little or no consequences, to massive abruption leading to fetal death and
severe maternal morbidity.
The maternal effect of abruption depends primarily on its severity, whereas its effect on
the fetus is determined both by its severity and the gestational age at which it occurs. Maternal
complications include antepartum and postpartum hemorrhage, disseminated intravascular
coagulation (DIC) and acute renal failure, need for blood transfusions, hysterectomy, and less
commonly, maternal death. Fetal complications include a high perinatal mortality, preterm
delivery, fetal hypoxia and/or exsanguination, and growth restriction.
This high perinatal mortality is largely due to preterm delivery, because approximately
one half of the excess perinatal deaths are associated with early delivery. Abruption may be
implicated in up to 10% of preterm births.
Although placental abruption is an important cause of spontaneous preterm birth, it is
also often an indication for iatrogenic preterm delivery. Premature separation of the placenta
before delivery may deprive the fetus of oxygen and nutrition, leading to long-term handicap
among survivors.
Hypertensive diseases in pregnancy are strongly associated with placental abruption.
However, the severity of hypertension does not necessarily correlate with the incidence of
abruption.
Table 1. Evidence and Strength of Association Linking Major Risk Factors with Placental
Abruption Based on Published Studies

Risk Factors Strength of Evidence RR or OR

Chronic hypertension ++ 1.8 5.1
Mild and Severe Preeclampsia ++ 0.4 -4.5
Chronic hypertension with Preeclampsia +++ 7.8
RR, relative risk; OR, odds ratio. These estimates are the ranges of RR or OR found in independent studies.
Reprinted from Yeo L, Ananth CV, Vintzileos AM. Placental abruption. In: Sciarra J, editor. Gynecology and
obstetrics. Vol 2. Hagerstown (MD). Lippincott, Williams & Wilkins; 2003. 2003 Lippincott Williams & Wilkins.

Clinical Presentation

The clinical presentation of abruption varies widely from totally asymptomatic cases to
those where there is fetal death with severe maternal morbidity. The classically described
symptoms of placental abruption are vaginal bleeding and abdominal pain. Abruptio placenta
must be considered whenever bleeding occurs in the second half of pregnancy.
It is also possible to have severe abruption without neither or just of one of these signs. The
amount of vaginal bleeding correlates poorly with the degree of abruption. The severity of
symptoms depends on the location of the abruption, whether it is revealed or concealed, and the
degree of abruption. There is a correlation between the extent of placental separation and the risk
of stillbirth, with stillbirth occurring in most cases in which there is greater than 50% placental
separation.
Typically, there is uterine hypertonus with associated high-frequency, low- amplitude
uterine contractions. The uterus is frequently tender and may feel hard on palpation. Backache
may be the only symptom, especially when the placental location is posterior. There may be
acute fetal distress, and in cases where more than 50% of the placenta has separated, fetal
demise. Rarely fetal death due to abruption may occur with no other symptoms or signs. In some
cases, evidence of abruption may be found on ultrasonographic examination of asymptomatic
patients. Finally, abruption may present as idiopathic preterm labor.
A variety of fetal heart rate patterns have been described in association with abruption.
There may be recurrent late or variable decelerations, reduced variability, bradycardia, or a
sinusoidal fetal heart rate pattern. More infrequently, in cases of concealed abruption associated
with fetal death, the first clinical sign may be of evidence of abnormal bleeding, the result of
disseminated intravascular coagulopathy. In addition, there may be maternal hypovolemic shock.
Labor typically proceeds fairly rapidly in cases of abruption. Placental abruption may be
associated with acute tubular necrosis and acute cortical necrosis, leading to oliguria and renal
failure.

Diagnosis

The diagnosis of placental abruption is made primarily on clinical presentation.

