Original Research ajog.

org

OBSTETRICS
Pregnancy as a window to future health: maternal placental
syndromes and short-term cardiovascular outcomes
Mary Ashley Cain, MD; Jason L. Salemi, PhD, MPH; Jean Paul Tanner, MPH; Russell S. Kirby, PhD, MS;
Hamisu M. Salihu, MD, PhD; Judette M. Louis, MD, MPH

BACKGROUND: Cardiovascular disease is the leading cause of death
among women. Identifying risk factors for future cardiovascular disease
may lead to earlier lifestyle modifications and disease prevention. Addi-
tionally, interpregnancy development of cardiovascular disease can lead to
increased perinatal morbidity in subsequent pregnancies. Identification
and implementation of interventions in the short term (within 5 years of first
pregnancy) may decrease morbidity in subsequent pregnancies.
OBJECTIVE: We identified the short-term risk (within 5 years of first
pregnancy) of cardiovascular disease among women who experienced a
maternal placental syndrome, as well as preterm birth and/or delivered a
small-for-gestational-age infant.
STUDY DESIGN: We conducted a retrospective cohort study using a
population-based, clinically enhanced database of women in the state of
Florida. Nulliparous women and girls aged 15-49 years experiencing their
first delivery during the study time period with no prepregnancy history of
diabetes mellitus, hypertension, or heart or renal disease were included in
the study. The risk of subsequent cardiovascular disease was compared
among women who did and did not experience a placental syndrome
during their first pregnancy. Risk was then reassessed among women with
placental syndrome and preterm birth or delivering a small-for-gestational-
age infant vs those without these adverse pregnancy outcomes.
RESULTS: The final study population was 302,686 women and girls.
Median follow-up time for each patient was 4.9 years. The unadjusted rate
of subsequent cardiovascular disease among women and girls with any
placental syndrome (11.8 per 1000 women) was 39% higher than the rate
among women and girls without a placental syndrome (8.5 per 1000
women). Even after adjusting for sociodemographic factors, preexisting
conditions, and clinical and behavioral conditions associated with the
current pregnancy, women and girls with any placental syndrome expe-
rienced a 19% increased risk of cardiovascular disease (hazard ratio, 1.19;
95% confidence interval, 1.07e1.32). Women and girls with >1 placental
syndrome had the highest cardiovascular disease risk (hazard ratio, 1.43;
95% confidence interval, 1.20e1.70), followed by those with eclampsia/
preeclampsia alone (hazard ratio, 1.42; 95% confidence interval,
1.14e1.76). When placental syndrome was combined with preterm
birth and/or small for gestational age, the adjusted risk of cardiovascular
disease increased 45% (95% confidence interval, 1.24e1.71). Women
and girls with placental syndrome who then developed cardiovascular
disease experienced a 5-fold increase in health careerelated costs during
follow-up, compared to those who did not develop cardiovascular disease.
CONCLUSION: Women and girls experiencing placental syndromes
and preterm birth or small-for-gestational-age infant are at increased risk
of subsequent cardiovascular disease in short-term follow-up. Strategies
to identify and improve cardiovascular disease risk in the postpartum
period may improve future heart disease outcomes.
Key words: cardiovascular disease, preeclampsia, preterm birth, small
for gestational age

Introduction investigates the impact of PS and subse-

Cardiovascular disease (CVD) is the
leading cause of death among women in
the United States.1 An increasing body
of evidence indicates that pregnancy-
related morbidities, including pre-
eclampsia, placental infarction, and
abruption, are associated with the
development of subsequent CVD and
can be referred to as maternal placental
syndromes (PS).2-5 Furthermore, the
adverse pregnancy outcomes of preterm
Cite this article as: Cain MA, Salemi JL, Tanner JP, et al.
Pregnancy as a window to future health: maternal
placental syndromes and short-term cardiovascular out-
comes. Am J Obstet Gynecol 2016;215:484.e1-14.
0002-9378/free
ª 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2016.05.047
Related editorial, page 406.
delivery, and infants born small for
gestational age (SGA), resulting from
intrauterine growth restriction, may be
referred to as fetal PS and also appear to
confer CVD risk.4,6-10
Both retrospective and prospective
epidemiological studies have reported
associations between hypertensive dis-
orders of pregnancy, preterm birth
(PTB), and maternal PS and an increased
risk of future CVD.4,7-9,11 While most of
these studies focus on long-term CVD
risk, up to 15 years after giving birth,
limited data exist regarding the short-
term risk of CVD. CVD occurring
within the first 5 years of the index
delivery will likely occur in the mother’s
reproductive lifespan and therefore lead
to further morbidity in subsequent
pregnancies. No prior research
quent CVD on health care utilization or
costs. We hypothesized that the short-
term risk of CVD (within 5 years of
first pregnancy) would be increased
among women with maternal PS. Addi-
tionally we examined health care utili-
zation and direct medical costs in the
years immediately following preg-
nancy with and without placental
complications.
Materials and Methods
Design, data source, and study
population
We conducted a population-based
retrospective cohort study using a
statewide maternal and infant longitu-
dinally linked database.12,13 For Florida-
resident births from 1998 through 2009,
birth certificates were linked both to
infant birth and maternal delivery

