Obstetrics: Original Research
Perinatal and Peripartum Outcomes in
Vanishing Twin Pregnancies Achieved by In
Vitro Fertilization
Phillip A. Romanski, MD, Daniela A. Carusi, MD, MSc, Leslie V. Farland, ScD, Stacey A. Missmer,
Daniel J. Kaser, MD, Brian W. Walsh, MD, Catherine Racowsky, PhD, and Paula C. Brady, MD
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OBJECTIVE: To compare perinatal and peripartum out-
comes of vanishing twin gestations with singleton and
dichorionic twin gestations in pregnancies conceived by
in vitro fertilization.
METHODS: We conducted a retrospective cohort study
of vanishing twin pregnancies after fresh and cryopre-
served autologous in vitro fertilization cycles performed
at our institution from 2007 to 2015. Singleton, dichor-
ionic twin, and dichorionic twin pregnancies with spon-
taneous reduction to one by 14 weeks of gestation
(vanishing twins) were included. Analysis was restricted
to patients with a live birth delivery at our institution at
or beyond 24 weeks of gestation. The primary outcomes
were gestational age and birth weight at delivery;
secondary outcomes included peripartum morbidities.
A subanalysis further differentiated the vanishing twin
pregnancies between those in which demise of the twin
occurred before compared with after identification of
fetal cardiac activity. Logistic regression models were
used to estimate the adjusted odds ratio (OR) with a 95%
CI of outcomes.
From the Department of Obstetrics, Gynecology and Reproductive Biology,
Brigham and Women’s Hospital and Harvard Medical School, and the Depart-
ment of Epidemiology, Harvard T.H. Chan School of Public Health, Boston,
Massachusetts; the Department of Obstetrics, Gynecology, and Reproductive Biol-
ogy, College of Human Medicine, Michigan State University, Grand Rapids,
Michigan; and Reproductive Medicine Associates of New Jersey, Basking Ridge,
New Jersey.
The authors thank Cassandra Thomas for her assistance in data acquisition for
this study.
Each author has indicated that he or she has met the journal’s requirements for
authorship.
Corresponding author: Phillip A. Romanski, MD, Department of Obstetrics,
Gynecology and Reproductive Biology, Brigham & Women’s Hospital, 75 Fran-
cis Street, Boston, MA 02115; email: promanski@partners.org.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2018 by American College of Obstetricians and Gynecologists. Published by
Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0029-7844/18
VOL. 131, NO. 6, JUNE 2018
Copyright Ó by American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
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ScD,
RESULTS: There were 1,189 pregnancies that met inclu-
sion criteria (798 singleton, 291 twin, and 100 vanishing
twin). The mean gestational age at birth and birth
weights were 38.662.3 weeks of gestation and
3,2076644 g in singleton pregnancies, 35.562.7 weeks
of gestation and 2,5396610 g in twin pregnancies, and
38.561.8 weeks of gestation and 3,1756599 g in vanish-
ing twin pregnancies. When compared with twins, those
with a vanishing twin had lower odds of preterm delivery
(OR 0.13, 95% CI 0.07–0.23; adjusted OR 0.12, 95% CI
0.07–0.22) and small-for-gestational-age birth weight
(OR 0.24, 95% CI 0.13–0.45; adjusted OR 0.14, 95% CI
0.07–0.28).
CONCLUSION: In pregnancies conceived by in vitro
fertilization that progress to at least 24 weeks of
gestation, vanishing twin and singleton pregnancies had
similar perinatal and peripartum outcomes. Both were
significantly better than twin pregnancies.
(Obstet Gynecol 2018;131:1011–20)
DOI: 10.1097/AOG.0000000000002595
T he vanishing twin phenomenon, first identified by
Stoeckel in 1945, describes the spontaneous reduc-
tion of one fetus in a twin pregnancy.1 Recent studies
have estimated that a vanishing twin occurs in 14.8–
36% of twin pregnancies resulting from in vitro fertil-
ization (IVF).2–4 As a result of the frequent and early
gestation ultrasonographic evaluation of IVF preg-
nancies, this population affords an excellent opportu-
nity to evaluate outcomes after a vanishing twin.
Clinical outcomes of surviving singletons in
vanishing twin pregnancies have become an area of
debate within the literature. Some studies demonstrate
an increased risk of low birth weight and preterm
birth when compared with singletons,5–8 whereas
others report no difference in perinatal outcomes.3,9,10
These discrepancies may be the result of differences in
exclusion criteria regarding gestational age of the
OBSTETRICS & GYNECOLOGY 1011
vanishing twin at demise and of the remaining single-
ton at birth. Moreover, findings may be complicated
by the influence of IVF techniques on perinatal out-
comes, such as the association of cryopreserved (as
compared with fresh) embryos with large-for-
gestational-age (LGA) birth weight and of day 5
(as compared with day 3) embryos with preterm
birth.11–14
Peripartum complications are infrequently evalu-
ated in studies of pregnancies with a vanishing twin,
and consideration of maternal morbidity is vital to
elucidating the full peripartum and perinatal risks
after a vanishing twin.6,7 The present study was per-
formed to help address these knowledge gaps. We
assessed vanishing twin, singleton, and twin pregnan-
cies resulting from IVF in our program to determine
whether the perinatal and peripartum outcomes more
closely resemble those of singleton or twin
pregnancies.
MATERIALS AND METHODS
This study was approved by the Partners Human
Research Committee at the Brigham and Women’s
Hospital (Protocol #2016P000545).
This was a retrospective cohort study of women
undergoing their first IVF cycle at the Brigham and
Women’s Hospital from January 1, 2007, to Decem-
ber 31, 2015. Data were collected from our prospec-
tively maintained departmental database and the
hospital electronic medical record system. In vitro
fertilization cycle and embryology data are entered
into the database prospectively by clinicians and em-
bryologists. This database is routinely audited twice
yearly. The peripartum database is updated prospec-
tively by obstetric clinicians and nurses directly
involved in patient care and serves as the official
delivery record for the hospital. Key data points and
missing data, including patient demographics and
pregnancy data and outcomes, were verified in the
electronic medical record.
Only those women who had fresh or cryopre-
served autologous day 3 or day 5 embryo(s) trans-
ferred during the study period and who delivered
a liveborn neonate at our institution at or beyond 24
weeks of gestation were included. Our infertility
center has a large referral area and many of our
patients choose to deliver at their local hospital. To
ensure data validity, we limited our study population
to patients with directly verifiable outcomes in our
electronic medical record. As a result of the variability
in research and clinical definitions of viability before
24 weeks of gestation, the resultant variability in
clinical management in this range, and the overall
1012 Romanski et al Pregnancy Outcomes After Vanishing Twin
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poor prognosis for deliveries before 24 weeks of
gestation, we chose to define live birth as deliveries
occurring at or beyond the broadly accepted thresh-
old of viability (24 weeks of gestation or greater).
Gestational age was calculated as the interval from
embryo transfer plus 2 weeks and the duration of
embryo culture (3 or 5 days). Additional exclusion
criteria were use of preimplantation genetic diagnosis
or screening, a mixed source of fresh and cryopre-
served embryos or both day 3 and 5 embryos,
gestational carrier or donor oocyte cycles, and ges-
tations with monochorionic twins or selective fetal