Symptoms may vary, depending on how much of the placenta has separated and the age of
gestation it occurs. The classic presentation of abruption is the presence of painful cramps or
contractions with dark red or bright red vaginal bleeding after the 20th week of pregnancy.
Frequency of the clinical findings in women with placental abruption are the following:
vaginal bleeding (76%), fetal non-reassuring testing (60%), uterine-abdominal tenderness/back
pain (66%), uterine contractions >5 / 10 minutes (17%), uterine hypertonus (17%). About 10 %
of abruption present with only concealed bleeding. Occasionally the presenting sign is fetal
death. Severity of abruption often depends on how quickly the woman is seen following
symptom onset. With delay, the likelihood of extensive separation causing fetal death is
increased remarkably. Maintaining a high index of suspicion even in the absence of the classic
signs of shock is warranted.
Do not perform a digital examination on a pregnant patient with vaginal bleeding without
first ascertaining the location of the placenta. Before a pelvic examination can be performed
safely, an ultrasonographic examination should be performed to exclude placenta previa.
Ultrasound is primarily useful in ruling out other causes of third trimester bleeding.
However, when the ultrasonogram seems to show an abruption, the likelihood that there is
indeed an abruption is extremely high. Importantly, a negative ultrasonogram does not rule out
an abruption. If clinical circumstances of ultrasound findings are confusing, magnetic resonance
imaging (MRI) may help better define the location of the placenta and the presence pf abrutpion.
Ultrasonography may also predict prognosis in abruption; Nyberg and colleagues in a
retrospective review of 69 cases of abruption, found that fetal mortality correlated with the
ultrasonographically estimated percentage of abruption and with the location, with the worst
prognosis occurring in retroplacental abruptions.
The differential diagnosis includes all causes of abdominal pain and bleeding. These
include placenta previa, appendicitis, urinary tract infections, preterm labor, fibroid
degeneration, ovarian pathology, and muscular pain.
The Kleihauer-Betke test has limited usefulness in the diagnosis of abruption. A negative
test should not be used to rule out abruption, nor does a positive test necessarily confirm
abruption. However, a Kleihauer-Betke test allows quantification of feto-maternal transfusion to
guide dosing of Rh-immune globulin in Rh-negative women.

Classification

Class 1 mildest type, 48%

1. No vaginal bleeding to mild bleeding
2. Slightly tender uterus
3. Normal maternal BP and HR
4. No coagulopathy
5. No fetal distress

Class 2 moderate, 27%

1. No vaginal bleeding to mild bleeding
2. Moderate to severe uterine tenderness with possible tetanic contractions
3. Maternal tachycardia with orthostatic changes in BP and HR
4. Fetal distress
5. Low fibrinogen levels present
Class 3 severe, 24%
1. No vaginal bleeding to heavy bleeding
2. Very painful tetanic uterus
3. Maternal shock
4. Coagulopathy
5. Fetal death

Management

The goals in the management of abruption are to assess, control and restore the amount of
blood lost and to deliver a viable infant to prevent coagulation disorders. History, physical
examination, laboratory and ultrasonographic studies guide management.
Admission is required if abruptio placenta is considered. The following should be
performed once it is diagnosed:
1. Obtain intravenous access using 2 large-bore IV lines.
2. Institute crystalloid resuscitation.
3. Begin external fetal monitoring for both fetal heart rate and contractions.
4. Type and cross-match blood.
5. Foley catheter should be placed and the hourly urine output should be monitored
closely.
6. Begin blood transfusion if patient is hemodynamically unstable after fluid resuscitation.
7. Correct coagulopathy.
8. Administer Rh immune globulin is patient is Rh-negative.