484.e1 American Journal of Obstetrics & Gynecology OCTOBER 2016

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hospitalization discharge records using a
hierarchical deterministic linking strat-
egy.14 After establishing events that
occur at birth, we then linked in death
certificates and all subsequent infant and
maternal inpatient, outpatient, and
emergency department discharge re-
cords available through the end of
follow-up (Dec. 31, 2010). For mothers,
we also linked to all hospital discharge
data preceding the index pregnancy, as
far back as Jan. 1, 1998. Details of the
data linkage process, which achieved
>92% linkage rate, and an evaluation of
the validity and reliability of database
have been published previously.14 The
study population consisted initially of
318,362 nulliparous pregnant women
and girls aged 15-49 years who gave
FIGURE 1
Flow diagram representing final determination of study population
Flow diagram representing final determination of study population of nulliparous, Florida-resident
women and girls aged 15-49 years whose first singleton live birth occurred from 2004
through 2007.
CVD, cardiovascular disease; ED, emergency department.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.
OBSTETRICS
birth to a live born singleton infant from
Jan. 1, 2004, through Dec. 31, 2007
(Figure 1). This time frame was chosen
to review medical history in the 5-year
period before pregnancy, incorporate
potential confounders present only on
the new version of the Florida birth
certificate, and allow for a minimum of 3
years of follow-up after the index delivery.
Women diagnosed with prepregnancy
CVD, hypertension, diabetes, or renal
disease in the 5-year period before the
index delivery hospitalization
(n ¼ 14,165) and those giving birth
to infants with implausible gestational
age-birthweight combinations based on -
national fetal growth curves15 (n ¼ 416)
were excluded. The final study population
consisted of 302,686 women and girls.
OCTOBER 2016 American Journal of Obstetrics & Gynecology
Original Research
PS and adverse infant outcomes
Using International Classification of
Diseases, Ninth Revision, Clinical Modi-
fication (ICD-9-CM) diagnosis codes
from discharge records, supplemented
with birth certificate indicators to
improve sensitivity, we determined
whether each mother had a PSe
preeclampsia (642.4, 642.5), eclampsia
(642.6 or birth certificate indicator),
gestational hypertension (642.3 or birth
certificate indicator), placental infarc-
tion (656.7), or placental abruption
(641.2)ediagnosed during her index
delivery hospitalization. Three expo-
sures were used in analyses: (1) a 2-level
“any PS” variable; (2) a 5-level variable to
capture the nature and number of PS
conditions; and (3) a 4-level variable that
combined PS with PTB (20-37 weeks’
gestation) and SGA (birthweight <10th
percentile for gestational age).
Cardiovascular health outcomes
The primary outcome was incident
CVD, operationalized as presence of 1
ICD-9-CM diagnosis codes indicative
of coronary heart disease, cerebrovas-
cular disease, peripheral artery disease,
or congestive heart failure, or an
ICD-9-CM procedure code for cardiac or
peripheral arterial revascularization. To
prevent capturing the immediate effect
of the index delivery on risk of CVD,4
assessment of CVD included encoun-
ters taking place 90 days after discharge
from the index delivery hospitalization.
Follow-up continued through Dec. 31,
2010. A detailed list of the ICD-9-CM
codes used to define CVD is presented
in the Appendix.
Health care utilization indices
We explored the associations between
PS and 3 indicators of health care utili-
zation: (1) number of encounters,
(2) length of stay (LOS) across encoun-
ters, and (3) cost of providing direct
medical care. The number of encounters
was calculated as the number of unique
inpatient, outpatient, and emergency
department discharge records with date
of admission 90 days after discharge
from the index delivery hospitalization.
To calculate LOS in days for any type of
encounter, we subtracted the dates of
484.e2
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TABLE 1
Distribution of women with and without placental syndrome during their index pregnancies by selected maternal
sociodemographic, clinical, behavioral, and infant characteristics
Characteristica Placental syndrome, N ¼ 36,713 No placental syndrome, N ¼ 265,973 Pb
c
Follow-up time (days), median (Q1eQ3) 1770 (1428e2121) 1775 (1433e2129) .03
Sociodemographics
Age, y, mean  SD 24.9  6.1 25.1  6.0 <.01
Race/ethnicity <.01
Non-Hispanic white 19,139 (52.1) 131,193 (49.3)
Non-Hispanic black 8325 (22.7) 47,207 (17.7)
Hispanic 7840 (21.4) 72,476 (27.2)
Non-Hispanic other 1247 (3.4) 13,938 (5.2)
Nativity, foreign-born 7773 (21.2) 78,250 (29.4) <.01
Education <.01
<High school 6714 (18.3) 46,812 (17.6)
High school 11,619 (31.6) 79,405 (29.9)
>High school 18,172 (49.5) 138,134 (51.9)
Per-capita income, US$d, median (Q1eQ3) 23.6 (18.9e28.5) 23.8 (19.4e29.5) <.01
Had another live birth 13,472 (36.7) 99,872 (37.5) <.01
Comorbidities, 5-y history
Hyperlipidemia 52 (0.1) 244 (0.1) <.01
Migraine 433 (1.2) 2059 (0.8) <.01
Lupus 63 (0.2) 230 (0.1) <.01
Comorbidities, current pregnancy
BMI, kg/m2, mean  SD 26.3  6.5 24.2  5.3 <.01
Prepregnancy BMI <.01
Underweight 1529 (4.2) 17,677 (6.6)
Normal 15,884 (43.3) 148,153 (55.7)
Overweight 8720 (23.8) 51,611 (19.4)
Obese I 4603 (12.5) 20,392 (7.7)
Obese II 2208 (6.0) 7784 (2.9)
Obese III 1428 (3.9) 4206 (1.6)
Gestational diabetes 2733 (7.4) 11,384 (4.3) <.01
Behavioral factors
Tobacco use during pregnancy 2754 (7.5) 20,470 (7.7) .19
Alcohol use during pregnancy 142 (0.4) 978 (0.4) .57
Drug use during pregnancy 425 (1.2) 2444 (0.9) <.01
Infant characteristics
Male sex 18,919 (51.5) 136,179 (51.2) .23
Small for gestational age 6215 (16.9) 26,603 (10.0) <.01
Preterm birth 7517 (20.5) 18,821 (7.1) <.01
BMI, body mass index.
a
Binary characteristics are presented as frequency and percentage that reflect presence of condition; b Generated from c2 test of statistical independence for categorical variables, and from
independent samples t test or Wilcoxon-Mann-Whitney test for continuous variables; c Quartile; d Presented in thousands of dollars.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