reduction. Women who delivered a singleton from
either a vanishing twin gestation or a singleton
gestation and those who delivered dichorionic–
diamniotic twins were identified and analyzed in
three groups: vanishing twin, singleton, and twin.
A vanishing twin pregnancy was defined as
having two gestational sacs recorded on ultrasonog-
raphy with the demise of one twin at or before 14
weeks of gestation or the absence of identification of
either a yolk sac or embryonic pole in one of the
gestational sacs with a resulting singleton live birth at
or beyond 24 weeks of gestation. At the time of
vanishing twin diagnosis, the gestational age in days
was recorded as was the furthest documented devel-
opmental stage (gestational sac only, gestational sac
with yolk sac, presence of a fetal pole without cardiac
activity, or presence of a fetal pole with cardiac
activity). For subanalyses, vanishing twin pregnancies
were further stratified into two groups according to
whether they were diagnosed before compared with
after the identification of fetal cardiac activity. A
singleton pregnancy was defined as having only one
gestational sac ever documented by early ultrasonog-
raphy (at 5–8 weeks of gestation) and which resulted
in a singleton live birth at or beyond 24 weeks of
gestation. A twin pregnancy was defined as having
only two gestational sacs documented by early ultra-
sonography (5–8 weeks of gestation) and which re-
sulted in a twin live birth at or beyond 24 weeks of
gestation.
Stimulation protocols for fresh and cryopreserved
embryo transfer cycles are listed in Appendix 1,
available online at http://links.lww.com/AOG/
B87.15–18 Approximately 2 weeks after embryo trans-
fer, patients had at least two serum human chorionic
gonadotropin (hCG) levels checked at 2-day intervals.
If at any point the hCG level rise was below 66%, an
early ultrasonogram was obtained at approximately 5
weeks of gestation, with further monitoring and man-
agement dictated by clinical findings. From January 1,
2007, to November 1, 2012, a pelvic ultrasonogram
OBSTETRICS & GYNECOLOGY
was obtained at both 6 and 8 weeks of gestation if the
serial serum hCG levels rose normally (greater than
66% in 2 days). After November 2012, patients with
such normally rising hCG levels underwent a single
pelvic ultrasonogram at 7–8 weeks of gestation as
a result of a change in practice.
Preterm birth was defined as delivery before 37
weeks of gestation. Birth weight (grams) was re-
corded as both a continuous variable and as a cate-
gorical variable as follows: low birth weight (less than
2,500 g), appropriate birth weight (2,500–4,000 g),
and high birth weight (greater than
4,000 g). Furthermore, gestational age-specific cate-
gorization of birth weight (Z-scores) were calculated
using published data derived from U.S. birth certifi-
cates and corrected for gestational age and neonatal
sex.19 These scores were used to qualify a neonate as
small for gestational age (SGA), appropriate for ges-
tational age, or LGA. In twin pregnancies, the birth
weight and growth category of each twin were re-
corded to identify whether either twin was LGA or
SGA. A twin pregnancy was categorized as appropri-
ate birth weight or appropriate for gestational age
only if both twins were either appropriate birth
weight or appropriate for gestational age, respec-
tively. To calculate the mean birth weight of the
entire cohort of twin pregnancies, only the larger
twin in each pregnancy was included. This method
was chosen to identify how even the best grown twins
would compare with singleton and vanishing twin
birth weights. Had the smaller twin in each preg-
nancy also been included in the birth weight calcu-
lation, the mean birth weight of the twin group would
be smaller. Good-quality cleavage-stage embryos
were defined as having seven cells or more, less than
10% fragmentation, and perfect or moderate asym-
metry of blastomeres. Good-quality blastocysts were
defined as expanded, hatching, or hatched blasto-
cysts with fair- or good-quality inner cell mass or
trophectoderm.
Maternal records were evaluated for peripartum
complications including gestational hypertensive dis-
eases (gestational hypertension or preeclampsia), ges-
tational diabetes mellitus, estimated blood loss,
postpartum hemorrhage, abruption, primary cesarean
delivery, abnormal placentation (placenta previa with
the placental edge coming within 2.0 cm of the
internal os on final ultrasonogram; or placenta accre-
ta, increta, or percreta diagnosed clinically at the time
of delivery or on pathology review), and hysterec-
tomy. The placentas of all deliveries with a suspected
abruption were evaluated by a pathologist, and an
abruption was only included in the analyses if noted
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on the pathology report as a pathologic diagnosis.
Postpartum hemorrhage was defined as an estimated
blood loss greater than 1,500 mL or if the patient
received a red blood cell transfusion.
Logistic regression analysis was used to estimate the
odds ratio (OR) and 95% CI of patient demographics,
IVF cycle characteristics, perinatal outcomes, and peri-
partum outcomes associated with vanishing twin live
births (referent) as compared with singleton live births
and compared with twin live births separately. The
primary outcomes were gestational age and birth weight
at delivery; secondary outcomes included peripartum
morbidities. Patient age at oocyte retrieval was included
a priori in all analyses. Further variables were retained in
the regression model if their addition to the base model
changed the OR from the crude model by 10% or
more.20 Accordingly, logistic regression analysis of
patient and cycle characteristics was adjusted for the
number of embryos transferred to estimate the adjusted
OR and 95% CI of a vanishing twin. Additional cova-
riates that were tested as confounders of the relationship
between vanishing twin and perinatal outcomes
included gestational hypertensive diseases, gestational
diabetes mellitus, body mass index (calculated as weight
(kg)/[height (m)]2), assisted hatching, day of embryo
transfer, and cryopreserved or fresh transfer; these did
not meet criteria for inclusion in the final adjusted
model. Birth weight analyses were adjusted a priori for
gestational age at birth and neonatal sex given the
known effect of these variables on birth weight.21 Statis-
tical analyses were performed using SAS 9.3.
RESULTS
After excluding 1,698 patients because of delivery at
an outside institution and 51 patients as a result of
a miscarriage occurring between 14 and 24 weeks of
gestation (two were vanishing twin pregnancies), this
study consisted of 100 vanishing twin pregnancies,
798 singleton pregnancies, and 291 twin pregnancies
(Fig. 1). Demographic characteristics for patients in
each of the three exposure groups are shown in
Table 1. Vanishing twins occurred in patients who
were older at oocyte retrieval (37.263.7 years) com-
pared with patients with singletons (35.263.8 years)
or twins (35.063.8 years). Patients with vanishing twin
pregnancies had more embryos transferred (2.861.4)
than those with singleton pregnancies (2.161.2). The
proportion of day 3 embryo transfers was 85% in van-
ishing twin pregnancies, 74% in singleton pregnan-
cies, and 77% in twin pregnancies. Additionally, the
proportion of fresh embryo transfers was 81% in van-
ishing twin pregnancies, 79% in singleton pregnan-
cies, and 82% in twin pregnancies.
Pregnancy Outcomes After Vanishing Twin 1013
Fig. 1. Flowchart for all eligible embryo transfers. *Miscarriages between 14 and 24 weeks of gestation (n551); vanishing
twin (n52).
Romanski. Pregnancy Outcomes After Vanishing Twin. Obstet Gynecol 2018.

