ACOG SMFM Joint Practice Bulletin Multiple Gestation 2004

ACOG
PRACTICE
BULLETIN
CLINICAL MANAGEMENT GUIDELINES FOR
OBSTETRICIANGYNECOLOGISTS
NUMBER 56, OCTOBER 2004
(Replaces Educational Bulletin Number 253, November 1998)
This Practice Bulletin was
developed by the ACOG Committee on Practice Bulletins
Obstetrics, the Society for
Maternal-Fetal Medicine and
ACOG Joint Editorial Committee with the assistance of
Katharine Wenstrom, MD, and
contributors John Elliot, MD;
Roger Newman, MD; Alan
Peaceman, MD; and Suneet
Chahaun, MD. The information
is designed to aid practitioners
in making decisions about
appropriate obstetric and gynecologic care. These guidelines
should not be construed as dictating an exclusive course of
treatment or procedure. Variations in practice may be warranted based on the needs of the
individual patient, resources,
and limitations unique to the
institution or type of practice.
The Society for

Maternal-Fetal Medicine
VOL. 104, NO. 4, OCTOBER 2004
Multiple Gestation:
Complicated Twin,
Triplet, and High-Order
Multifetal Pregnancy
In 2002, more than 130,000 infants were born of multifetal gestations in the
United States (1). Since 1980, there has been a 65% increase in the frequency
of twins and a 500% increase in triplet and high-order births (1). Most of this
increase results from increased use of ovulation induction agents and assisted
reproductive technology (ART); the risk of multiple gestation associated with
these therapies may be as high as 25% (2). Similar increases in multifetal gestation have occurred worldwide (36).
Although multifetal births account for only 3% of all live births, they are
responsible for a disproportionate share of perinatal morbidity and mortality
(Table 1). They account for 17% of all preterm births (before 37 weeks of gestation), 23% of early preterm births (before 32 weeks of gestation), 24% of lowbirth-weight infants (<2,500 g), and 26% of very-low-birth-weight infants
(<1,500 g) (1, 79). Although twins do have an increased risk of morbidity and
mortality, a far greater proportion of triplet and high-order multiple gestations
have poor outcomes. All survivors of preterm multifetal births have an increased
risk of mental and physical handicap.
The purpose of this document is to address the risks associated with these
pregnancies and present an evidence-based approach to management when
possible. Because the literature on high-order multiple gestation is still largely
composed of case reports or small series, experience is important in the decision-making process for complicated twin or high-order multiple gestations.
ACOG Practice Bulletin No. 56 Multiple Gestation: Complicated Twin, Triplet,

and High-Order Multifetal Pregnancy
869
Background
Infant and Maternal Morbidity
One fifth of triplet pregnancies and one half of quadruplet pregnancies result in at least 1 child with a major
long-term handicap, such as cerebral palsy (10). Cerebral
palsy occurs 17 times more often in triplet pregnancies
and more than 4 times more often in twin pregnancies
than in singleton pregnancies (10, 11). This risk is not
solely related to preterm birth. When matched for gestational age at delivery, infants from multifetal pregnancies
have a nearly 3-fold greater risk of cerebral palsy (12,
13). One confounding factor may be growth restriction,
which complicates approximately 5060% of triplet and
quadruplet pregnancies (14). Growth-restricted preterm
infants, regardless of plurality, have a significantly higher risk of morbidity (including an excess of neurodevel-
opmental abnormalities) and mortality than appropriately grown infants of the same gestational age (1519).
Multifetal gestations also are associated with significantly higher maternal morbidity and associated health
care costs. Women with multiple gestations are nearly
6 times more likely to be hospitalized with complications, including preeclampsia, preterm labor, preterm
premature rupture of membranes, placental abruption,
pyelonephritis, and postpartum hemorrhage (2026).
Hospital costs for women with multiple gestations are on
average 40% higher than for women with gestationalage-matched singleton pregnancies because of their
longer length of stay and obstetric complications.
Neonatal intensive care unit (NICU) admission is
required for one fourth of twins, three fourths of triplets,
and virtually all quadruplets, with average NICU stays of
18 days, 30 days, and 58 days, respectively (20, 2325,
2729).
Table 1. Morbidity and Mortality in Multiple Gestation

Characteristic
Twins
1
Triplets
Quadruplets
Average birth weight
2,347 g
1,687 g
1,309 g
Average gestational age at delivery1
35.3 wk
32.2 wk
29.9 wk
Percentage with growth restriction2
1425
5060
5060
Percentage requiring admission to

neonatal intensive care unit3
25
75
100
Average length of stay in neonatal

intensive care unit39
18 days
30 days
58 days
Percentage with major handicap9, 10