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TABLE 2
Hazard ratios and 95% confidence intervals representing association between placental syndromes during
current pregnancy and subsequent cardiovascular diseasea
CVD CVD Unadjusted model Adjusted model 1c Adjusted model 2d Adjusted model 3e
Exposure category cases rateb HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI)
Any PS
No 2269 8.5 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
f f f
Yes 432 11.8 1.39 (1.25e1.54) 1.27 (1.14e1.40) 1.26 (1.13e1.39) 1.19 (1.07e1.32)f
Nature/no. of PS conditions
No PS 2269 8.5 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
Eclampsia/preeclampsia alone 87 13.7 1.60 (1.29e1.98)f 1.48 (1.20e1.84)f 1.47 (1.18e1.82)f 1.42 (1.14e1.76)f
Gestational hypertension alone 178 10.0 1.18 (1.01e1.37)f 1.07 (0.91e1.24) 1.06 (0.91e1.24) 0.99 (0.85e1.16)
Placental abruption/infarction alone 32 10.5 1.22 (0.86e1.73) 1.12 (0.78e1.60) 1.12 (0.78e1.60) 1.09 (0.76e1.57)
f f f
More than one placental syndrome condition 135 14.3 1.69 (1.42e2.01) 1.54 (1.29e1.83) 1.53 (1.28e1.82) 1.43 (1.20e1.70)f
PS and adverse infant outcomes
No PS, no PTB, no SGA 1854 8.3 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
f f f
PS alone 268 10.7 1.29 (1.14e1.47) 1.16 (1.02e1.32) 1.16 (1.02e1.32) 1.08 (0.95e1.23)
f
PTB/SGA alone 415 9.6 1.16 (1.04e1.29) 1.10 (0.99e1.22) 1.10 (0.98e1.22) 1.07 (0.96e1.20)
PS and PTB/SGA 164 14.1 1.70 (1.45e2.00)f 1.56 (1.33e1.83)f 1.54 (1.31e1.81)f 1.45 (1.24e1.71)f
CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
a
Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system;
b
Rate expressed as no. of incident CVD cases per 1000 women; c Crude model þ adjusted for maternal age, race/ethnicity, nativity, education, and income; d Adjusted model 1 þ adjusted for 5-y
history of hyperlipidemia, migraine, and lupus; e Adjusted model 2 þ adjusted for prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex; f HRs statistically
significantly different from 1.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

admission and discharge. Same day visits
were assigned an LOS of 1 day since these
hospitalizations constitute a distinct stay
and are billed as 1 day for room/board.16
For each woman or girl, the number of
days across all admissions was summed.
Hospital discharge records in our linked
database contain detailed department-
level charges for each encounter.
Charges reflect what a hospital bills for
services and are a poor estimate of actual
cost.17 The degree of markup from cost
to billed charges varies considerably
across hospitals, departments within the
same hospital, and over time. We devel-
oped an algorithm18 to convert charges
to cost using time-, hospital-, and
department-specific cost-to-charge ra-
tios from hospital cost reports, and
further adjusted estimates for inflation to
2010 dollars using the medical care
component of the Consumer Price
Index.19 Due to the lack of reliable
cost-to-charge ratio to fit our data,
outpatient visits were not included in
determining the cost of medical care
during follow-up.
To remove the impact of subsequent
pregnancies on health care utilization
metrics, we excluded nonindex delivery
hospitalizations. We stratified total LOS
and direct medical costs into those
occurring during the index delivery
hospitalization and during the post-90-
day follow-up period.
Sociodemographic, behavioral, and
clinical covariates
Using both birth certificate and
ICD-9-CM codes, we examined socio-
demographic characteristics (age at the
index delivery, race/ethnicity, nativity,
education, and per-capita income),
health behaviors (tobacco, alcohol, and
drug use), clinical comorbidities (a 5-year
history of hyperlipidemia, migraine,
and lupus), prepregnancy body mass
index (BMI), and gestational diabetes
that could plausibly confound the asso-
ciations between PS and the study
outcomes. Specific ICD-9-CM codes and
birth certificate indicator variables used
are provided in the Appendix.
Statistical analysis
Descriptive statistics were used to
describe the distribution of nulliparous
women with and without a PS by socio-
demographic, clinical, behavioral, and
infant characteristics. The c2 test (cate-
gorical data) and independent-samples t
tests or Wilcoxon-Mann-Whitney tests
(continuous data) were used to assess the
statistical significance of bivariate asso-
ciations. Kaplan-Meier curves were used
to describe the risk of incident CVD for
women with and without PS, and Cox
proportional hazards regression was used
to calculate hazard ratios (HR) and 95%
confidence intervals (CI) that represent
the association between PS and time to
CVD. Women and girls were censored if
they did not experience a CVD-related
event by Dec. 31, 2010. Ties, in which
2 women or girls experience a CVD at

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Original Research OBSTETRICS
the same recorded time, were handled
using the Efron approximation. The
proportional hazards assumption was
assessed using plots of Schoenfeld re-
siduals versus time; linearity was exam-
ined using plots of Martingale residuals
and each covariate. To compare mean
health care utilization indices across
exposure and outcome groups, we used
generalized linear modeling to calculate
adjusted measures of association (eg, cost
ratios) and 95% CIs. Due to the positively
skewed nature of LOS and cost data, we
considered various nonnormal distribu-
tions with the best-fitting model selected
based on Akaike information criterion.20
For each exposure-outcome association,
3 multivariable models were constructed
to demonstrate the relative confounding
effects of 3 types of factors: (1) adjusting
for sociodemographic characteristics; (2)
additional adjustment for 5-year history
of hyperlipidemia, migraine, and lupus;
and (3) additional adjustment for pre-
pregnancy BMI, gestational diabetes, and
tobacco, drug, and alcohol use during the
index pregnancy.
We conducted sensitivity analyses to
evaluate the robustness of our results to
alternative eligibility criteria and model
inputs. Although index pregnancies in
the current study were only nulliparous
women and girls, subsequent pregnancies
may have occurred during the follow-up
period. These pregnancies could increase
the risk of CVD independent of PS during
the index pregnancy. Therefore, we re-ran
all analyses after restricting to women
and girls with no subsequent deliveries.
Our cost analyses did not include outpa-
tient visits, therefore we analyzed charges
among all encounters, and compared
calculated charge ratios to cost ratios. All
analyses were conducted using software
(SAS 9.4; SAS Institute Inc, Cary, NC)
using a 5% type I error rate and 2-sided
hypothesis tests. The linked database was
deidentified prior to use and the study was
approved by the institutional review
boards of the Florida Department of
Health, University of South Florida, and
Baylor College of Medicine.
Results
We identified 36,713 (13.8%) mothers
with a PS during their index delivery
484.e5 American Journal of Obstetrics & Gynecology OCTOBER 2016
ajog.org
hospitalization. Mothers with PS were for confounders. When PS was com-
more likely to be black non-Hispanic, bined with PTB and/or SGA, the
have a high school education or less, adjusted risk of CVD increased 45%
have lower income, have a higher pre- (95% CI, 1.24e1.71) (Figure 2). Women
pregnancy BMI, have gestational dia- and girls with PS without PTB or SGA
betes, and use illicit drugs during did not demonstrate increased CVD risk,
pregnancy (Table 1). Infants of mothers relative to women and girls without PS,
with PS were more likely to be born PTB, or SGA.
preterm and be SGA.
PS and health care utilization
PS and risk of subsequent CVD Table 3 describes the frequency of clin-
Women or girls with any PS were at a ical encounters and LOS based on the
39% higher risk of subsequently devel- presence/absence of PS, adverse preg-
oping CVD than women or girls without nancy outcomes, and CVD. Women and
PS (95% CI, 1.25e1.54) (Table 2). The girls with any PS had more hospital en-
risk was reduced to 19% after adjusting counters and increased mean LOS than
for sociodemographic, clinical, and women and girls without PS. The mean
behavioral factors, and infant sex (95% number of hospital encounters, admis-
CI, 1.07e1.32). Women or girls with >1 sions, and LOS differed depending on
PS condition had the highest CVD risk the type of PS. Women and girls with >1
(HR, 1.43; 95% CI, 1.20e1.70), followed PS experienced the highest mean num-
by those with eclampsia/preeclampsia ber of all encounters (4.1 days). 23.4% of
alone (HR, 1.42; 95% CI, 1.14e1.76). women and girls with >1PS experienced
Although women or girls with gesta- greater than or equal to 6 hospital en-
tional hypertension alone experienced counters. Women and girls with no PS
an 18% increased crude risk of CVD, the had the smallest number of hospital
risk was not significant after adjustment encounters. Similarly, women and girls
FIGURE 2
Kaplan-Meier survival estimates representing risk of cardiovascular
disease across groups
Crude Kaplan-Meier survival estimates representing risk of cardiovascular disease (CVD) across
groups that differ on presence/absence of placental syndromes (PS) and adverse infant outcomes.
PTB, preterm birth; SGA, small for gestational age.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.
ajog.org OBSTETRICS Original Research