Among all vanishing twin pregnancies, the gesta- of patients by the furthest developmental stage docu-
tional age by IVF dating at demise ranged from 41 to 85 mented before identification of a vanishing twin were:
days with a mean of 59.2610.9 days. The distributions 15 patients (15%) had only a gestational sac; 21 (21%) had

Table 1. Demographic Characteristics In Vanishing Twin, Singleton, and Twin Pregnancies

Vanishing Twin Pregnancy Singleton Pregnancy Twin Pregnancy

Characteristic (n5100) (n5798) (n5291)

Patient age at retrieval (y) 37.263.7 35.263.8 35.063.8

BMI (kg/m2)
Less than 18.50 5 (5.0) 24 (3.0) 9 (3.1)
18.5–24.99 62 (62.0) 476 (59.7) 178 (61.2)
25–29.99 23 (23.0) 163 (20.4) 68 (23.4)
30.00 or greater 10 (10.0) 135 (16.9) 36 (12.4)
Gravidity 1.0 (0.0–1.0) 0.0 (0.0–1.0) 0.0 (0.0–1.0)
Parity 0.0 (0.0–1.0) 0.0 (0.0–0.0) 0.0 (0.0–0.0)
Prior SAB 35 (35.0) 215 (26.9) 75 (25.8)
Primary infertility diagnosis
Male factor 23 (23.0) 262 (32.8) 99 (34.0)
Decreased ovarian reserve 12 (12.0) 129 (16.2) 30 (10.3)
Anovulatory 9 (9.0) 107 (13.4) 40 (13.8)
Tubal 15 (15.0) 66 (8.3) 25 (8.6)
Uterine 4 (4.0) 23 (2.9) 8 (2.8)
Endometriosis 11 (11.0) 47 (5.9) 18 (6.2)
Unknown 40 (40.0) 265 (33.2) 97 (33.3)
Fresh embryo transfer 81 (81.0) 631 (79.1) 238 (81.8)
Day 3 embryo transfer 83 (83.0) 588 (73.7) 224 (77.0)
No. of embryos transferred 2.0 (2.0–3.0) 2.0 (1.0–2.0) 2.0 (1.0–2.0)
No. of high-quality embryos 2.0 (0.5–2.0) 1.0 (0.0–2.0) 2.0 (2.0–2.0)
transferred
BMI, body mass index; SAB, spontaneous abortion.
Data are mean6SD, n (%), or median (interquartile range).