Risk of cerebral palsy9, 10
1113
Risk of death by age 1 year
20
50
4 times more than singletons
17 times more than singletons
7 times higher than singletons
20 times higher than singletons
Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML. Births: final data for 2002. Natl Vital Stat Rep 2003;52(10):1102.
Mauldin JG, Newman RB. Neurologic morbidity associated with multiple gestation. Female Pat 1998;23(4):278, 30, 356, passim.
Ettner SL, Christiansen CL, Callahan TL, Hall JE. How low birthweight and gestational age contribute to increased inpatient costs for multiple births. Inquiry
199798;34:32539.
4
McCormick MD, Brooks-Gunn J, Workman-Daniels K, Turner J, Peckham GJ. The health and developmental status of very low-birth-weight children at school age. JAMA
1992;267:22048.
5
Luke B, Bigger HR, Leurgans S, Sietsema D. The cost of prematurity: a case-control study of twins vs singletons. Am J Public Health 1996;86:80914.
Albrecht JL, Tomich PG. The maternal and neonatal outcome of triplet gestations. Am J Obstet Gynecol 1996;174:15516.
Newman RB, Hamer C, Miller MC. Outpatient triplet management: a contemporary review. Am J Obstet Gynecol 1989;161:54753; discussion 5535.
Seoud MA, Toner JP, Kruithoff C, Muasher SJ. Outcome of twin, triplet, and quadruplet in vitro fertilization pregnancies: the Norfolk experience. Fertil Steril
1992;57:82534.
9
Elliott JP, Radin TG. Quadruplet pregnancy: contemporary management and outcome. Obstet Gynecol 1992;80:4214.
10
Grether JK, Nelson KB, Cummins SK. Twinning and cerebral palsy: experience in four northern California counties, births 1983 through 1985. Pediatrics
1993;92:8548.
11
Luke B, Minogue J. The contribution of gestational age and birth weight to perinatal viability in singletons versus twins. J Mat-Fetal Med 1994;3:26374.
12
Kiely JL, Kleinman JC, Kiely M. Triplets and higher order multiple births: time trends and infant mortality. Am J Dis Child 1992;146:8628.
13
Luke B, Keith LG. The contribution of singletons, twins, and triplets to low birth weight, infant mortality, and handicap in the United States. J Reprod Med
1992;37:6616.
870

OBSTETRICS & GYNECOLOGY
Role of Assisted Reproductive

Technology
In 1980, there were 37 pregnancies delivered of triplets
or more for every 100,000 live births; by 2002, this number had increased to 184 pregnancies per 100,000 live
births (1). This marked increase in the number of highorder multiple gestations was a result of the increased
use of ART and ovulation-induction agents during this
period. A similar proportion of triplet and high-order
gestations result from ART procedures and ovulation
induction (43% and 38%, respectively), whereas spontaneous conception accounts for the remainder (19%) (30).
Major morbidity in these pregnancies results from the
associated high rates of preterm birth and low birth
weight (see Table 1), although the characteristics of
women seeking these therapies also may be a factor.
One unexpected complication of ART is the high
incidence of monochorionic twins. One group evaluated
218 ART pregnancies and found the incidence of monochorionicity was 3.2%, compared with the background
rate of 0.4% (31). Other studies have reported an incidence of monochorionicity ranging from 1% to 5% in
association with both ART and ovulation induction (32).
Both animal and human data indicate that manipulation
of the zona pellucida or slowed movement through the
fallopian tube can provoke monozygotic twinning
(3335), and both of these may occur during fertility
treatments. Monozygotic twinning not only increases the
incidence of high-order multiple gestations (ie, 3
embryos are implanted but 4 fetuses result), but also
complicates fetal growth and development and can lead
to rare complications, such as twintwin transfusion syndrome or acardiac twinning. It also increases the morbidity of a pregnancy reduction procedure.
Maternal Age
The a priori risk of a poor perinatal outcome in a highorder multiple gestation is further increased by the
womans age. The growing proportion of older women
successfully undergoing fertility treatment has resulted
in an increase in pregnancies complicated by adult-onset
diseases, such as hypertension and diabetes, labor abnormalities, and cesarean delivery.
Multifetal gestations in older women also complicates prenatal genetic screening and diagnosis. Increased
maternal age alone increases the risk of fetal trisomies,
such as Down syndrome. The presence of multiple fetuses increases the mathematical probability that 1 or more
fetuses will be affected and, thus, results in a higher risk
for the pregnancy than that attributed to maternal age
alone. For example, because either 1 or both fetuses in a
twin pair could have Down syndrome, the ultimate risk
of Down syndrome in a twin pregnancy carried by a

33-year-old woman is the same as the risk in a singleton
pregnancy carried by a 35-year-old woman (36).
Accordingly, a Down syndrome risk equivalent to that of
a 35-year-old woman will occur at successively younger
maternal ages as the number of fetuses increases.
Prenatal Diagnosis
Amniocentesis or chorionic villous sampling may be
technically difficult to accomplish in patients with multiple gestations (3742). Technical problems unique to
high-order multiple gestation include the need to traverse
another fetus sac to reach a different fetus for sampling,
incorrect fetal karyotype caused by cross contamination
with other sacs, difficulty in accurately mapping the
fetuses and determining which fetus is being sampled,
difficulty in accurately determining whether any of the
fetuses are monochorionic twins, and difficulty in locating and reducing only the affected fetus in the event an
aneuploidy is diagnosed and termination chosen.
Complications of
Pregnancy
Gestational Diabetes
The incidence of gestational diabetes in twin pregnancies is higher than in singleton pregnancies (43), and the
incidence in triplet pregnancies is higher than in twin
pregnancies; up to 2239% of triplet pregnancies are
complicated by gestational diabetes, compared with
36% of twin pregnancies (44, 45). One study of 95 twin
and 26 triplet pregnancies, which controlled for other
factors that influence the incidence of gestational diabetes, such as maternal age, weight, and parity, estimated
that each additional fetus increases the risk of gestational diabetes by a factor of 1.8 (45). Another study has
shown that pregnancy reduction significantly reduces the
incidence of gestational diabetes from 22% in triplet
pregnancies to 6% in reduced twin pregnancies (44).
Many aspects of the diagnosis and management of
gestational diabetes in multiple gestation remain unexamined. The best time for testing, the ideal number of daily
calories, the optimal weight gain, whether women treated
with oral hypoglycemic agents for polycystic ovary syndrome should continue taking them, the best form of
insulin to use, the best method of fetal surveillance, and
the ideal time for delivery are all currently unknown.
Consultation with an obstetriciangynecologist who has
expertise in the management of pregnant women with
diabetes, such as a maternalfetal medicine specialist,
and with a dietitian would be helpful.

