ACOG SMFM Joint Practice Bulletin Multiple Gestation 2004

VOL. 104, NO. 4, OCTOBER 2004 ACOG Practice Bulletin No. 56 Multiple Gestation: Complicated Twin, Triplet, 869and High-Order Multifetal Pregnancy

ACOGPRACTICEBULLETIN

CLINICAL MANAGEMENT GUIDELINES FOROBSTETRICIAN–GYNECOLOGISTS

NUMBER 56, OCTOBER 2004

(Replaces Educational Bulletin Number 253, November 1998)

This Practice Bulletin wasdeveloped by the ACOG Com-mittee on Practice Bulletins—Obstetrics, the Society forMaternal-Fetal Medicine andACOG Joint Editorial Com-mittee with the assistance ofKatharine Wenstrom, MD, andcontributors John Elliot, MD;Roger Newman, MD; AlanPeaceman, MD; and SuneetChahaun, MD. The informationis designed to aid practitionersin making decisions aboutappropriate obstetric and gyne-cologic care. These guidelinesshould not be construed as dic-tating an exclusive course oftreatment or procedure. Varia-tions in practice may be war-ranted based on the needs of theindividual patient, resources,and limitations unique to theinstitution or type of practice.

Multiple Gestation:Complicated Twin,Triplet, and High-OrderMultifetal PregnancyIn 2002, more than 130,000 infants were born of multifetal gestations in theUnited States (1). Since 1980, there has been a 65% increase in the frequencyof twins and a 500% increase in triplet and high-order births (1). Most of thisincrease results from increased use of ovulation induction agents and assistedreproductive technology (ART); the risk of multiple gestation associated withthese therapies may be as high as 25% (2). Similar increases in multifetal ges-tation have occurred worldwide (3–6).

Although multifetal births account for only 3% of all live births, they areresponsible for a disproportionate share of perinatal morbidity and mortality(Table 1). They account for 17% of all preterm births (before 37 weeks of ges-tation), 23% of early preterm births (before 32 weeks of gestation), 24% of low-birth-weight infants (<2,500 g), and 26% of very-low-birth-weight infants(<1,500 g) (1, 7–9). Although twins do have an increased risk of morbidity andmortality, a far greater proportion of triplet and high-order multiple gestationshave poor outcomes. All survivors of preterm multifetal births have an increasedrisk of mental and physical handicap.

The purpose of this document is to address the risks associated with thesepregnancies and present an evidence-based approach to management whenpossible. Because the literature on high-order multiple gestation is still largelycomposed of case reports or small series, experience is important in the deci-sion-making process for complicated twin or high-order multiple gestations.

The Society for Maternal-Fetal Medicine

870 ACOG Practice Bulletin No. 56 Multiple Gestation: Complicated Twin, Triplet, OBSTETRICS & GYNECOLOGYand High-Order Multifetal Pregnancy

Background

Infant and Maternal Morbidity

One fifth of triplet pregnancies and one half of quadru-plet pregnancies result in at least 1 child with a majorlong-term handicap, such as cerebral palsy (10). Cerebralpalsy occurs 17 times more often in triplet pregnanciesand more than 4 times more often in twin pregnanciesthan in singleton pregnancies (10, 11). This risk is notsolely related to preterm birth. When matched for gesta-tional age at delivery, infants from multifetal pregnancieshave a nearly 3-fold greater risk of cerebral palsy (12,13). One confounding factor may be growth restriction,which complicates approximately 50–60% of triplet andquadruplet pregnancies (14). Growth-restricted preterminfants, regardless of plurality, have a significantly high-er risk of morbidity (including an excess of neurodevel-

opmental abnormalities) and mortality than appropriate-ly grown infants of the same gestational age (15–19).

Multifetal gestations also are associated with signif-icantly higher maternal morbidity and associated healthcare costs. Women with multiple gestations are nearly 6 times more likely to be hospitalized with complica-tions, including preeclampsia, preterm labor, pretermpremature rupture of membranes, placental abruption,pyelonephritis, and postpartum hemorrhage (20–26).Hospital costs for women with multiple gestations are onaverage 40% higher than for women with gestational-age-matched singleton pregnancies because of theirlonger length of stay and obstetric complications.Neonatal intensive care unit (NICU) admission isrequired for one fourth of twins, three fourths of triplets,and virtually all quadruplets, with average NICU stays of18 days, 30 days, and 58 days, respectively (20, 23–25,27–29).