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Table 2. Perinatal and Peripartum Outcomes In Vanishing Twin Pregnancies Compared With Singleton and
Twin Pregnancies

Vanishing Twin vs Vanishing

Singleton Twin vs Twin
Pregnancies Pregnancies
Vanishing
Twin Singleton Twin Adjusted Crude Adjusted
Pregnancy Pregnancy Pregnancy Crude OR OR* OR OR*
Outcome (n5100) (n5798) (n5291) (95% CI) (95% CI) (95% CI) (95% CI)

Gestational 38.561.8 38.662.3 35.562.7 — — — —

age at
delivery (wk)
Gestational 17 (17.0) 118 (14.8) 178 (61.2) 1.18 1.18 0.13 0.12
age less (0.67–2.06) (0.67–2.06) (0.07–0.23) (0.07–0.22)
than 37 wk
Birth weight (g)†‡ 3,1756599 3,2076644 2,5396610 — — — —
Less than 2,500 13 (13.0) 82 (10.3) 118 (40.6) 1.30 1.90 0.24 2.34
(0.69–2.45) (0.83–4.35) (0.13–0.45) (0.87–6.33)
2,500–4,000 79 (79.0) 649 (81.3) 172 (59.1) 1.00 1.00 1.00 1.00
(referent) (referent) (referent) (referent)
Greater than 8 (8.0) 67 (8.4) 1 (0.3) 0.98 (0.45– 1.11 17.42 4.90
4,000 2.12) (0.50–2.45) (2.14–141.65) (0.36–66.8)
Z-score§
SGA 14 (14.0) 77 (9.7) 123 (42.3) 1.53 1.67 0.24 0.14
(0.83–2.28) (0.88–3.15) (0.13–0.45) (0.07–0.28)
AGA 78 (78.0) 657 (82.3) 165 (56.7) 1.00 1.00 1.00 1.00
(referent) (referent) (referent) (referent)
LGA 8 (8.0) 64 (8.0) 3 (1.0) 1.05 1.11 5.64 1.00
(0.83–2.84) (0.50–2.44) (1.46–21.85) (0.14–6.99)
Gestational 9 (9.0) 73 (9.2) 75 (25.8) 0.98 1.01 0.29 0.30
hypertensive (0.48–2.03) (0.48–2.11) (0.14–0.59) (0.14–0.64)
diseases
GDM 3 (3.0) 42 (5.3) 14 (4.8) 0.56 0.50 0.61 0.63
(0.17–1.83) (0.15–1.65) (0.17–2.18) (0.17–2.33)
Abnormal 5 (5.0) 48 (6.0) 13 (4.5) 0.82 0.85 1.13 0.96
placentationk (0.32–2.12) (0.33–2.21) (0.39–3.24) (0.32–2.86)
Estimated 554.66290.1 600.36433.8 806.26316.4 — — — —
blood loss
Postpartum 1 (1.0) 29 (3.6) 17 (5.8) 0.27 0.26 0.16 0.15
hemorrhage¶ (0.04–1.99) (0.03–1.91) (0.02–1.24) (0.02–1.14)
Abruption 4 (4.0) 25 (3.1) 21 (7.2) 1.29 1.23 0.54 0.52
(0.44–3.78) (0.41–3.67) (0.18–1.60) (0.17–1.60)
Primary 29 (29.0) 273 (34.2) 213 (73.2) 0.79 0.69 0.15 0.17
cesarean (0.50–1.24) (0.43–1.09) (0.09–0.25) (0.10–0.28)
delivery
Hysterectomy 0 (0) 4 (0.5) 2 (0.7) — — — —
OR, odds ratio; SGA, small for gestational age; AGA, appropriate for gestational age; LGA, large for gestational age, GDM, gestational
diabetes mellitus.
Data are mean6SD or n (%) unless otherwise specified.
* Adjusted a priori for patient age at retrieval.
†
Birth weight measurements additionally adjusted for gestational age at delivery and neonatal sex.
‡
For twins, the birth weight of the larger twin was utilized.
§
Refer to the text for explanation of Z-score.
k
Placenta previa, with the placental edge coming within 2.0 cm of the internal os on final ultrasonogram; or placenta accreta, increta, or
percreta diagnosed clinically at the time of delivery or on pathology review.
¶
Estimated blood loss greater than 1,500 mL or if the patient received a red blood cell transfusion.

a gestational sac with a yolk sac; nine (9%) had a fetal Perinatal outcomes in the three exposure groups
pole with no documented cardiac activity; and 55 (55%) of patients are shown in Table 2. The mean gesta-
had documented fetal cardiac activity. tional age at birth and birth weights were 38.662.3