TABLE 3
Frequency and length of stay during inpatient, outpatient, and emergency department encounters, based on presence/
absence of placental syndrome, adverse pregnancy outcomes, and cardiovascular diseasea
All nondelivery hospital
encountersb LOS: index delivery LOS: other encountersb
Exposure/outcome category Mean  SD 6 Visits Mean  SD 6 d Mean  SD 21 d
Any PS
No 3.1  5.5 17.0% 2.7  1.7 1.3% 3.8  7.9 2.6%
Yes 3.8  6.6 21.2% 3.7  2.6 8.9% 4.7  10.2 3.7%
Nature/no. of PS conditions
No PS 3.1  5.5 17.0% 2.7  1.7 1.3% 3.8  7.9 2.6%
Eclampsia/preeclampsia alone 3.9  6.3 22.2% 4.0  2.9 12.7% 5.0  12.9 4.2%
Gestational hypertension alone 3.6  6.7 19.8% 3.2  1.6 3.4% 4.4  8.9 3.2%
Placental abruption/infarction alone 3.8  6.6 20.7% 3.6  4.3 7.0% 4.6  8.3 3.7%
More than one placental syndrome condition 4.1  6.6 23.4% 4.4  3.1 17.3% 5.2  10.7 4.4%
PS and adverse infant outcomes
No PS, no PTB, no SGA 3.0  5.2 15.9% 2.7  1.0 0.6% 3.6  7.4 2.4%
PS alone 3.6  6.5 20.0% 3.3  1.6 4.3% 4.4  8.5 3.3%
PTB/SGA alone 3.9  6.5 22.3% 3.2  3.6 4.9% 4.8  10.2 3.9%
PS and PTB/SGA 4.2  6.8 23.8% 4.5  3.9 18.8% 5.4  13.0 4.6%
CVD
No 3.1  5.4 17.1% 2.9  1.9 2.2% 3.8  7.6 2.6%
Yes 12.0  14.9 61.7% 3.0  3.2 3.6% 17.6  30.3 23.6%
PS and CVD
No PS or CVD 3.0  5.2 16.6% 2.7  1.7 1.3% 3.7  7.4 2.5%
PS, did not develop CVD 3.7  6.4 20.7% 3.7  2.6 8.8% 4.5  9.1 3.4%
No PS, developed CVD 11.8  15.2 61.1% 2.9  3.1 1.7% 16.9  28.5 22.8%
PS, developed CVD 12.9  13.7 65.0% 4.0  3.7 13.2% 21.4  38.3 27.5%
CVD, cardiovascular disease; LOS, length of stay; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
a
Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system;
b
Includes all inpatient, outpatient, and emergency department encounters, excluding all hospitalizations in which delivery occurred.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

with >1 PS had the highest mean LOS
during the index delivery (4.4 days) and
during the follow-up period (5.2 days).
Over 17% of these women and girls,
and 12.7% of women and girls with
eclampsia/preeclampsia alone, spent 6
days in the hospital during the index
delivery, compared with 1.3% of women
and girls without PS.
Women and girls with CVD had the
most clinical encounters and the longest
LOS during follow-up (Table 3).
Approximately 65% of women and girls
with PS who subsequently developed
CVD had 6 nondelivery hospital
encounters and the mean number of
encounters was 12.9. Women and girls
with no PS who developed CVD had the
next highest number of nondelivery
hospital encounters, followed by women
and girls with PS who did not develop
CVD, and women and girls with no PS or
CVD. The presence of PS appeared to
drive the length of the delivery hospi-
talization and development of CVD was
a better predictor of the frequency and
duration of clinical encounters during
follow-up.
PS, CVD, and direct costs of
medical care
Table 4 describes the costs associated with
direct medical care during inpatient and
emergency department encounters for
women who had PS, adverse pregnancy
outcomes, and CVD. Women and girls
with any PS and those with PS subgroups
had higher mean hospital costs than
women and girls with no PS, both during
the index delivery hospitalization and
during follow-up. The highest crude
mean costs of care were among women
and girls with PS and PTB and/or SGA.