Table 1. Morbidity and Mortality in Multiple Gestation

Characteristic Twins Triplets Quadruplets

Average birth weight1 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 14–25 50–60 50–60

Percentage requiring admission to 25 75 100neonatal intensive care unit3

Average length of stay in neonatal 18 days 30 days 58 daysintensive care unit3–9

Percentage with major handicap9, 10 — 20 50

Risk of cerebral palsy9, 10 4 times more than singletons 17 times more than singletons —

Risk of death by age 1 year11–13 7 times higher than singletons 20 times higher than singletons —

1Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML. Births: final data for 2002. Natl Vital Stat Rep 2003;52(10):1–102.2Mauldin JG, Newman RB. Neurologic morbidity associated with multiple gestation. Female Pat 1998;23(4):27–8, 30, 35–6, passim.3Ettner SL, Christiansen CL, Callahan TL, Hall JE. How low birthweight and gestational age contribute to increased inpatient costs for multiple births. Inquiry1997–98;34:325–39.4McCormick 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. JAMA1992;267:2204–8.5Luke B, Bigger HR, Leurgans S, Sietsema D. The cost of prematurity: a case-control study of twins vs singletons. Am J Public Health 1996;86:809–14.6Albrecht JL, Tomich PG. The maternal and neonatal outcome of triplet gestations. Am J Obstet Gynecol 1996;174:1551–6.7Newman RB, Hamer C, Miller MC. Outpatient triplet management: a contemporary review. Am J Obstet Gynecol 1989;161:547–53; discussion 553–5.8Seoud MA, Toner JP, Kruithoff C, Muasher SJ. Outcome of twin, triplet, and quadruplet in vitro fertilization pregnancies: the Norfolk experience. Fertil Steril1992;57:825–34.9Elliott JP, Radin TG. Quadruplet pregnancy: contemporary management and outcome. Obstet Gynecol 1992;80:421–4.10Grether JK, Nelson KB, Cummins SK. Twinning and cerebral palsy: experience in four northern California counties, births 1983 through 1985. Pediatrics1993;92:854–8.11Luke B, Minogue J. The contribution of gestational age and birth weight to perinatal viability in singletons versus twins. J Mat-Fetal Med 1994;3:263–74.12Kiely JL, Kleinman JC, Kiely M. Triplets and higher order multiple births: time trends and infant mortality. Am J Dis Child 1992;146:862–8.13Luke B, Keith LG. The contribution of singletons, twins, and triplets to low birth weight, infant mortality, and handicap in the United States. J Reprod Med1992;37:661–6.

Role of Assisted ReproductiveTechnologyIn 1980, there were 37 pregnancies delivered of tripletsor more for every 100,000 live births; by 2002, this num-ber had increased to 184 pregnancies per 100,000 livebirths (1). This marked increase in the number of high-order multiple gestations was a result of the increaseduse of ART and ovulation-induction agents during thisperiod. A similar proportion of triplet and high-ordergestations result from ART procedures and ovulationinduction (43% and 38%, respectively), whereas sponta-neous conception accounts for the remainder (19%) (30).Major morbidity in these pregnancies results from theassociated high rates of preterm birth and low birthweight (see Table 1), although the characteristics ofwomen seeking these therapies also may be a factor.

One unexpected complication of ART is the highincidence of monochorionic twins. One group evaluated218 ART pregnancies and found the incidence of mono-chorionicity was 3.2%, compared with the backgroundrate of 0.4% (31). Other studies have reported an inci-dence of monochorionicity ranging from 1% to 5% inassociation with both ART and ovulation induction (32).Both animal and human data indicate that manipulationof the zona pellucida or slowed movement through thefallopian tube can provoke monozygotic twinning(33–35), and both of these may occur during fertilitytreatments. Monozygotic twinning not only increases theincidence of high-order multiple gestations (ie, 3embryos are implanted but 4 fetuses result), but alsocomplicates fetal growth and development and can leadto rare complications, such as twin–twin transfusion syn-drome or acardiac twinning. It also increases the mor-bidity of a pregnancy reduction procedure.