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weeks and 3,2076644 g in singleton pregnancies,
35.562.7 weeks of gestation and 2,5396610 g in twin
pregnancies, and 38.561.8 weeks of gestation and
3,1756599 g in vanishing twin pregnancies, respec-
tively. Comparison of vanishing twin and singleton
pregnancies revealed a similar incidence of preterm
birth (17.0% vs 14.8%, respectively; OR 1.18, 95% CI
0.67–2.06; adjusted OR 1.18, 95% CI 0.67–2.06),
a similar incidence of SGA (14.0% vs 9.7%; OR
1.53, 95% CI 0.83–2.28; adjusted OR 1.67, 95% CI
0.88–3.15), and an identical incidence of LGA (8.0%
vs 8.0%; OR 1.05, 95% CI 0.83–2.84; adjusted OR
1.11, 95% CI 0.50–2.44) neonates. Conversely, gesta-
tional age and birth weight outcomes were all clini-
cally and statistically significantly different between
vanishing twin and twin pregnancies. Preterm births
occurred in 17% of vanishing twin pregnancies and
61% of twin pregnancies (OR 0.13, 95% CI 0.07–
0.23; adjusted OR 0.12, 95% CI 0.07–0.22); and neo-
nates were SGA in 14% of vanishing twin pregnancies
vs 42% of twin pregnancies (OR 0.24, 95% CI 0.13–
0.45; adjusted OR 0.14, 95% CI 0.07–0.28) (Fig. 2).
Peripartum complications in the three exposure
groups are shown in Table 2. When comparing van-
ishing twin with singleton pregnancies, no difference
was statistically significant; however, the study was
not powered to detect uncommon complications. In
contrast, when comparing vanishing twin and twin
pregnancies, gestational hypertensive diseases, post-
partum hemorrhage, and primary cesarean deliveries
were more common in twin pregnancies. Gestational
hypertensive diseases occurred in 25.8% of twin preg-
nancies as compared with 9% of vanishing twin
Romanski. Pregnancy Outcomes After Vanishing Twin. Obstet Gynecol 2018.
1016 Romanski et al Pregnancy Outcomes After Vanishing Twin
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pregnancies (OR 0.29, 95% CI 0.14–0.59; adjusted
OR 0.30, 95% CI 0.14–0.64); postpartum hemorrhage
occurred in 5.8% of twin pregnancies and 1.0% of
vanishing twin pregnancies (OR 0.16, 95% CI 0.02–
1.24; adjusted OR 0.15, 95% CI 0.02–1.14); primary
cesarean deliveries occurred in 73.2% of twin preg-
nancies and 29% of vanishing twin pregnancies (OR
0.15, 95% CI 0.09–0.25; adjusted OR 0.17, 95% CI
0.10–0.28). The odds of placental abnormalities (pla-
centa previa or accreta), abruption, and hysterectomy
were similar among all groups.
The demographic characteristics of vanishing
twin pregnancies further stratified by whether diag-
nosis occurred before (n545 [45%]) or after (n555
[55%]) documentation of fetal cardiac activity are
shown in Table 3. No patient characteristic or IVF
cycle characteristic was statistically significantly asso-
ciated with absence or presence of fetal cardiac activ-
ity before a vanishing twin diagnosis. The day of
embryo transfer was similar for both groups. Day 3
transfers occurred in 80% of pregnancies with vanish-
ing before fetal cardiac activity and 85% of pregnan-
cies with vanishing after fetal cardiac activity (OR
1.47, 95% CI 0.52–4.18; adjusted OR 1.76, 95% CI
0.60–5.23). Likewise, use of fresh embryo transfer was
similar between the two groups: 80% and 82% of pa-
tients, respectively (OR 1.13, 95% CI 0.41–3.06;
adjusted OR 1.21, 95% CI 0.43–3.38). Furthermore,
no differences in presence or absence of fetal cardiac
activity were observed regarding odds of adverse peri-
natal outcome or peripartum complications (Table 4).
Of note, however, there was a threefold increase in
odds of primary cesarean delivery in those
Fig. 2. Perinatal outcomes compar-
ing vanishing twin, singleton, and
twin pregnancies. Odds ratio was
controlled a priori for patient age at
retrieval. No significant differences
were found in perinatal outcomes
between vanishing twin and single-
ton pregnancies. *Preterm delivery
defined as delivery before 37 weeks
of gestation. †Small for gestational
age calculated using Z-score, which
is a gestational age-specific catego-
rization of birth weight calculated
using published data derived from
U.S. birth certificates and corrected
for gestational age and neonatal
gender. ‡Odds of preterm delivery
and small for gestational age were
not statistically significant between
vanishing twin and singleton preg-
nancies.
OBSTETRICS & GYNECOLOGY
Table 3. Demographic Characteristics Associated With Presence or Absence of Fetal Cardiac Activity in the
Vanishing Twin

Vanishing Twin Before Presence of Vanishing Twin After

Fetal Cardiac Activity (referent; Presence of Fetal Cardiac Crude OR Adjusted OR*
Characteristic n545) Activity (n555) (95% CI) (95% CI)