871
Hypertension and Preeclampsia

Multiple gestations are at higher risk than singleton
gestations of developing gestational hypertension. The
incidence of preeclampsia is 2.6 times higher in twin gestations than in singleton gestations (46) and is higher in
triplet gestations than in twin gestations (47). In addition,
when multiple gestation is complicated by preeclampsia,
it is significantly more likely to occur earlier and to be
severe (46, 48, 49). Gestational hypertension before
35 weeks of gestation, preeclampsia before 35 weeks of
gestation, and hypertension with a diastolic blood pressure level greater than 110 mm Hg occur 12.4 times, 6.7
times, and 2.2 times more often, respectively, in twin gestations compared with singleton gestations (48).
Placental abruption also is 8.2 times more likely (48).
Multiple gestations as a result of ART seem to be at
greater risk of developing hypertensive complications
than spontaneous multiple gestations, for reasons that are
not entirely known. One study of 198 ART multiple gestations compared with 330 spontaneous multiple gestations found that the ART pregnancies were at increased
risk (relative risk, 2.1) of developing mild or severe
preeclampsia even after controlling for maternal age and
parity (50). High-order multiple gestations also are more
likely to develop atypical preeclampsia (51). One study
of women with triplet or quadruplet pregnancies and
preeclampsia found that only 50% had hypertension,
only 38% had edema, and only 19% had proteinuria
before delivery, whereas 60% had epigastric pain and
56% had hemolysis, elevated liver enzymes, and low
platelets (HELLP) syndrome (52). Multifetal reduction
may decrease the risk of preeclampsia. One study reported that 14% of 59 twin pregnancies remaining after multifetal reduction developed preeclampsia compared with
30% of 54 triplet pregnancies (53).
The management of hypertensive complications in
high-order multiple gestations has not been studied
prospectively. Although many women with high-order
multiple gestations are placed on bed rest, this therapy
has been associated with increased fetal weight but not
with prolongation of pregnancy or avoidance of hypertensive complications (54). If severe preeclampsia,
HELLP syndrome, or another serious hypertensive complication develops before term, transfer to a tertiary care
center may improve outcome for both the woman and her
fetuses. It is unclear whether the risks associated with
postponing delivery to administer steroids are outweighed by the benefits of antenatal steroid exposure in
multifetal pregnancies.
Other Pregnancy Complications

Multiple gestations also are disproportionately affected
by more serious pregnancy complications, such as acute
872
fatty liver (55). Acute fatty liver, which is marked by

severe coagulopathy, hypoglycemia, and hyperammonemia, can lead to fetal or maternal death (55). Although
delivery usually halts the disease process, the postpartum
period can be complicated by pancreatitis or diabetes
insipidus or both. The coagulopathy makes delivery itself
difficult in high-order multiple gestations because cesarean delivery usually is required. Diagnosis is frequently
delayed because the symptoms, which typically include
anorexia, nausea and vomiting, and malaise beginning
late in pregnancy and developing over several days or
weeks, are vague and nonspecific, and there is concurrent
evidence of preeclampsia in at least one third of affected
women (56).
Acute fatty liver is rare, occurring in 1 in 10,000 singleton gestations. However, 14% of reported cases have
occurred in twin gestations even though they represent
fewer than 2% of all pregnancies, and recent reports
indicate that the rate may be as high as 7% in triplet pregnancies (55, 57). Many cases are associated with an autosomal recessive disorder, long-chain 3-hydroxyacyl-CoA
dehydrogenase deficiency (58, 59). Disease occurs only
when both the woman and the fetus are carrying at least 1
affected gene; multiple gestations are disproportionately
affected with this and other genetic conditions because
the more fetuses there are, the greater the chance that at
least 1 of them has inherited the womans gene mutation.
Pulmonary embolism is a leading cause of maternal
death in the United States and around the world (60, 61),
and thromboembolism is 6 times more likely during
pregnancy or the puerperium than in the nonpregnant
state. The factors most commonly associated with thromboembolism are multiple pregnancy, cesarean delivery,
delivery before 36 weeks of gestation, a body mass index
of 25 or higher, and maternal age of 35 years or older; all
are more common in multiple gestation (62). In addition,
women with multiple gestation frequently are placed on
bed rest, and the enlarged uterus mechanically obstructs
venous return and contributes to lower extremity stasis.
One study of more than 395,000 births found that multiple gestation was associated with significantly increased
risk of thromboembolism even after controlling for all
other associated risks (62).
Prompt and sustained anticoagulation is needed for
confirmed thrombosis or thromboembolism. Because the
volume of distribution is increased to a much greater
degree in multiple gestations than in singleton gestations,
it may be difficult to achieve a therapeutic level of anticoagulation. In addition, because high-order multiple
gestations are at significantly increased risk of preterm
labor, cesarean delivery, and bleeding complications,
such as abruption, the form of anticoagulation chosen
should be readily reversible. Consultation with an indi-

vidual with expertise in maternalfetal medicine or

hematology may be helpful.
Other less common pregnancy complications occur
more frequently in multiple gestations than in singleton
gestations. A recent study of 142 multiple gestations
found that 3% of twin gestations and 14% of triplet gestations were complicated by pruritic urticarial papules
and pustules of pregnancy, compared with only 0.5% of
singleton gestations (63). Pruritic urticarial papules and
pustules of pregnancy is a dermatosis that most commonly affects primigravid women in the third trimester
(63). It usually starts in abdominal striae, and striae are
common in multiple gestations because of excessive
weight gain and rapid abdominal distention. Recently,
fetal DNA has been detected in the dermis of affected
women, which suggests that fetalmaternal cell trafficking and immune phenomena play a role (64).
Multifetal Reduction and Selective