Maternal AgeThe a priori risk of a poor perinatal outcome in a high-order multiple gestation is further increased by thewoman’s age. The growing proportion of older womensuccessfully undergoing fertility treatment has resultedin an increase in pregnancies complicated by adult-onsetdiseases, such as hypertension and diabetes, labor abnor-malities, and cesarean delivery.

Multifetal gestations in older women also compli-cates prenatal genetic screening and diagnosis. Increasedmaternal age alone increases the risk of fetal trisomies,such as Down syndrome. The presence of multiple fetus-es increases the mathematical probability that 1 or morefetuses will be affected and, thus, results in a higher riskfor the pregnancy than that attributed to maternal agealone. For example, because either 1 or both fetuses in atwin 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 singletonpregnancy carried by a 35-year-old woman (36).Accordingly, a Down syndrome risk equivalent to that ofa 35-year-old woman will occur at successively youngermaternal ages as the number of fetuses increases.

Prenatal DiagnosisAmniocentesis or chorionic villous sampling may betechnically difficult to accomplish in patients with mul-tiple gestations (37–42). Technical problems unique tohigh-order multiple gestation include the need to traverseanother fetus’ sac to reach a different fetus for sampling,incorrect fetal karyotype caused by cross contaminationwith other sacs, difficulty in accurately mapping thefetuses and determining which fetus is being sampled,difficulty in accurately determining whether any of thefetuses are monochorionic twins, and difficulty in locat-ing and reducing only the affected fetus in the event ananeuploidy is diagnosed and termination chosen.

Complications ofPregnancyGestational DiabetesThe incidence of gestational diabetes in twin pregnan-cies is higher than in singleton pregnancies (43), and theincidence in triplet pregnancies is higher than in twinpregnancies; up to 22–39% of triplet pregnancies arecomplicated by gestational diabetes, compared with3–6% of twin pregnancies (44, 45). One study of 95 twinand 26 triplet pregnancies, which controlled for otherfactors that influence the incidence of gestational dia-betes, such as maternal age, weight, and parity, estimatedthat each additional fetus increases the risk of gestation-al diabetes by a factor of 1.8 (45). Another study hasshown that pregnancy reduction significantly reduces theincidence of gestational diabetes from 22% in tripletpregnancies to 6% in reduced twin pregnancies (44).

Many aspects of the diagnosis and management ofgestational diabetes in multiple gestation remain unexam-ined. The best time for testing, the ideal number of dailycalories, the optimal weight gain, whether women treatedwith oral hypoglycemic agents for polycystic ovary syn-drome should continue taking them, the best form ofinsulin to use, the best method of fetal surveillance, andthe ideal time for delivery are all currently unknown.Consultation with an obstetrician–gynecologist who hasexpertise in the management of pregnant women withdiabetes, such as a maternal–fetal medicine specialist,and with a dietitian would be helpful.



Hypertension and PreeclampsiaMultiple gestations are at higher risk than singleton gestations of developing gestational hypertension. Theincidence of preeclampsia is 2.6 times higher in twin ges-tations than in singleton gestations (46) and is higher intriplet 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 besevere (46, 48, 49). Gestational hypertension before 35 weeks of gestation, preeclampsia before 35 weeks ofgestation, and hypertension with a diastolic blood pres-sure level greater than 110 mm Hg occur 12.4 times, 6.7times, and 2.2 times more often, respectively, in twin ges-tations 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 atgreater risk of developing hypertensive complicationsthan spontaneous multiple gestations, for reasons that arenot entirely known. One study of 198 ART multiple ges-tations compared with 330 spontaneous multiple gesta-tions found that the ART pregnancies were at increasedrisk (relative risk, 2.1) of developing mild or severepreeclampsia even after controlling for maternal age andparity (50). High-order multiple gestations also are morelikely to develop atypical preeclampsia (51). One studyof women with triplet or quadruplet pregnancies andpreeclampsia found that only 50% had hypertension,only 38% had edema, and only 19% had proteinuriabefore delivery, whereas 60% had epigastric pain and56% had hemolysis, elevated liver enzymes, and lowplatelets (HELLP) syndrome (52). Multifetal reductionmay decrease the risk of preeclampsia. One study report-ed that 14% of 59 twin pregnancies remaining after mul-tifetal reduction developed preeclampsia compared with30% of 54 triplet pregnancies (53).