Gestational age at 51.466.3 66.269.7 — —

diagnosis (d)
54.0 (46.0–56.0) 65.0 (58.0–72.0)
Patient age at 37.564.2 37.063.2 0.96 (0.86–1.07) 0.99 (0.86–1.14)
retrieval (y)
38.1 (35.4–40.4) 37.1 (34.5–39.6)
BMI (kg/m2) 25.567.0 23.864.6 0.95 (0.88–1.02) 0.94 (0.88–1.02)†
24.0 (21.6–27.5) 22.6 (20.8–25.5)
Gravidity 0.960.8 1.161.3 1.17 (0.82–1.68) 1.22 (0.84–1.77)
1.0 (0.0–1.0) 1.0 (0.0–1.0)
Parity 0.460.5 0.360.6 0.83 (0.39–1.77) 0.84 (0.39–1.81)
0.0 (0.0–1.0) 0.0 (0.0–1.0)
Prior SAB 14 (31.1) 21 (38.2) 1.37 (0.59–3.15) 1.50 (0.63–3.55)
Fresh embryo 36 (80.0) 45 (81.8) 1.13 (0.41–3.06) 1.21 (0.43–3.38)
transfer
Day 3 embryo 36 (80.0) 47 (85.5) 1.47 (0.52–4.18) 1.76 (0.60–5.23)
transfer
No. of embryos 3.061.8 2.761.1 0.86 (0.64–1.14) 0.86 (0.60–1.25)
transferred
2.0 (2.0–4.0) 2.0 (2.0–3.0)
No. of high- 1.460.9 1.461.1 1.00 (0.67–1.50) 1.03 (0.69–1.54)
quality embryos
transferred
Subchorionic 3 (6.7) 7 (12.7) 2.04 (0.50–8.40) 1.89 (0.45–7.89)
hematoma
OR, odds ratio; BMI, body mass index; SAB, spontaneous abortion.
Data are mean6SD, median (interquartile range), or n (%) unless otherwise specified.
* Adjusted a priori for patient age at retrieval; additionally adjusted for the number of embryos transferred.
†
Odds ratio calculated per 1-unit incremental increase.

pregnancies in which the vanishing twin was identi-
fied after the presence of fetal cardiac activity (38% vs
18%; OR 2.86, 95% CI 1.12–7.30; adjusted OR 3.10,
95% CI 1.19–8.09).
DISCUSSION
The most notable findings of this study are 1)
vanishing twin pregnancies had comparable perinatal
and peripartum outcomes with singleton pregnancies
and improved outcomes compared with twin preg-
nancies and 2) occurrence of twin demise after
documentation of fetal cardiac activity was not
associated with increased risk of adverse outcomes
other than primary cesarean delivery rate.
Our rate of 25.6% vanishing of all twin pregnan-
cies is consistent with previous studies.2–4 Our demo-
graphic predictors of a vanishing twin pregnancy are
in agreement with risk factors for multiple pregnancy
and miscarriage. Additionally, that our vanishing twin
patient population was older than either singletons or
twins is likely explained by the age-related risk of mis-
carriage, largely attributable to aneuploidy.22
The increased perinatal and peripartum morbid-
ity associated with twin pregnancies as compared with
vanishing twin pregnancies is consistent with known
risks of multifetal gestations as compared with single-
ton births.23 Of note, our perinatal and peripartum
findings indicate that demise of one twin in the first
trimester returns the patient and the surviving twin to
the risk profile of a singleton pregnancy.
Despite the theoretically increased vascularity
and tissue mass of a twin demised at a more advanced
developmental stage, timing of demise was not
associated with increased risk for any adverse perina-
tal or peripartum outcome, apart from primary
cesarean delivery rate. The etiology underlying the
association between increased use of cesarean deliv-
ery when vanishing occurred after the presence of
fetal cardiac activity is unclear and warrants a more
detailed obstetric investigation. In the absence of any
biological plausibility to explain this association, we

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Table 4. Perinatal and Peripartum Outcomes by Timing of Demise of the Vanishing Twin

Vanishing Twin Before Vanishing Twin After

Presence of Fetal Cardiac Presence of Fetal
Activity Cardiac Crude OR Adjusted OR*
Outcome (referent; n545) Activity (n555) (95% CI) (95% CI)

Fetal outcomes
Female sex of the 27 (60.0) 28 (50.9) 0.70 (0.31–1.53) 0.68 (0.31–1.52)
surviving twin
Gestational age at 38.561.9 38.561.7 — —
delivery (wk)
Gestational age less 9 (20.0) 8 (14.6) 0.68 (0.24–1.94) 0.71 (0.25–2.03)
than 37 wk
Birth weight (g)† 3,1686686 3,1816522 — —
Less than 2,500 8 (17.8) 5 (9.1) 0.45 (0.14–1.50) 0.24 (0.05–1.26)
2,500–4,000 33 (73.3) 46 (83.6) 1.00 (referent) 1.00 (referent)
Greater than 4,000 4 (8.9) 4 (7.3) 0.72 (0.17–3.08) 0.92 (0.20–4.34)
Z-score‡
SGA 8 (17.8) 6 (10.9) 0.55 (0.17–1.74) 0.55 (0.17–1.77)
AGA 33 (73.3) 45 (81.8) 1.00 (referent) 1.00 (referent)
LGA 4 (8.9) 4 (7.3) 0.73 (0.17–3.15) 0.91 (0.19–4.27)
Peripartum outcomes
Gestational hypertensive 5 (11.1) 4 (7.3) 0.63 (0.16–2.49) 0.71 (0.17–2.89)
diseases
GDM 2 (4.4) 1 (1.8) 0.40 (0.04–4.54) 0.38 (0.03–4.39)
Abnormal placentation§ 2 (4.4) 3 (5.5) 1.24 (0.20–7.77) 1.35 (0.21–8.66)
Estimated blood loss 560.26352.7 550.06230.5 — —
Postpartum hemorrhagek 1 (2.2) 0 (0) — —
Abruption 2 (4.4) 2 (3.6) 0.81 (0.11–6.0) 0.78 (0.11–5.81)
Primary cesarean delivery 8 (17.8) 21 (38.2) 2.86 (1.12–7.30) 3.10 (1.19–8.09)
OR, odds ratio; SGA, small for gestational age; AGA, appropriate for gestational age; LGA, large for gestational age; GDM, gestational
diabetes mellitus.
Data are n (%) or mean6SD unless otherwise specified.
* Adjusted a priori for patient age at retrieval.
†
Birth weight measurements additionally adjusted for gestational age at delivery (weeks) and neonatal sex.
‡
Refer to the text for explanation of Z-score.
§
Placenta previa, with the placental edge coming within 2.0 cm of the internal os on final ultrasonogram; or placenta accreta, increta, or
percreta diagnosed clinically at the time of delivery or on pathology review.
k
Estimated blood loss greater than 1,500 mL or if the patient received a red blood cell transfusion.