Fetal Termination
Clinical Considerations and

Recommendations
High-order multiple gestation creates a medical and ethical dilemma. If a pregnancy with 4 or more fetuses is
continued, the probability is high that not all fetuses will
survive intact and that the woman will experience serious
morbidity. However, fetal reduction to triplet or twin gestations is associated with a significant risk of losing
either another fetus or the whole pregnancy. Most studies
have concluded that the risks associated with a quadruplet or higher pregnancy clearly outweigh the risks associated with fetal reduction.
The largest report of perinatal outcome after fetal
reduction, which included 1,789 reduction procedures
over a period of 9 years, noted an overall postprocedure
pregnancy loss rate of 11.7% and a very early preterm (ie,
between 25 and 28 weeks of gestation) delivery rate of
4.5% (65). The chance of losing either an additional fetus
or the whole pregnancy, and the chance of early preterm
delivery, increased according to the starting number of
fetuses; 23% of pregnancies that started with 6 or more
fetuses were lost before 24 weeks of gestation, and only
20% were delivered at 37 weeks of gestation or later.
Whether to reduce high-order multiple gestations to twin
or triplet gestations and whether to reduce triplet gestations at all are both areas of controversy.
Fetal reduction of a high-order multiple pregnancy
has been associated with an increased risk of intrauterine
fetal growth restriction (IUGR) in the remaining twins in
some studies but not in others (6669). One study found
the incidence of IUGR was 36% in twins reduced from
triplets, 42% in twins reduced from quadruplets, and
50% in twins reduced from quintuplets or greater, compared with 19% in twins who had not been reduced (67).
Another study found a significant risk of IUGR in the
remaining twins only when the starting number of fetuses was 5 or more (70).
Monochorionicity can complicate the reduction procedure; if one fetus of a monochorionic twin pair is inadvertently reduced, sudden hypotension and thrombotic
phenomena could result in death or damage of the
remaining twin fetus. This is illustrated by one series of
high-order multiple gestations (quadruplets and quintuplets) in which every pregnancy included a monochorionic twin pair (71). In each case, although the authors
selectively reduced only 1 of the monochorionic twins by
injection of potassium chloride, subsequent demise of all
the co-twins was confirmed.
Selective fetal termination is the application of the
fetal reduction technique to the selective termination of an
anomalous or aneuploid fetus that is part of a multiple gestation. The risks of this procedure are higher than those
associated with multifetal reduction (72). The pregnancy
usually is more advanced by the time the anomaly is diagnosed (ie, 1822 weeks of gestation compared with 1012
weeks of gestation), and the location of the anomalous
fetus may be associated with increased risk. The risk of
losing the whole pregnancy, having a preterm birth, or having an infant with a birth weight less than 2,500 g is highest when the reduced fetus overlies the cervix and when
the pregnancy is at or beyond 20 weeks of gestation (73).
Can preterm labor be predicted in multiple

gestation?
Cervical Length Measurement by

Ultrasonography
A shortened cervix identified by endovaginal ultrasonography is strongly predictive of preterm delivery in twin
pregnancies (7476). A large multicenter study of cervical length in twin pregnancies found that a cervix shorter
than 25 mm at 24 weeks of gestation was the best predictor of delivery before 32, 35, and 37 weeks of gestation (74) and was significantly more common in twin
gestations than in singleton gestations at both 24 and
28 weeks of gestation. One study of 32 triplet pregnancies reported similar data, with cervical measurements
comparable to those reported for twin pregnancies (77).
Cervical Length Measurement by

Digital Examination
Serial digital examinations by an experienced examiner,
assessing both cervical length and dilation, have been
reported to have positive predictive values of 6070% in

873
twin and triplet gestations (7779). However, digital

examination may be less objective than ultrasonographic
measurement and does not allow assessment of the internal os.
Fetal Fibronectin
Fetal fibronectin is a high-molecular-weight extracellular
matrix glycoprotein that is normally found in fetal membranes, placental tissues, and amniotic fluid. Its presence
in cervicalvaginal fluids at concentrations higher than
50 ng/mL is abnormal and has been shown to predict
preterm delivery in singleton gestations. Four studies
examining the utility of measuring fetal fibronectin in
twin or triplet gestations showed that a single fetal
fibronectin test had a high negative predictive value, and
serial tests had a fairly high positive predictive value
(range: 3853%) (74, 8082). However, at least 1 study
found that fetal fibronectin levels were not predictive of
preterm delivery in twin gestations after controlling for
cervical length (74).
Home Uterine Activity Monitoring
Are there interventions that can prolong

pregnancy in multiple gestation?
Current data from U.S. birth records indicate that

5557% of all multiple gestations are delivered preterm,
and 4963% of these infants weigh less than 2,500 g
(84). Twelve percent of twin pregnancies, 36% of triplet
pregnancies, and 60% of quadruplet pregnancies are born
before 32 weeks of gestation, when perinatal morbidity
and mortality are greatest. The same factors that contribute to preterm birth in singleton pregnancies affect
multiple gestations and may be more common: lower and
upper genital tract infection; uterine overdistension; cervical incompetence; maternal medical complications;
maternal stress; and fetal, placental, or uterine abnormalities. However, the identification of these risk factors has
not lead to the development of effective protocols or therapies to prevent preterm delivery, although many different therapies have been investigated.
874
The value of prophylactic cerclage in prolonging highorder multiple gestation has not been assessed, but its use
in twin pregnancy has been studied in at least 2 prospective trials, including 50 and 74 sets of twins, respectively;
cerclage did not prolong gestation or improve perinatal
outcome in either study (85, 86). The studies of cerclage
in triplet pregnancies are all retrospective, making bias in
assignment of this therapy highly likely.
Routine Hospitalization
No trials of routine hospitalization of high-order multiple
gestations have been published. Four prospective randomized trials and one retrospective study have shown
that bed rest in the hospital does not prolong twin gestation (54, 8790). Retrospective series assessing the value
of elective hospitalization for triplet pregnancies also
have failed to identify any significant differences in perinatal outcome after hospitalization (91, 92).
Restriction of Activities and