The management of hypertensive complications inhigh-order multiple gestations has not been studiedprospectively. Although many women with high-ordermultiple gestations are placed on bed rest, this therapyhas been associated with increased fetal weight but notwith prolongation of pregnancy or avoidance of hyper-tensive complications (54). If severe preeclampsia,HELLP syndrome, or another serious hypertensive com-plication develops before term, transfer to a tertiary carecenter may improve outcome for both the woman and herfetuses. It is unclear whether the risks associated withpostponing delivery to administer steroids are out-weighed by the benefits of antenatal steroid exposure inmultifetal pregnancies.

Other Pregnancy ComplicationsMultiple gestations also are disproportionately affectedby more serious pregnancy complications, such as acute

fatty liver (55). Acute fatty liver, which is marked bysevere coagulopathy, hypoglycemia, and hyperammone-mia, can lead to fetal or maternal death (55). Althoughdelivery usually halts the disease process, the postpartumperiod can be complicated by pancreatitis or diabetesinsipidus or both. The coagulopathy makes delivery itselfdifficult in high-order multiple gestations because cesare-an delivery usually is required. Diagnosis is frequentlydelayed because the symptoms, which typically includeanorexia, nausea and vomiting, and malaise beginninglate in pregnancy and developing over several days orweeks, are vague and nonspecific, and there is concurrentevidence of preeclampsia in at least one third of affectedwomen (56).

Acute fatty liver is rare, occurring in 1 in 10,000 sin-gleton gestations. However, 14% of reported cases haveoccurred in twin gestations even though they representfewer than 2% of all pregnancies, and recent reportsindicate that the rate may be as high as 7% in triplet preg-nancies (55, 57). Many cases are associated with an auto-somal recessive disorder, long-chain 3-hydroxyacyl-CoAdehydrogenase deficiency (58, 59). Disease occurs onlywhen both the woman and the fetus are carrying at least 1affected gene; multiple gestations are disproportionatelyaffected with this and other genetic conditions becausethe more fetuses there are, the greater the chance that atleast 1 of them has inherited the woman’s gene mutation.

Pulmonary embolism is a leading cause of maternaldeath in the United States and around the world (60, 61),and thromboembolism is 6 times more likely duringpregnancy or the puerperium than in the nonpregnantstate. The factors most commonly associated with throm-boembolism are multiple pregnancy, cesarean delivery,delivery before 36 weeks of gestation, a body mass indexof 25 or higher, and maternal age of 35 years or older; allare more common in multiple gestation (62). In addition,women with multiple gestation frequently are placed onbed rest, and the enlarged uterus mechanically obstructsvenous return and contributes to lower extremity stasis.One study of more than 395,000 births found that multi-ple gestation was associated with significantly increasedrisk of thromboembolism even after controlling for allother associated risks (62).

Prompt and sustained anticoagulation is needed forconfirmed thrombosis or thromboembolism. Because thevolume of distribution is increased to a much greaterdegree in multiple gestations than in singleton gestations,it may be difficult to achieve a therapeutic level of anti-coagulation. In addition, because high-order multiplegestations are at significantly increased risk of pretermlabor, cesarean delivery, and bleeding complications,such as abruption, the form of anticoagulation chosenshould be readily reversible. Consultation with an indi-


vidual with expertise in maternal–fetal medicine orhematology may be helpful.

Other less common pregnancy complications occurmore frequently in multiple gestations than in singletongestations. A recent study of 142 multiple gestationsfound that 3% of twin gestations and 14% of triplet ges-tations were complicated by pruritic urticarial papulesand pustules of pregnancy, compared with only 0.5% ofsingleton gestations (63). Pruritic urticarial papules andpustules of pregnancy is a dermatosis that most com-monly affects primigravid women in the third trimester(63). It usually starts in abdominal striae, and striae arecommon in multiple gestations because of excessiveweight gain and rapid abdominal distention. Recently,fetal DNA has been detected in the dermis of affectedwomen, which suggests that fetal–maternal cell traffick-ing and immune phenomena play a role (64).