conclude that perinatal and peripartum outcomes do
not appear adversely affected by timing of vanishing
during the first trimester.
Prior publications have reported inconsistent
associations between vanishing twin and singleton
pregnancies for perinatal outcomes ranging from no
adverse outcome in the surviving twin to significantly
reduced gestational age and birth weight.3,6,7,9 One
explanation for these varied observations is lack of
a consistent definition of vanishing twin, which could
lead to misclassification of the exposure. The majority
of prior research has included demises occurring in
the second and third trimesters.6,7,24 It is well estab-
lished that first-trimester losses are most commonly
associated with cytogenetic abnormalities; for losses
beyond the first trimester, placental dysfunction,
maternal disease, and infection become more com-
mon causes of demise.25,26 Although a more liberal
definition of a vanishing twin may help increase study
power, it can have unintended effects on reported out-
comes as a result of the occurrence of varying pathol-
ogies at different points in a gestation. We therefore
chose to limit the definition of a vanishing twin to
demise of one twin occurring within the first trimester.
Furthermore, many prior studies do not define a lower
limit of gestational age at which the surviving twin is
delivered. This, in turn, may lead to bias in perinatal
outcome data, because previable deliveries are often
related to maternal anatomy or infections and cannot
be attributed solely to the vanishing twin. By includ-
ing these patients, previously reported perinatal and
maternal outcomes likely were influenced by multiple
pathologic processes unrelated to the vanished twin
per se, thereby introducing substantial bias.
We acknowledge several limitations of our study:
1) the medically complex patients referred to our