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TABLE 4
Hospital costs associated with direct medical care during inpatient and emergency department encounters, based on
presence/absence of placental syndrome, adverse pregnancy outcomes, and cardiovascular diseasea
Costsa of care during nondelivery
Costsa of care during index delivery encounters
Exposure/outcome Cost ratiob Cost ratiob
category N Mean  SD $10,000 (95% CI) Mean  SD $10,000 (95% CI) Excess costc
Any PS
No 265,973 4.7  2.9 1.7% 1.00 (Reference) 2.7  8.7 6.1% 1.00 (Reference) Reference
Yes 36,713 6.1  3.5 7.7% 1.29 (1.28e1.30) 3.5  11.8 8.4% 1.14 (1.12e1.16) 63,385,729
Nature/no. of PS
conditions
No PS 265,973 4.7  2.9 1.7% 1.00 (Reference) 2.7  8.7 6.1% 1.00 (Reference) Reference
Eclampsia/ 6369 6.8  4.4 12.6% 1.45 (1.43e1.46) 4.0  16.3 9.7% 1.31 (1.26e1.36) 18,638,687
preeclampsia alone
Gestational 17,852 5.3  2.4 3.5% 1.14 (1.13e1.14) 3.1  8.5 7.4% 1.04 (1.02e1.07) 13,566,092
hypertension alone
Placental abruption/ 3037 6.0  4.8 6.6% 1.28 (1.26e1.29) 3.3  9.9 8.2% 1.14 (1.07e1.20) 5,101,735
infarction alone
More than one 9455 7.0  3.9 12.9% 1.48 (1.47e1.49) 3.9  13.9 9.6% 1.22 (1.18e1.26) 26,723,801
placental syndrome
condition
PS and adverse infant
outcomes
No PS, no PTB, 222,755 4.6  2.5 1.2% 1.00 (Reference) 2.5  8.1 5.7% 1.00 (Reference) Reference
no SGA
PS alone 25,067 5.6  2.5 4.4% 1.21 (1.20e1.21) 3.1  9.2 7.7% 1.09 (1.07e1.11) 29,851,037
PTB/SGA alone 43,218 5.1  4.6 4.2% 1.11 (1.11e1.12) 3.4  11.1 8.1% 1.16 (1.14e1.18) 39,303,314
PS and PTB/SGA 11,646 7.2  4.9 14.8% 1.55 (1.54e1.56) 4.2  16.0 10.1% 1.34 (1.31e1.38) 38,217,514
CVD
No 299,985 4.8  3.0 2.4% 1.00 (Reference) 2.6  8.0 6.1% 1.00 (Reference) Reference
Yes 2701 5.1  5.1 3.4% 1.06 (1.04e1.08) 17.4  45.3 34.5% 3.87 (3.69e4.06) 21,217,327
PS and CVD
No PS or CVD 263,704 4.7  2.9 1.7% 1.00 (Reference) 2.6  7.8 5.8% 1.00 (Reference) Reference
PS, did not 36,281 6.1  3.5 7.7% 1.29 (1.28e1.30) 3.2  9.2 8.1% 1.12 (1.10e1.14) 60,187,277
develop CVD
No PS, developed 2269 4.8  5.2 2.3% 1.05 (1.03e1.07) 16.0  40.3 33.7% 3.71 (3.52e3.90) 16,227,502
CVD
PS, developed 432 6.4  4.2 9.3% 1.36 (1.31e1.42) 24.6  65.4 39.1% 5.13 (4.56e5.77) 5,280,306
CVD
CI, confidence interval; CVD, cardiovascular disease; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
a
Unadjusted costs associated with direct medical care in inpatient or emergency department setting, per mother, in thousands of 2010 US dollars; b Cost ratios presented were estimated from
models with total cost as outcome, were constructed using generalized linear model with gamma distribution and log link, and were adjusted for maternal age, race/ethnicity, nativity, education,
income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex; c Represents hospital costs associated with
direct medical care that could be saved by converting each nonreference level to reference leveleestimated by first calculating adjusted difference in cost between each nonreference group and
reference group, and then multiplying that difference by total no. of individuals in that group. Excess costs during index delivery were combined with excess costs from other, nondelivery encounters.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

After adjusting for confounders, this cost encounters, respectively. Women and to those who did not develop CVD. Pre-
was 55% and 34% higher than women girls who then developed CVD experi- vention of PS in the 36,713 nulliparous
and girls without PS, SGA, and/or PTB enced a 5-fold increase in health caree women and girls with PS in our study
during the index delivery and follow-up related costs during follow-up, compared population would result in estimated