Rest at Home
Although this is the most commonly prescribed therapy
for multiple gestation, it has not been evaluated in a
prospective randomized manner. Most of the retrospective analyses of bed rest for multiple gestation are strongly biased by the indications for bed rest, and some
studies were performed so long ago that bed rest was not
instituted until the third trimester because the multiple
pregnancy was not diagnosed until then (9395).
Although initially presented as a potentially effective tool

for identifying preterm labor early enough to allow for
treatment, several studies have now cast considerable
doubt on the utility of home uterine activity monitoring
for this purpose. In one large randomized prospective
trial, 2,422 pregnant women, including 844 twin pregnancies, were randomly assigned to weekly contact with
a perinatal nurse, daily contact with a perinatal nurse, or
daily contact with a perinatal nurse and home uterine
activity monitoring (83). There was no difference in outcome among the twin gestations in the 3 groups.
Prophylactic Cerclage
How is preterm labor managed in multiple

gestation?
Tocolytics
If effective tocolytic therapy were available, identifying
women at risk of preterm delivery could reduce the incidence of preterm birth. The use of prophylactic tocolysis
in twin gestations has been examined in at least 7
prospective studies (96102). These trials showed no
consistent effect on preterm birth, birth weight, or neonatal mortality. Importantly, the risks associated with each
tocolytic are amplified in multiple gestations. Betamimetics are associated with increased maternal and fetal
cardiac stress and gestational diabetes; these complications occur more frequently in multiple gestations even
without -mimetic therapy (103, 104). In addition,
women with multiple gestations are at increased risk of
developing pulmonary edema resulting in severe respiratory distress when tocolytic agents, steroids, and intravenous fluids are administered together (105, 106).

Therefore, because of the associated risks of tocolytics

in high-order pregnancies, they should be used
judiciously.
Corticosteroids
The effect of antenatal steroid administration and the
possible effects of steroid dose on efficacy in multiple
gestations have not been examined. Nevertheless, the
National Institutes of Health recommends that all
women in preterm labor who have no contraindications
to steroid use be given one course of steroids, regardless
of the number of fetuses (107).
How should growth restriction or discordant

growth be diagnosed and managed in multiple gestation?
Fetuses of a multiple gestation generally do not grow at

the same rate as singleton fetuses. One obvious etiology
is placental pathology; multiple gestations are at
increased risk to include at least 1 fetus with a suboptimal placental implantation site or abnormal umbilical
cord morphology. For example, one study of 39 sets of
triplets found that 28% included at least 1 fetus with a
velamentous cord insertion site that was likely to be
growth restricted as a result (108). Depending on the
number of fetuses, a diminution in fetal growth may be
discernible as early as 22 weeks of gestation (68). The
long held theory that low-birth-weight infants from a
multiple gestation do better than low-birth-weight singleton infants is not correct. Because infants of multiple
gestations are likely to be both preterm and low birth
weight, their outcome may actually be worse (109).
Abnormally slow fetal growth in a multiple gestation may be easier to recognize when not all of the fetuses are affected equally. Discordant fetal growth is
common in multiple gestation and usually is defined by
a 1525% reduction in the estimated fetal weight of the
smaller fetus when compared with the largest (110).
Most published studies examine discordance in twins;
twin weight discordance is associated with structural
malformations, stillbirth, IUGR, preterm delivery,
cesarean delivery for nonreassuring fetal heart tracing,
umbilical arterial pH less than 7.1, admission to the
NICU, respiratory distress syndrome, and neonatal death
within 7 days of delivery (6, 8, 9). The threshold at
which discordant growth is most strongly associated
with adverse outcomes is still a matter of debate, even in
twin gestations (1, 6, 7).
Some discordance is expected in multiple gestations, especially those resulting from ovulation induction
or the implantation of 3 or more embryos, when the
fetuses are not genetically identical and may be of dif-
ferent sexes. They would not be expected to be more

similar in weight than any other siblings. If 2 fetuses are
discordant but both have normal estimated weights and
grow appropriately on their own growth curves, the discordance may not indicate a pathologic process (111).
Conversely, concordance would not be desirable if both
fetuses are growth restricted. One study of 279 twin pairs
showed that when birth weight and gestational age at
delivery were evaluated separately, discordance itself
was not a strong predictor of neonatal outcome (112).
However, attribution of fetal weight differences to
zygosity should only be considered once other more serious etiologies have been ruled out.
Discordance can be caused by structural or genetic
fetal anomalies; discordant infection; an unfavorable
placental implantation or umbilical cord insertion site;
placental damage (ie, partial abruption); or complications related to monochorionic placentation, such as
twintwin transfusion syndrome. All of these complications occur more frequently in high-order multiple gestations. The workup should include a review of all
prenatal exposures, a specialized ultrasound examination, and, depending on the gestational age, a test of fetal
well-being.
Because of the inherent difficulty in fully evaluating
each fetus, the ultrasound examination should be performed by someone with skill and experience in scanning multiple gestations. If an anomaly is identified, the
patient should receive counseling, and testing should be
offered, if applicable. In rare cases (for example,
twintwin transfusion syndrome), therapy may be available. Before performing a preterm delivery to benefit the
growth-restricted fetus, the well-being of the other fetuses needs to be considered. A consultation with an obstetriciangynecologist with expertise in the management
of high-risk pregnancies, such as a maternalfetal medicine specialist, may be helpful.
How is the death of one fetus managed?
Multiple gestations, especially high-order multiple gestations, are at increased risk of losing 1 or more fetuses
remote from delivery. One report described the outcome
of every twin, triplet, and higher order multiple gestation
delivered at one perinatal center during a 5-year period
(113). Of 310 twin and 45 triplet or higher pregnancies,
19 were complicated by the spontaneous demise of one
fetus, a loss rate of 6%. Six losses occurred in the first
trimester and 13 in the second or third trimester; an additional 9 pregnancies underwent fetal reduction, and one
of these pregnancies was miscarried afterward. The
causes of the first-trimester losses could not be determined, but the later losses were caused by twintwin