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center for antepartum and intrapartum care may
result in selection bias, with overrepresentation of
adverse outcomes in our study cohort compared
with lower risk populations; 2) we included only
IVF pregnancies, which are associated with
increased risk of perinatal and peripartum compli-
cations compared with spontaneous pregnan-
cies,23,27 and the generalizability of these results to
spontaneous twin pregnancies, which may have
a higher incidence of a vanishing twin,28 is
unknown; 3) by excluding monochorionic pregnan-
cies (as a result of the low incidence and different
pathophysiology compared with dichorionic preg-
nancies), our results cannot be generalized to mono-
chorionic pregnancies; and 4) although our sample
size of vanishing twin pregnancies is larger than
most previous studies, we likely lacked statistical
power to detect differences in uncommon peripar-
tum outcomes and these nonsignificant findings
should not be generalized.
In summary, this study demonstrates that twins
vanishing in the first trimester after IVF result in live
births that resemble singleton pregnancies regarding
perinatal and peripartum outcomes. Our results are
reassuring to patients diagnosed with a vanishing twin
pregnancy after IVF and provide a foundation for
counseling in that associated risks of adverse out-
comes after 24 weeks of gestation are comparable with
those of singleton pregnancies. Our findings show that
vanishing twin outcomes are likely improved by the
early demise of one twin rather than if they continued
as a twin pregnancy. Future areas of investigation may
include noninvasive prenatal testing to determine
karyotypes of failed twins, which may elucidate the
pathophysiology of this pregnancy complication.29
Additionally, validation of the association between
cesarean delivery rate and developmental stage at
vanishing twin demise should be performed with
a more comprehensive obstetric analysis of this
outcome.
REFERENCES
1. Stoeckel W. Lehbuch der geburstchilfe. Jena (Germany): Gus-
tav Fisher; 1945. p. 258.
2. Dickey RP, Taylor SN, Lu PY, Sartor BM, Storment JM, Rye PH,
et al. Spontaneous reduction of multiple pregnancy: incidence and
effect on outcome. Am J Obstet Gynecol 2002;186:77–83.
3. La Sala GB, Nucera G, Gallinelli A, Nicoli A, Villani MT,
Blickstein I. Spontaneous embryonic loss following in vitro fer-
tilization: incidence and effect on outcomes. Am J Obstet Gy-
necol 2004;191:741–6.
4. Pinborg A, Lidegaard O, la Cour Freiesleben N, Andersen AN.
Consequences of vanishing twins in IVF/ICSI pregnancies.
Hum Reprod 2005;20:2821–9.
VOL. 131, NO. 6, JUNE 2018 Romanski et al
Copyright Ó by American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
5. Almog B, Levin I, Wagman I, Kapustiansky R, Lessing JB,
Amit A, et al. Adverse obstetric outcome for the vanishing
twin syndrome. Reprod Biomed Online 2010;20:256–60.
6. Evron E, Sheiner E, Friger M, Sergienko R, Harlev A. Vanish-
ing twin syndrome: is it associated with adverse perinatal out-
come? Fertil Steril 2015;103:1209–14.
7. Pinborg A, Lidegaard O, Freiesleben N, Andersen AN. Vanish-
ing twins: a predictor of small-for-gestational age in IVF single-
tons. Hum Reprod 2007;22:2707–14.
8. Shebl O, Ebner T, Sommergruber M, Sir A, Tews G. Birth
weight is lower for survivors of the vanishing twin syndrome:
a case-control study. Fertil Steril 2008;90:310–4.
9. Mansour R, Serour G, Aboulghar M, Kamal O, Al-Inany H.
The impact of vanishing fetuses on the outcome of ICSI preg-
nancies. Fertil Steril 2010;94:2430–2.
10. Rodríguez-González M, Serra V, Garcia-Velasco JA, Pellicer A,
Remohi J. The ‘vanishing embryo’ phenomenon in an oocyte
donation programme. Hum Reprod 2002;17:798–802.
11. Pelkonen S, Koivunen R, Gissler M, Nuojua-Huttunen S,
Suikkari AM, Hydén-Granskog C, et al. Perinatal outcome
of children born after frozen and fresh embryo transfer: the
Finnish cohort study 1995–2006. Hum Reprod 2010;25:
914–23.
12. Sazonova A, Källen K, Thurin-Kjellberg A, Wennerholm UB,
Bergh C. Obstetric outcome in singletons after in vitro fertiliza-
tion with cryopreserved/thawed embryos. Hum Reprod 2012;
27:1343–50.
13. Dar S, Lazer T, Shah PS, Librach CL. Neonatal outcomes
among singleton births after blastocyst versus cleavage stage
embryo transfer: a systematic review and meta-analysis. Hum
Reprod Update 2014;20:439–48.
14. Källén B, Finnström O, Lindam A, Nilsson E, Nygren KG,
Olausson PO. Blastocyst versus cleavage stage transfer in
in vitro fertilization: differences in neonatal outcome? Fertil
Steril 2010;94:1680–3.
15. Cheung LP, Lam PM, Lok IH, Chiu TT, Yeung SY, Tjer CC,
et al. GnRH antagonist versus long GnRH agonist protocol in
poor responders undergoing IVF: a randomized controlled
trial. Hum Reprod 2005;20:616–21.
16. Dragisic KG, Davis OK, Fasouliotis SJ, Rosenwaks Z. Use of
a luteal estradiol patch and a gonadotropin-releasing hormone
antagonist suppression protocol before gonadotropin stimula-
tion for in vitro fertilization in poor responders. Fertil Steril
2005;84:1023–6.
17. Surrey ES, Bower J, Hill DM, Ramsey J, Surrey MW. Clinical
and endocrine effects of a microdose GnRH agonist flare reg-
imen administered to poor responders who are undergoing
in vitro fertilization. Fertil Steril 1998;69:419–24.
18. Tummon IS, Daniel SA, Kaplan BR, Nisker JA, Yuzpe AA.
Randomized, prospective comparison of luteal leuprolide ace-
tate and gonadotropins versus clomiphene citrate and gonado-
tropins in 408 first cycles of in vitro fertilization. Fertil Steril
1992;58:563–8.
19. Oken E, Kleinman KP, Rich-Edwards J, Gillman MW. A nearly
continuous measure of birth weight for gestational age using
a United States national reference. BMC Pediatr 2003;3:6.
20. Mickey RM, Greenland S. The impact of confounder selec-
tion criteria on effect estimation [published erratum appears
in Am J Epidemiol 1989;130:1066]. Am J Epidemiol 1989;
129:125–37.
21. Gardosi J, Chang A, Kalyan B, Sahota D, Symonds EM.
Customised antenatal growth charts. Lancet 1992;339:
283–7.
Pregnancy Outcomes After Vanishing Twin 1019
22. Spandorfer SD, Davis OK, Barmat LI, Chung PH, Rosenwaks Z.
Relationship between maternal age and aneuploidy in in vitro fer-
tilization pregnancy loss. Fertil Steril 2004;81:1265–9.
23. Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal
outcome of singletons and twins after assisted conception: a sys-
tematic review of controlled studies. BMJ 2004;328:261.
24. Zhou L, Gao X, Wu Y, Zhang Z. Analysis of pregnancy out-
comes for survivors of the vanishing twin syndrome after
in vitro fertilization and embryo transfer. Eur J Obstet Gynecol
Reprod Biol 2016;203:35–9.
25. Levy B, Sigurjonsson S, Pettersen B, Maisenbacher MK, Hall
MP, Demko Z, et al. Genomic imbalance in products of con-
ception: single-nucleotide polymorphism chromosomal micro-
array analysis. Obstet Gynecol 2014;124:202–9.
1020 Romanski et al Pregnancy Outcomes After Vanishing Twin
Copyright Ó by American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
26. Silver RM, Varner MW, Reddy U, Goldenberg R, Pinar H,
Conway D, et al. Work-up of stillbirth: a review of the evi-
dence. Am J Obstet Gynecol 2007;196:433–44.
27. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal
outcomes in singletons following in vitro fertilization: a meta-
analysis. Obstet Gynecol 2004;103:551–63.
28. Márton V, Zádori J, Kozinszky Z, Keresztúri A. Prevalences
and pregnancy outcome of vanishing twin pregnancies
achieved by in vitro fertilization versus natural conception. Fer-
til Steril 2016;106:1399–406.
29. Curnow KJ, Wilkins-Haug L, Ryan A, Kırkızlar E, Stosic M,
Hall MP, et al. Detection of triploid, molar, and vanishing twin
pregnancies by a single-nucleotide polymorphism-based non-
invasive prenatal test. Am J Obstet Gynecol 2015;212:79.e1–9.
OBSTETRICS & GYNECOLOGY