The management of placental abruption depends on the presentation, the gestational age,
and the degree of maternal and fetal compromise. Because the presentation is widely variable, it
is important to individualize management on a case-by-case basis. More aggressive management,
desirable in cases of severe abruption, may not be appropriate in milder cases of abruption.
Prompt delivery is indicated if the pregnancy is at or near term. The main question is
whether vaginal delivery can be achieved without fetal or maternal death or severe morbidity. In
cases in which there is evidence of fetal compromise and delivery is not imminent, cesarean
delivery should be performed promptly, because total placental detachment could occur without
warning.
When both maternal and fetal status are reassuring, conservative management, with the
goal of vaginal delivery, is reasonable. Labor, if established, should be allowed to progress,
otherwise induction of labor should be considered. Both mother and fetus should be monitored
closely during labor. Should the fetal heart rate tracing become non-reassuring, with bradycardia,
loss of variability, or persistent late decelerations, prompt cesarean delivery is indicated.
Similarly, should maternal compromise occur, the fetus should be delivered promptly.
However, if <34 weeks, expectant management for mild (grade 1) abruption may allow
time for glucocorticoid administration. Maternal or fetal compromise necessitates delivery. A
decision to delivery interval of </= 20 minutes is associated with a substantial reduction in
neonatal morbidity and mortality in cases of fetal bradycardia. When there is partial placental
abruption and the maternal and fetal status are reassuring, the patient may be managed
conservatively. Preterm birth is the leading cause of perinatal death in women with abruption,
and to optimize perinatal outcomes, it is desirable, if possible, to prolong gestation. However, it
cannot be overemphasized that these patients require extremely close monitoring, because there
is a significant risk of fetal death. In cases where the gestational age is between 24 and 34 weeks,
steroids should be administered to promote fetal lung maturation. Patients should be delivered in
a center with adequate neonatal facilities and the parents should be counseled by a neonatologist
regarding potential treatments and out- comes for the neonate. Prolonged hospitalization and
monitoring may be necessary. It may be possible to discharge these patients to outpatient
management if the fetal status is reassuring once they have remained stable for several days.
The mode of delivery is dependent primarily on the condition of the mother and the fetus:
1. In most cases, for mild abruption (grade I), no evidence of maternal or fetal compromise,
vaginal delivery is indicated.
2. Moderate abruption (grade 2, evidence of fetal non-reassuring testing, - rapid delivery
typically by cesarean is indicated.
3. Severe abruption (grade 3), fetal demise, often with DIC vaginal delivery is indicated if
patient is stable.

In cases of severe abruption with fetal death, regardless of gestational age, as long as the
mother is stable, it is reasonable, in the absence of other con- traindications, to allow the patient
to have a vaginal delivery. Typically, the uterus is contracting vigorously, and labor rapidly
progresses.
Amniotomy is frequently sufficient to speed up delivery. Amniotomy is not proven to
decrease bleeding from spiral arteries and reduce the entry of thromboplastin into the maternal
circulation. If the fetus is reasonably mature, rupture of the membranes may hasten delivery. If
the fetus is immature, the intact sac may facilitate cervical dilatation.
Oxytocin is given in standard doses to effect vaginal delivery if there has been no previous
uterine surgery and there are no rhythmic superimposed contractions noted. There is no
evidence that oxytocin might predispose to DIC by enhancing entry of thromboplastin into the
maternal circulation.
There is a significant risk of coagulopathy and hypovolemic shock. Intravenous access
should be established and blood and coagulation factors should be replaced aggressively.
Meticulous attention should be paid the amount of blood loss; clinicians frequently
underestimate this.
It is prudent to involve an anesthesiologist in the patients care early. When labor does not
progress rapidly, and in cases in which there is feto-pelvic disproportion, fetal malpresentation,
or a prior classical cesarean delivery, cesarean delivery may be necessary to avoid worsening of
the coagulopathy.
Bleeding from surgical incisions in the presence of DIC may be difficult to control, and it
is important to stabilize the patient and to correct any coagulation derangement during surgery.
After delivery, the patient should be monitored closely, with particular attention paid to vital
signs, amount of blood loss, and urine output. In addition, the uterus should be observed closely
to ensure that it remains contracted and is not increasing in size, and blood loss should be
monitored closely. The uterus may be hypotonic, and occasionally hysterectomy may be
necessary. Blood should be drawn for complete blood count and coagulation studies at regular
intervals until the patient is stable. Finally, some cases of abruption may be associated with
severe preeclampsia, which may be masked because the patient may be normotensive due to
hypovolemia. Thus, there should be a high index of suspicion for severe preeclampsia in patients
with abruption not resulting from an obvious cause such as trauma or cocaine use. In such cases,
the patients may benefit from close volume status monitoring, early recognition of hypovolemia,
and adequate blood replacement.
The extensive extravasation of blood into the uterine musculature, a condition known as
Couvelaires uterus, seldom interferes with myometrial contractions to cause atony. It is not an
indication for hysterectomy