875
Multiple gestations are at increased risk of stillbirth. The

risk in multifetal pregnancies is higher than the risk in
singleton pregnancies at each week of gestation, and the
loss is likely to occur at a much earlier gestational age
than in singleton or twin pregnancies (117). The most
effective fetal surveillance system for such pregnancies
is not known. Because of the increased risk, clinicians
frequently initiate fetal heart rate testing. Both the nonstress test and the fetal biophysical profile have been
shown to be effective in identifying the compromised
twin or triplet gestation (118122). However, none of
these data are based on prospective study and none per-
876
How is delayed delivery of the second twin

managed?
Rarely, preterm labor results in expulsion of a single

fetus followed by cessation of uterine contractions and
uterine quiescence. Often, the placenta remains in situ,
with the umbilical cord visibly protruding through the
cervical os. Whether such an event should prompt delivery of the remaining fetuses is controversial. In view of
the paucity of objective, prospective, randomized data
and the risk involved, consultation with individuals with
training, experience, and expertise in maternalfetal
medicine and neonatology is indicated.
Is there a role for routine antepartum fetal

surveillance?
tain to high-order multiple gestations. Additionally, several issues have not been resolved. For example, it is not
known at what gestational age testing should be initiated, whether testing should be performed once or twice
per week, or whether there is a need to test normally
growing dichorionic twins. At present, antepartum fetal
surveillance in multiple gestations is recommended in all
situations in which surveillance would ordinarily be performed in a singleton pregnancy (eg, IUGR, maternal
disease, decreased fetal movement). Further studies are
needed to determine whether routine antepartum fetal
surveillance provides objective benefit in the absence of
other high-risk conditions.
transfusion syndrome (n = 4), severe IUGR (n = 3), placental insufficiency (n = 4), and placental abruption
(n = 1); the cause of 1 loss was unknown. Because highorder multiple gestations are significantly more likely to
sustain the complications causing fetal demise in this
study and others, the loss rates for high-order multiple
gestations may be considerably higher than 6%.
No fetal monitoring protocol has been shown to predict most of these losses. In addition, authorities disagree
about the preferred antepartum surveillance method and
management once a demise has occurred. Some investigators have advocated immediate delivery of the remaining fetuses (114). However, if the death is the result of an
abnormality of the fetus itself rather than maternal or
uteroplacental pathology, and the pregnancy is remote
from term, expectant management may be appropriate.
The most difficult cases are those in which the fetal
demise occurs in 1 fetus of a monochorionic twin pair.
Because virtually 100% of monochorionic placentas
contain vascular anastomoses that link the circulations of
the 2 fetuses, the surviving fetus is at significant risk of
sustaining damage caused by the sudden, severe, and
prolonged hypotension that occurs at the time of the
demise or by embolic phenomena that occurs later (115,
116). By the time the demise is discovered, the greatest
harm has most likely already been done, and there may
not be any benefit in immediate delivery, especially if the
surviving fetuses are very preterm and otherwise healthy.
In such cases, allowing the pregnancy to continue may
provide the most benefit.
Although maternal disseminated intravascular coagulopathy (DIC) remains a theoretical risk, it rarely
occurs. One series of 28 multiple gestations complicated
by the demise of one fetus remote from term included no
cases of DIC (113). Fibrinogen and fibrin degradation
product levels can be monitored serially until delivery,
and delivery can be expedited if DIC develops.
How are problems caused by monochorionic

placentation managed?
TwinTwin Transfusion Syndrome

Twintwin transfusion syndrome is believed to occur as
the result of uncompensated arteriovenous anastomoses
in a monochorionic placenta, which lead to greater net
blood flow going to one twin at the expense of the other
(123). The donor twin usually is anemic and growth
restricted and appears stuck to one spot in the uterus
because the lack of amniotic fluid in its sac precludes
movement; the recipient twin usually is plethoric and
much larger, and hydramnios is evident. The syndrome
usually becomes apparent in the second trimester and
can rapidly lead to premature rupture of membranes,
preterm labor, or early mortality because of heart failure
in either of the fetuses (124126). A variety of therapies
have been attempted, but serial therapeutic amniocenteses of the recipient twins amniotic sac is most frequently used. This therapy is believed to work by favorably
changing intraamniotic pressure and, thus, placental
intravascular pressure, allowing redistribution of placental blood flow and normalization of amniotic fluid volumes in each sac (123127). More aggressive therapies,
which usually are considered only for very early, severe

cases, include abolishing the placental anastomoses by

endoscopic laser coagulation or selective feticide by
umbilical cord occlusion (128131). Because both twins
are at significantly increased risk of sudden death resulting from either hypovolemic or hypervolemic heart failure, these pregnancies should be monitored closely.
Death of one fetus has been reported to result in the sudden transfusion of blood from the viable fetus to the low
pressure system of the dead fetus, resulting in exsanguination of the viable twin (132, 133). If the gestational age is such that survival is likely, immediate delivery
should be considered, recognizing that damage to the
remaining viable fetus may already have occurred.
Rare Complications
Are there special considerations for timing of

delivery in multiple gestations?
Are there special considerations for route of

delivery for multiple gestations?
The route of delivery for twins should be determined by