484.e7 American Journal of Obstetrics & Gynecology OCTOBER 2016

ajog.org
savings of >$63 million in the direct costs
of inpatient and emergency care during
the average 5-year follow-up period.
Our findings were robust to alterna-
tive eligibility criteria and model inputs.
We observed no significant differences
in observed associations between PS
and either CVD or hospital utilization
indices when we restricted our analyses
to women and girls without any
subsequent deliveries observed during
follow-up (Supplemental Tables 1-3).
Furthermore, when we analyzed charges
instead of costs, which permitted the
consideration of outpatient encounters
in addition to inpatient and emergency
department visits, the adjusted measures
of association (ie, charge ratios) were
only slightly attenuated compared to the
cost ratios calculated in our base case
analyses (Supplemental Table 4). Finally,
in an effort to distinguish differences in
CVD risk between those mothers expe-
riencing spontaneous vs induced PTB,
we analyzed these as separate exposures
and found almost no difference in CVD
risk when considered separately vs a
single exposure group.
Comment
This study demonstrated an increased
CVD risk in short-term follow-up
among women and girls with PS. The
highest risk of short-term CVD was
among women and girls with a PS
combined with PTB and/or SGA. These
findings suggest that maternal PS com-
bined with adverse fetal outcomes of
PTB or SGA may confer additional CVD
risk as soon as 3-5 years after delivery.
Furthermore, the study noted an in-
crease in health care utilization and costs
among those women and girls with a PS
and subsequent CVD.
Our findings of an association be-
tween maternal PS and short-term CVD
risk are similar to prior reports.4,21-24
The cardiovascular health after maternal
placental syndromes (CHAMPS) study
utilized a population-based retrospective
cohort with a median follow-up of 8.7
years. The authors identified an increased
risk of CVD among women with a PS
(HR, 2.0; 95% CI, 1.7e2.2); the risk
further increased among women with PS
with poor fetal growth (HR, 3.1; 95% CI,
OBSTETRICS
2.2e4.5)4. Our findings indicate that
the risk may occur earlier after delivery
and during their reproductive lifespan.
Postpartum interventions aimed at
improving cardiovascular profiles among
these patients may decrease subsequent
pregnancy morbidities.
The current study provides additional
insight into the severity of preterm PS
and demonstrates the additive effect of
PTB, SGA, and PS on the future risk of
CVD. Prior reports establish a relation-
ship between PTB and CVD risk.11 In
contrast, studies of the association
between PTB and maternal PS are
limited. Lykke et al22 found a relation-
ship between maternal PS, PTB, and
SGA offspring and mortality from car-
diovascular causes over a median follow-
up of 14.6 years. The current study noted
similar risks in a shorter follow-up
period. These findings may support the
theory of a more severe disease among
women with PTB or severe placental
disease leading to growth restriction.
No prior information exists regarding
the impact of maternal PS and subse-
quent CVD on future health care costs
and utilization unrelated to pregnancy.
The increases in cost among women with
CVD and maternal PS noted in this
study lend support for the necessity of
early risk factor recognition and inter-
vention in an effort to prevent future
CVD.
Our findings have several limitations.
The nature of the retrospective cohort
using ICD-9-CM diagnosis codes relies
on accurate coding of the exposures
and outcomes. The database does not
identify a uniform definition of pre-
eclampsia, eclampsia, and gestational
hypertension. Therefore provider and
coder discretion may lead to a nonuni-
form cohort. Furthermore, due to our
reliance on data linkage, it was not
possible to differentiate between medical
encounters and outcomes that did not
occur and those that happened but were
not captured by data linkage (ie, missing
data out migration). However, the effect
of out migration on our results is likely
negligible, since only about 3.6% of
those aged 18-49 years move to another
state after living in Florida during the
previous year.25 As out migration rates
OCTOBER 2016 American Journal of Obstetrics & Gynecology
Original Research
are likely nondifferential across exposure
groups, any bias in our reported mea-
sures of association is likely to be small
and toward the null. Inclusion criteria
were limited to data collected following
the inclusion of prepregnancy BMI in
the data set, leading to a median follow-
up of 4.9 years.
Although PTB and SGA offspring
were used as an exposure, in the final
analysis we did not discern between
spontaneous vs induced PTB. When
analyzed separately almost no difference
in CVD risk was noted and therefore we
utilized PTB as a single exposure. Our
findings support prior literature noting
increases in CVD risk factors following
all causes of PTB.26 Lastly, we conducted
cost analyses from a third-party payer
perspective and represent only the direct
medical costs from specific revenue-
generating centers associated with the
institutional portion of the hospital stay.
Our estimates of the excess maternal and
infant costs associated with PS, adverse
pregnancy outcomes, and CVD are
conservative and likely understated the
potential savings to society.
Our study included several strengths.
The database used included a large
number of women and girls with the
identified exposures. The ability to
adjust for multiple CVD risk factors,
including prepregnancy BMI, allowed
for a more accurate picture of disease
risk. The cohort included a large per-
centage of overweight and obese women
as well as racial/ethnic minorities, which
made the findings applicable to these
populations. Finally, our unprecedented
evaluation of hospital costs and health
care utilization further demonstrated the
health care burden among this group of
women.
Our findings show an increase in
CVD risk among women and girls with
maternal PS. PTB and/or SGA offspring
further increase CVD risk among
women with PS. The short-term nature
of these findings suggests an increase in
CVD among women and girls in subse-
quent pregnancies. Further studies may
determine if early identification and
intervention will be effective in the pre-
vention of CVD and future maternal
morbidity. n
484.e8
Original Research OBSTETRICS
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Author and article information
From the Division of Maternal-Fetal Medicine, Depart-
ment of Obstetrics and Gynecology, College of Medicine
(Drs Cain and Louis), and Birth Defects Surveillance
Program, Department of Community and Family Health,
College of Public Health (Mr Tanner and Dr Kirby), Uni-
versity of South Florida, Tampa, FL; and Department of
Family and Community Medicine, Baylor College of
Medicine, Houston, TX (Drs Salemi and Salihu).
Received Jan. 13, 2016; revised April 27, 2016;
accepted May 26, 2016.
Supported by grant number R01HS019997 from the
Agency for Healthcare Research and Quality, which
permitted the creation of the study database.
The authors report no conflict of interest.
The primary analyses used in this article were pre-
sented at the 35th annual meeting of the Society for
Maternal-Fetal Medicine, San Diego, CA, Feb. 2-7, 2014.
Corresponding author: Mary Ashley Cain, MD.
mcain@health.usf.edu
ajog.org OBSTETRICS Original Research

SUPPLEMENTAL TABLE 1
Comparison of hazard ratios and 95% confidence intervals representing association between placental syndromes
during current pregnancy and subsequent cardiovascular disease,a between women with and without
subsequent live birth during follow-up
Unadjusted model HR (95% CI) Adjusted model 3b HR (95% CI)
Entire study Excluding women with Entire study Excluding women with
population, subsequent live births, population, subsequent live births,
Exposure category n ¼ 302,686 n ¼ 189,342 n ¼ 302,686 n ¼ 189,342
Any PS
No 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
Yes 1.39 (1.25e1.54)c 1.40 (1.22e1.61)c 1.19 (1.07e1.32)c 1.18 (1.03e1.37)c
Nature/no. of PS conditions
No PS 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
c c c
Eclampsia/preeclampsia alone 1.60 (1.29e1.98) 1.45 (1.07e1.97) 1.42 (1.14e1.76) 1.29 (0.95e1.75)
Gestational hypertension alone 1.18 (1.01e1.37)c 1.24 (1.01e1.53)c 0.99 (0.85e1.16) 1.04 (0.84e1.28)
Placental abruption/infarction alone 1.22 (0.86e1.73) 1.32 (0.84e2.08) 1.09 (0.76e1.57) 1.18 (0.74e1.88)
c c c
More than one placental syndrome condition 1.69 (1.42e2.01) 1.66 (1.31e2.10) 1.43 (1.20e1.70) 1.38 (1.09e1.76)c
PS and adverse infant outcomes
No PS, no PTB, no SGA 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
c c
PS alone 1.29 (1.14e1.47) 1.29 (1.09e1.54) 1.08 (0.95e1.23) 1.07 (0.90e1.29)
c c
PTB/SGA alone 1.16 (1.04e1.29) 1.20 (1.04e1.39) 1.07 (0.96e1.20) 1.14 (0.99e1.32)
c c c
PS and PTB/SGA 1.70 (1.45e2.00) 1.76 (1.42e2.17) 1.45 (1.24e1.71) 1.51 (1.21e1.87)c
CI, confidence interval; HR, hazard ratio; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
a
Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system;
b
Crude model þ adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes,
tobacco use, drug use, and infant sex; c HRs statistically significantly different from 1.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