Tocolysis

It is generally taught that tocolytics, especially sympathomimetics such as terbutaline, are

contraindicated in the presence of vaginal bleeding, because side effects such as tachycardia
could mask the clinical signs of blood loss. However, a few retrospective cohort and case
control studies have evaluated the use of tocolytics (including sympathomimetics) in the
presence of bleeding in the second half of pregnancy, including patients with suspected stable
placental abruption before 35 weeks gestation. Based on these reports tocolytics may be used in
caution in stable women remote from term who
Most cases of placental abruption cannot be predicted or prevented. However, in some
cases, maternal and infant outcomes can be optimized through attention to the risks and benefits
of conservative management, ongoing evaluation of fetal and maternal well-being, and through
expeditious delivery where appropriate.

Algorithm for the management of placental abruption in term or near term (A) and preterm
births (B). In all cases, complete blood count and coagulation indices should be checked; blood
or blood volume should be replaced; coagulopathy should be corrected; and intake, output, and
renal function should be monitored.4
References

1. Obstetric evidence based guidelines by Vincenzo Berghella, 2007; p 193-200.

2. Cunningham L, et. al. Williams Obstetrics, 23rd edition, 2010; p 761-769.
3. Neilson JP. Interventions for treating placental abruption. Cochrane Database Syst Rev 2009.
4. Oyelese Y, Ananth CV. Placental abruption. Obstet Gynecol 2006;108:1005-1016.
5. Bernischke K, Kaufmann P. Pathology of the human placenta. 4th ed. New York (NY): Springer; 2000.
6. Saller DN Jr, Nagey DA, Pupkin MJ, Crenshaw MC Jr. Tocolysis in the management of third trimester
bleeding. J Perinatol 1990;10:1258.
7. Towers CV, Pircon RA, Heppard M. Is tocolysis safe in the management of third-trimester bleeding? Am J
Obstet Gynecol 1999;180:15728.
8. Ananth CV, Berkowitz GS, Savitz DA, Lapinski RH. Placental abruption and adverse perinatal outcomes.
JAMA 1999;282: 164651.
9. Nyberg DA, Cyr DR, Mack LA, Wilson DA, Shuman WP. Sonographic spectrum of placental abruption.
AJR Am J Roentgenol 1987;148:1614.
10. Glantz C, Purnell L. Clinical utility of sonography in the diagnosis and treatment of placental abruption. J
Ultrasound Med 2002;21:83740.
 APPENDIX

LEVELS OF EVIDENCE AND GRADES OF RECOMMENDATION

LEVEL DEFINITION
I Evidence obtained from at least one properly randomized controlled trial
Evidence obtained from well-designed controlled trials without
II-1
randomization
Evidence obtained from well-designed cohort or case-control analytic
II-2
studies, preferably from more than one center or research group
Evidence obtained from multiple time series with or without the
II-3
intervention.
Opinions of respected authorities, based on clinical experience; descriptive
III
studies and case reports or reports of expert committees.
!

GRADE DEFINITION
There is good evidence to support the recommendation of the practice in
A
the management of hypertensive complications of pregnancy.
There is fair evidence to support the recommendation of the practice in the
B
management of hypertensive complications of pregnancy.
There is insufficient evidence to recommend for or against the inclusion of
C the practice in the management of hypertensive complications of
pregnancy.
There is fair evidence to support the recommendation that the practice be
D
excluded in the management of hypertensive complications of pregnancy.
There is good evidence to support the recommendation that the practice be
E
excluded in the management of hypertensive complications of pregnancy.
A good practice point (GPP) is a recommendation for best practice based
GPP
on the experience of the Task Force.
!