Multifetal Reduction and Selective Fetal TerminationHigh-order multiple gestation creates a medical and eth-ical dilemma. If a pregnancy with 4 or more fetuses iscontinued, the probability is high that not all fetuses willsurvive intact and that the woman will experience seriousmorbidity. However, fetal reduction to triplet or twin ges-tations is associated with a significant risk of losingeither another fetus or the whole pregnancy. Most studieshave concluded that the risks associated with a quadru-plet or higher pregnancy clearly outweigh the risks asso-ciated with fetal reduction.

The largest report of perinatal outcome after fetalreduction, which included 1,789 reduction proceduresover a period of 9 years, noted an overall postprocedurepregnancy loss rate of 11.7% and a very early preterm (ie,between 25 and 28 weeks of gestation) delivery rate of4.5% (65). The chance of losing either an additional fetusor the whole pregnancy, and the chance of early pretermdelivery, increased according to the starting number offetuses; 23% of pregnancies that started with 6 or morefetuses were lost before 24 weeks of gestation, and only20% were delivered at 37 weeks of gestation or later.Whether to reduce high-order multiple gestations to twinor triplet gestations and whether to reduce triplet gesta-tions at all are both areas of controversy.

Fetal reduction of a high-order multiple pregnancyhas been associated with an increased risk of intrauterinefetal growth restriction (IUGR) in the remaining twins insome studies but not in others (66–69). One study foundthe incidence of IUGR was 36% in twins reduced fromtriplets, 42% in twins reduced from quadruplets, and50% in twins reduced from quintuplets or greater, com-pared 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 fetus-es was 5 or more (70).

Monochorionicity can complicate the reduction pro-cedure; if one fetus of a monochorionic twin pair is inad-vertently reduced, sudden hypotension and thromboticphenomena could result in death or damage of theremaining twin fetus. This is illustrated by one series ofhigh-order multiple gestations (quadruplets and quintu-plets) in which every pregnancy included a monochori-onic twin pair (71). In each case, although the authorsselectively reduced only 1 of the monochorionic twins byinjection of potassium chloride, subsequent demise of allthe co-twins was confirmed.

Selective fetal termination is the application of thefetal reduction technique to the selective termination of ananomalous or aneuploid fetus that is part of a multiple ges-tation. The risks of this procedure are higher than thoseassociated with multifetal reduction (72). The pregnancyusually is more advanced by the time the anomaly is diag-nosed (ie, 18–22 weeks of gestation compared with 10–12weeks of gestation), and the location of the anomalousfetus may be associated with increased risk. The risk oflosing the whole pregnancy, having a preterm birth, or hav-ing an infant with a birth weight less than 2,500 g is high-est when the reduced fetus overlies the cervix and whenthe pregnancy is at or beyond 20 weeks of gestation (73).

Clinical Considerations andRecommendations

Can preterm labor be predicted in multiplegestation?

Cervical Length Measurement byUltrasonographyA shortened cervix identified by endovaginal ultrasonog-raphy is strongly predictive of preterm delivery in twinpregnancies (74–76). A large multicenter study of cervi-cal length in twin pregnancies found that a cervix shorterthan 25 mm at 24 weeks of gestation was the best pre-dictor of delivery before 32, 35, and 37 weeks of gesta-tion (74) and was significantly more common in twingestations than in singleton gestations at both 24 and 28 weeks of gestation. One study of 32 triplet pregnan-cies reported similar data, with cervical measurementscomparable to those reported for twin pregnancies (77).

Cervical Length Measurement byDigital ExaminationSerial digital examinations by an experienced examiner,assessing both cervical length and dilation, have beenreported to have positive predictive values of 60–70% in

▲


twin and triplet gestations (77–79). However, digitalexamination may be less objective than ultrasonographicmeasurement and does not allow assessment of the inter-nal os.

Fetal FibronectinFetal fibronectin is a high-molecular-weight extracellularmatrix glycoprotein that is normally found in fetal mem-branes, placental tissues, and amniotic fluid. Its presencein cervical–vaginal fluids at concentrations higher than50 ng/mL is abnormal and has been shown to predictpreterm delivery in singleton gestations. Four studiesexamining the utility of measuring fetal fibronectin intwin or triplet gestations showed that a single fetalfibronectin test had a high negative predictive value, andserial tests had a fairly high positive predictive value(range: 38–53%) (74, 80–82). However, at least 1 studyfound that fetal fibronectin levels were not predictive ofpreterm delivery in twin gestations after controlling forcervical length (74).