OCTOBER 2016 American Journal of Obstetrics & Gynecology 484.e10

Original Research OBSTETRICS ajog.org

SUPPLEMENTAL TABLE 2
Frequency and length of stay during inpatient, outpatient, and emergency department encounters, based on
presence/absence of placental syndrome, adverse pregnancy outcomes, and cardiovascular disease,a restricted
to women without subsequent live birth during follow-up (n [ 189,342)
All nondelivery hospital
encountersb LOS: index delivery LOS: other encountersb
Exposure/outcome category Mean  SD 6 Visits Mean  SD 6 d Mean  SD 21 d
Any PS
No 2.5  4.7 13.0% 2.8  1.9 1.3% 3.1  7.6 1.8%
Yes 3.0  5.2 16.2% 3.7  2.7 9.4% 3.9  9.0 2.5%
Nature/no. of PS conditions
No PS 2.5  4.7 13.0% 2.8  1.9 1.3% 3.1  7.6 1.8%
Eclampsia/preeclampsia alone 3.0  5.1 16.8% 4.1  2.8 13.1% 4.1  9.9 3.1%
Gestational hypertension alone 2.8  4.9 15.0% 3.2  1.6 3.7% 3.6  8.2 2.2%
Placental abruption/infarction alone 3.0  5.7 15.7% 3.8  4.8 7.6% 3.7  7.0 2.4%
More than one placental syndrome condition 3.2  5.6 18.1% 4.4  3.1 17.9% 4.2  10.3 2.8%
PS and adverse infant outcomes
No PS, no PTB, no SGA 2.4  4.4 12.3% 2.7  1.0 0.6% 3.0  7.0 1.6%
PS alone 2.8  4.8 15.5% 3.3  1.6 4.5% 3.6  7.4 2.1%
PTB/SGA alone 3.0  5.8 16.5% 3.2  4.0 5.2% 3.8  10.1 2.7%
PS and PTB/SGA 3.3  5.8 17.7% 4.6  4.0 19.8% 4.5  11.7 3.3%
CVD
No 2.5  4.5 13.1% 2.9  2.0 2.3% 3.1  7.1 1.7%
Yes 10.8  14.8 56.6% 3.1  3.9 3.4% 17.7  24.6 21.5%
PS and CVD
No PS or CVD 2.4  4.5 12.7% 2.8  1.8 1.3% 3.0  7.0 1.7%
PS, did not develop CVD 2.9  5.0 15.8% 3.7  2.7 9.4% 3.7  7.9 2.3%
No PS, developed CVD 10.8  15.2 56.6% 3.0  4.1 1.6% 17.1  33.4 20.9%
PS, developed CVD 10.8  12.5 56.4% 3.9  2.7 12.8% 20.9  40.1 24.8%
CVD, cardiovascular disease; LOS, length of stay; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
a
Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system;
b
Includes all inpatient, outpatient, and emergency department encounters, excluding all hospitalizations in which delivery occurred.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

484.e11 American Journal of Obstetrics & Gynecology OCTOBER 2016

ajog.org OBSTETRICS Original Research

SUPPLEMENTAL TABLE 3
Comparison of hospital costs associated with direct medical care during inpatient, outpatient, and emergency
department encounters, based on presence/absence of placental syndrome, adverse pregnancy outcomes, and
cardiovascular disease,a between women with and without subsequent live birth during follow-up
Costs accrued during index delivery Costs accrued during nondelivery encounters
Cost ratio (95% CI)b Cost ratio (95% CI)b
Entire study Excluding women with Entire study Excluding women with
population, subsequent live births, population, subsequent live births,
Exposure/outcome category n ¼ 302,686 n ¼ 189,342 n ¼ 302,686 n ¼ 189,342
Any PS
No 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
c c c
Yes 1.29 (1.28e1.30) 1.30 (1.29e1.31) 1.14 (1.12e1.16) 1.13 (1.10e1.15)c
Nature/no. of PS conditions
No PS 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
c c
Eclampsia/preeclampsia alone 1.45 (1.43e1.46) 1.45 (1.43e1.47) 1.31 (1.26e1.36)c 1.32 (1.26e1.39)c
Gestational hypertension alone 1.14 (1.13e1.14)c 1.14 (1.13e1.15)c 1.04 (1.02e1.07)c 1.04 (1.01e1.08)c
Placental abruption/infarction alone 1.28 (1.26e1.29)c 1.30 (1.27e1.32)c 1.14 (1.07e1.20)c 1.01 (0.94e1.09)
c c
More than one placental syndrome 1.48 (1.47e1.49) 1.49 (1.47e1.50) 1.22 (1.18e1.26)c 1.17 (1.13e1.22)c
condition
PS and adverse infant outcomes
No PS, no PTB, no SGA 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
c c c
PS alone 1.21 (1.20e1.21) 1.21 (1.20e1.22) 1.09 (1.07e1.11) 1.05 (1.02e1.08)c
PTB/SGA alone 1.11 (1.11e1.12)c 1.12 (1.12e1.13)c 1.16 (1.14e1.18)c 1.15 (1.13e1.18)c
PS and PTB/SGA 1.55 (1.54e1.56)c 1.57 (1.55e1.58)c 1.34 (1.31e1.38)c 1.36 (1.31e1.42)c
CVD
No 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
c c c
Yes 1.06 (1.04e1.08) 1.08 (1.06e1.10) 3.87 (3.69e4.06) 4.57 (4.28e4.88)c
PS and CVD
No PS or CVD 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
c c c
PS, did not develop CVD 1.29 (1.28e1.30) 1.30 (1.29e1.31) 1.12 (1.10e1.14) 1.11 (1.08e1.13)c
No PS, developed CVD 1.05 (1.03e1.07)c 1.09 (1.06e1.11)c 3.71 (3.52e3.90)c 4.42 (4.12e4.76)c
PS, developed CVD 1.36 (1.31e1.42)c 1.31 (1.24e1.38)c 5.13 (4.56e5.77)c 5.75 (4.89e6.77)c
CI, confidence interval; CVD, cardiovascular disease; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
a
Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system;
b
Crude model þ adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes,
tobacco use, drug use, and infant sex; c Cost ratios statistically significantly different from 1.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