the position of the fetuses, the ease of fetal heart rate
monitoring, and maternal and fetal status. Data are insufficient to determine the best route of delivery for highorder multiple gestations. There are retrospective case
series that validate vaginal delivery as a potential mode of
delivery, especially for triplet gestations. However, most
such pregnancies are delivered by cesarean delivery.
Summary of
Recommendations
The following recommendations are based on limited or inconsistent scientific evidence (Level B):
The nadir of perinatal mortality for twin pregnancies

occurs at approximately 38 completed weeks of gestation and at 35 completed weeks of gestation for triplets;
the nadir for quadruplet and other high-order multiple
gestations is not known (137). Fetal and neonatal morbidity and mortality begin to increase in twin and triplet
pregnancies extended beyond 37 and 35 weeks of gestation, respectively (137, 138). However, no prospective
randomized trials have tested the hypothesis that elective
delivery at these gestational ages improves outcomes in
these pregnancies. If the fetuses are appropriate in size
An acardiac or acephalus twin is a monozygotic fetus

without a normally developed heart or brain, respectively, as the result of abnormal division of the zygote at the
time of twinning. These fetuses are nonviable and survive antenatally only because they receive blood flow
from their monochorionic co-twin. Because the pump
twin is supplying blood flow to both its own body and
that of its abnormal twin, death from heart failure is a
common complication (134). Such pregnancies require
close monitoring, with consideration of early delivery or
selective feticide of the abnormal co-twin by umbilical
cord occlusion if heart failure develops (135).
When division of the embryonic disc is not complete, twins can be joined at the head, thorax, abdomen,
or spine and often share organs. Management of conjoined twins is directed by their chance of long-term
survival. If postnatal separation or survival without separation is possible, the twins should be monitored closely for heart failure or other signs of stress and be
delivered atraumatically, usually by cesarean delivery
(136). Pregnancies in which survival of either fetus is
unlikely can be managed expectantly but also may
require cesarean delivery for dystocia.
for gestational age with evidence of sustained growth

and there is normal amniotic fluid volume and reassuring
antepartum fetal testing in the absence of maternal complications, such as preeclampsia or gestational diabetes,
the pregnancy can be continued. Alternatively, if the
woman is experiencing morbidities that would improve
with delivery but do not necessarily mandate delivery
(eg, worsening dyspnea, inability to sleep, severe
dependent edema, painful superficial varicosities), delivery may be considered at these gestational ages.
Determination of fetal pulmonary maturity before
delivery may be necessary for twin and other multiple
gestations if prenatal care was late, if the woman desires
a scheduled delivery, or if the pregnancy is complicated
by preterm labor or preterm premature rupture of
membranes. Several reports have noted that beyond
3132 weeks of gestation, the biochemical markers of
pulmonary maturity (lecithin/sphingomyelin ratio or fluorescence polarization immunoassay) are higher in twin
pregnancies than in singleton pregnancies at comparable
gestational ages (139, 140). Recent publications note
that asynchronous pulmonary maturity occurs in more
than 5% of twins, regardless of fetal sex and size. Before
32 weeks of gestation, 25% of twin pairs have a significant disparity, usually resulting from one twin having a
lecithin/sphingomyelin ratio that is more mature than
expected for gestational age (141). Accordingly, some
authorities recommend that the gestational sac of each
twin be sampled if technically feasible. There are insufficient data to make a similar recommendation for pregnancies with 3 or more fetuses.
Tocolytic agents should be used judiciously in multiple gestations.

877
Women with high-order multiple gestations should

be queried about nausea, epigastric pain, and other
unusual third-trimester symptoms because they are
at increased risk to develop HELLP syndrome, in
many cases before symptoms of preeclampsia have
appeared.
The higher incidence of gestational diabetes

and hypertension in high-order multiple gestations
warrants screening and monitoring for these
complications.
The following recommendations are based primarily on consensus and expert opinion (Level C):
The National Institutes of Health recommends that

women in preterm labor with no contraindication to
steroid use be given one course of steroids, regardless of the number of fetuses.
Cerclage, hospitalization, bed rest, or home uterine

activity monitoring have not been studied in highorder multiple gestations, and, therefore, should not
be ordered prophylactically. There currently is no
evidence that their prophylactic use improves outcome in these pregnancies.
6. Roberts CL, Raynes-Greenow CH, Algert CS, Peat B.

Higher order multiple pregnancies in New South Wales
19901999. Aust N Z J Obstet Gynaecol 2002;42:514.
(Level III)
7. Stevenson DK, Wright LL, Lemons JA, Oh W, Korones
SB, Papile LA, et al. Very low birth weight outcomes of
the National Institute of Child Health and Human
Development Neonatal Research Network, January 1993
through December 1994. Am J Obstet Gynecol 1998;
179:16329. (Level II-3)
8. Powers WF, Kiely JL. The risk confronting twins: a
national perspective. Am J Obstet Gynecol 1994;170:
45661. (Level II-2)
9. Donovan EF, Ehrenkranz RA, Shankaran S, Stevenson
DK, Wright LL, Younes N, et al. Outcomes of very low
birth weight twins cared for in the National Institute of
Child Health and Human Development Neonatal
Research Networks intensive care units. Am J Obstet
Gynecol 1998;179:7429. (Level II-2)
10. Yokoyama Y, Shimizu T, Hayakawa K. Incidence of handicaps in multiple births and associated factors. Acta Genet
Med Gemellol (Roma) 1995;44:8191. (Level II-2)
11. Petterson B, Nelson KB, Watson L, Stanley F. Twins,
triplets, and cerebral palsy in births in Western Australia
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12. Grether JK, Nelson KB, Cummins SK. Twinning and
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Women should be counseled about the risks of highorder multiple gestation before beginning ART.
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278, 30, 356, passim. (Level III)
Because the risks of invasive prenatal diagnosis procedures, such as amniocentesis and chorionic villus
sampling, are inversely proportional to the experience of the operator, only experienced clinicians
should perform these procedures in high-order multiple gestations.
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Management of discordant growth restriction or

death of one fetus in a high-order multiple gestation
should be individualized, taking into consideration
the welfare of the other fetus(es).
14. Skrablin S, Kuvacic I, Pavicic D, Kalafatic D, Goluza T.