OCTOBER 2016 American Journal of Obstetrics & Gynecology 484.e12

Original Research OBSTETRICS ajog.org

SUPPLEMENTAL TABLE 4
Comparison of charges (for inpatient, outpatient, and emergency department) vs costs (for inpatient
and emergency department only)
Index delivery Nondelivery encounters
Cost ratio (95% CI)b Cost ratio (95% CI)b
Exposure/outcome category Charges Costs Charges Costs
Any PS
No 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
c c c
Yes 1.40 (1.39e1.40) 1.29 (1.28e1.30) 1.12 (1.10e1.14) 1.14 (1.12e1.16)c
Nature/no. of PS conditions
No PS 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
Eclampsia/preeclampsia alone 1.60 (1.59e1.62)c 1.45 (1.43e1.46)c 1.22 (1.18e1.27)c 1.31 (1.26e1.36)c
Gestational hypertension alone 1.19 (1.19e1.20)c 1.14 (1.13e1.14)c 1.05 (1.03e1.07)c 1.04 (1.02e1.07)c
Placental abruption/infarction alone 1.35 (1.33e1.37)c 1.28 (1.26e1.29)c 1.14 (1.08e1.20)c 1.14 (1.07e1.20)c
More than one placental syndrome condition 1.65 (1.63e1.67)c 1.48 (1.47e1.49)c 1.18 (1.15e1.21)c 1.22 (1.18e1.26)c
PS and adverse infant outcomes
No PS, no PTB, no SGA 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
c c c
PS alone 1.29 (1.28e1.30) 1.21 (1.20e1.21) 1.09 (1.07e1.11) 1.09 (1.07e1.11)c
PTB/SGA alone 1.11 (1.11e1.12)c 1.11 (1.11e1.12)c 1.14 (1.12e1.15)c 1.16 (1.14e1.18)c
c c c
PS and PTB/SGA 1.70 (1.69e1.72) 1.55 (1.54e1.56) 1.27 (1.24e1.30) 1.34 (1.31e1.38)c
CVDa
No 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
c c c
Yes 1.06 (1.04e1.08) 1.06 (1.04e1.08) 3.46 (3.31e3.62) 3.87 (3.69e4.06)c
PS and CVD
No PS or CVD 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
c c c
PS, did not develop CVD 1.40 (1.39e1.40) 1.29 (1.28e1.30) 1.11 (1.09e1.13) 1.12 (1.10e1.14)c
No PS, developed CVD 1.05 (1.03e1.07)c 1.05 (1.03e1.07)c 3.40 (3.24e3.56)c 3.71 (3.52e3.90)c
c c c
PS, developed CVD 1.46 (1.40e1.53) 1.36 (1.31e1.42) 4.13 (3.69e4.61) 5.13 (4.56e5.77)c
CI, confidence interval; CVD, cardiovascular disease; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
a
Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular
system; b Adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes,
tobacco use, drug use, and infant sex; c Cost ratios statistically significantly different from 1.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

484.e13 American Journal of Obstetrics & Gynecology OCTOBER 2016

ajog.org OBSTETRICS Original Research

APPENDIX
Diagnosis and procedure codes used to identify selected clinical and behavioral conditions
Condition ICD-9-CM codea Birth certificate indicatorb
c
Placental syndromes
Preeclampsia 642.4x, 642.5x No
Eclampsia 642.6x Yes
Gestational hypertension 642.3x Yes
Placental infarction 656.7x No
Placental abruption 641.2x No
d
Cardiovascular outcomes
Coronary heart disease 410e414x, 429.2, V45.81, V45.82 No
Cerebrovascular disease 430e438x No
Peripheral artery disease 440.2x, 440.3x, 440.8, 440.9, 443.9 No
Congestive heart failure 398.91, 402.01, 402.11, 402.91, 404.01, 404.03, No
404.11, 404.13, 404.91, 404.93, 428x
Cardiac or peripheral artery revascularization 36.0x, 36.1x, 36.3x, 37.41, 37.60, 37.91, 37.95, No
procedure 37.99, 38.1x, 38.3x, 38.4x, 39.22, 39.23, 39.62,
39.64, 39.65, 39.66, 39.71, 39.73, 39.74
Clinical comorbiditiese
Chronic hypertension 401e405x, 642.0x, 642.1x, 642.2x, 642.7x Yes
Prepregnancy diabetes 249x, 250x, 648.0x Yes
Renal disease 580e589x, 646.2x No
Hyperlipidemia 272.0, 272.1, 272.2, 272.3, 272.4 No
Migraine 346x No
Systemic lupus erythematosus 710.0 No
c
Behavioral factors
Tobacco use 305.1, 649.0x, 989.84 Yes
Alcohol use 291x, 303x, 305.0x, 425.5, 760.71, V11.3 Yes
Drug use 292.0x, 292.1x, 292.2x, 292.8x, 304x, 305.2x, 305.3x, No
305.4x, 305.5x, 305.6x, 305.7x, 305.9x, 648.3x,
655.5x, 760.72, 779.5, 760.75, 965.00, 965.02,
E935.1, E850.1
ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.
a
Presence of 1 of listed codes serves as positive indication of conditione“x” indicates that all subcodes with listed code prefix are part of the condition’s definition; b Reflects use of variable on birth
certificate to supplement identification through ICD-9-CM codeseif used, positive indication on birth certificate serves as positive indication of condition regardless of presence of 1 of listed ICD-9-
CM codes; c Assessment made using only index maternal delivery hospitalization; d Assessment made using 5-y history relative to admission date of index maternal delivery hospitalization (for
exclusion criteria) or using all encounters 90 d postdischarge from index delivery hospitalization (for determination of primary study outcome); e Assessment made using 5-y history relative to
admission date of index maternal delivery hospitalization.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

OCTOBER 2016 American Journal of Obstetrics & Gynecology 484.e14