Maternal neonatal outcome in quadruplet and quintuplet
versus triplet gestations. Eur J Obstet Gynecol Reprod
Biol 2000;88:14752. (Level II-2)
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The MEDLINE database, the Cochrane Library, and

ACOGs own internal resources and documents were used
to conduct a literature search to locate relevant articles published between January 1985 and March 2004. The search
was restricted to articles published in the English language.
Priority was given to articles reporting results of original
research, although review articles and commentaries also
were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate
for inclusion in this document. Guidelines published by
organizations or institutions such as the National Institutes
of Health and the American College of Obstetricians and
Gynecologists were reviewed, and additional studies were
located by reviewing bibliographies of identified articles.
When reliable research was not available, expert opinions
from obstetriciangynecologists were used.
Studies were reviewed and evaluated for quality according
to the method outlined by the U.S. Preventive Services Task
Force:
I
Evidence obtained from at least 1 properly designed
randomized controlled trial.
II-1 Evidence obtained from well-designed controlled
trials without randomization.
II-2 Evidence obtained from well-designed cohort or
casecontrol analytic studies, preferably from more
than 1 center or research group.
II-3 Evidence obtained from multiple time series with or
without the intervention. Dramatic results in uncontrolled experiments also could be regarded as this
type of evidence.
III Opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert
committees.
Based on the highest level of evidence found in the data,
recommendations are provided and graded according to the
following categories:
Level ARecommendations are based on good and consistent scientific evidence.
Level BRecommendations are based on limited or inconsistent scientific evidence.
Level CRecommendations are based primarily on consensus and expert opinion.
Copyright October 2004 by the American College of Obstetricians
and Gynecologists. All rights reserved. No part of this publication may
be reproduced, stored in a retrieval system, or transmitted, in any form
or by any means, electronic, mechanical, photocopying, recording, or
otherwise, without prior written permission from the publisher.
Requests for authorization to make photocopies should be directed to
Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA
01923, (978) 750-8400.
The American College of Obstetricians and Gynecologists
409 12th Street, SW, PO Box 96920, Washington, DC 20090-6920
12345/87654
Multiple gestation: complicated twin, triplet, and high-order multifetal
pregnancy. ACOG Practice Bulletin No. 56. American College of
Obstetricians and Gynecologists. Obstet Gynecol 2004;104:86983.

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ACOG

The Society for

VOL. 104, NO. 4, OCTOBER 2004

ACOG Practice Bulletin No. 56 Multiple Gestation: Complicated Twin, Triplet,

Table 1. Morbidity and Mortality in Multiple Gestation

Average birth weight

Average gestational age at delivery1

Percentage with growth restriction2

Percentage requiring admission to

Average length of stay in neonatal

Percentage with major handicap9, 10

Risk of death by age 1 year

4 times more than singletons

17 times more than singletons

7 times higher than singletons

20 times higher than singletons

ACOG Practice Bulletin No. 56 Multiple Gestation: Complicated Twin, Triplet,

OBSTETRICS & GYNECOLOGY

Role of Assisted Reproductive

VOL. 104, NO. 4, OCTOBER 2004

of Down syndrome in a twin pregnancy carried by a

ACOG Practice Bulletin No. 56 Multiple Gestation: Complicated Twin, Triplet,

Hypertension and Preeclampsia

Other Pregnancy Complications

fatty liver (55). Acute fatty liver, which is marked by

ACOG Practice Bulletin No. 56 Multiple Gestation: Complicated Twin, Triplet,

OBSTETRICS & GYNECOLOGY

vidual with expertise in maternalfetal medicine or

Multifetal Reduction and Selective

VOL. 104, NO. 4, OCTOBER 2004

Clinical Considerations and

Can preterm labor be predicted in multiple

Cervical Length Measurement by

Cervical Length Measurement by

ACOG Practice Bulletin No. 56 Multiple Gestation: Complicated Twin, Triplet,

twin and triplet gestations (7779). However, digital

Home Uterine Activity Monitoring

Are there interventions that can prolong

Current data from U.S. birth records indicate that

Restriction of Activities and

Although initially presented as a potentially effective tool

How is preterm labor managed in multiple

ACOG Practice Bulletin No. 56 Multiple Gestation: Complicated Twin, Triplet,

OBSTETRICS & GYNECOLOGY

Therefore, because of the associated risks of tocolytics

How should growth restriction or discordant

VOL. 104, NO. 4, OCTOBER 2004

Fetuses of a multiple gestation generally do not grow at

ferent sexes. They would not be expected to be more

How is the death of one fetus managed?

ACOG Practice Bulletin No. 56 Multiple Gestation: Complicated Twin, Triplet,

Multiple gestations are at increased risk of stillbirth. The

How is delayed delivery of the second twin

Rarely, preterm labor results in expulsion of a single

Is there a role for routine antepartum fetal

How are problems caused by monochorionic

TwinTwin Transfusion Syndrome

ACOG Practice Bulletin No. 56 Multiple Gestation: Complicated Twin, Triplet,

OBSTETRICS & GYNECOLOGY

cases, include abolishing the placental anastomoses by

Are there special considerations for timing of

VOL. 104, NO. 4, OCTOBER 2004

Are there special considerations for route of

The route of delivery for twins should be determined by