Home Uterine Activity MonitoringAlthough initially presented as a potentially effective toolfor identifying preterm labor early enough to allow fortreatment, several studies have now cast considerabledoubt on the utility of home uterine activity monitoringfor this purpose. In one large randomized prospectivetrial, 2,422 pregnant women, including 844 twin preg-nancies, were randomly assigned to weekly contact witha perinatal nurse, daily contact with a perinatal nurse, ordaily contact with a perinatal nurse and home uterineactivity monitoring (83). There was no difference in out-come among the twin gestations in the 3 groups.

Are there interventions that can prolongpregnancy in multiple gestation?

Current data from U.S. birth records indicate that55–57% of all multiple gestations are delivered preterm,and 49–63% of these infants weigh less than 2,500 g(84). Twelve percent of twin pregnancies, 36% of tripletpregnancies, and 60% of quadruplet pregnancies are bornbefore 32 weeks of gestation, when perinatal morbidityand mortality are greatest. The same factors that con-tribute to preterm birth in singleton pregnancies affectmultiple gestations and may be more common: lower andupper genital tract infection; uterine overdistension; cer-vical incompetence; maternal medical complications;maternal stress; and fetal, placental, or uterine abnormal-ities. However, the identification of these risk factors hasnot lead to the development of effective protocols or ther-apies to prevent preterm delivery, although many differ-ent therapies have been investigated.

Prophylactic CerclageThe value of prophylactic cerclage in prolonging high-order multiple gestation has not been assessed, but its usein twin pregnancy has been studied in at least 2 prospec-tive trials, including 50 and 74 sets of twins, respectively;cerclage did not prolong gestation or improve perinataloutcome in either study (85, 86). The studies of cerclagein triplet pregnancies are all retrospective, making bias inassignment of this therapy highly likely.

Routine HospitalizationNo trials of routine hospitalization of high-order multiplegestations have been published. Four prospective ran-domized trials and one retrospective study have shownthat bed rest in the hospital does not prolong twin gesta-tion (54, 87–90). Retrospective series assessing the valueof elective hospitalization for triplet pregnancies alsohave failed to identify any significant differences in peri-natal outcome after hospitalization (91, 92).

Restriction of Activities and Rest at HomeAlthough this is the most commonly prescribed therapyfor multiple gestation, it has not been evaluated in aprospective randomized manner. Most of the retrospec-tive analyses of bed rest for multiple gestation are strong-ly biased by the indications for bed rest, and some studies were performed so long ago that bed rest was notinstituted until the third trimester because the multiplepregnancy was not diagnosed until then (93–95).

How is preterm labor managed in multiplegestation?

TocolyticsIf effective tocolytic therapy were available, identifyingwomen at risk of preterm delivery could reduce the inci-dence of preterm birth. The use of prophylactic tocolysisin twin gestations has been examined in at least 7prospective studies (96–102). These trials showed noconsistent effect on preterm birth, birth weight, or neona-tal mortality. Importantly, the risks associated with eachtocolytic are amplified in multiple gestations. Beta-mimetics are associated with increased maternal and fetalcardiac stress and gestational diabetes; these complica-tions occur more frequently in multiple gestations evenwithout β-mimetic therapy (103, 104). In addition,women with multiple gestations are at increased risk ofdeveloping pulmonary edema resulting in severe respira-tory distress when tocolytic agents, steroids, and intra-venous fluids are administered together (105, 106).

▲

▲

Therefore, because of the associated risks of tocolyticsin high-order pregnancies, they should be used judiciously.

CorticosteroidsThe effect of antenatal steroid administration and thepossible effects of steroid dose on efficacy in multiplegestations have not been examined. Nevertheless, theNational Institutes of Health recommends that allwomen in preterm labor who have no contraindicationsto steroid use be given one course of steroids, regardlessof the number of fetuses (107).

How should growth restriction or discordantgrowth be diagnosed and managed in multi-ple gestation?

Fetuses of a multiple gestation generally do not grow atthe same rate as singleton fetuses. One obvious etiologyis placental pathology; multiple gestations are atincreased risk to include at least 1 fetus with a subopti-mal placental implantation site or abnormal umbilicalcord morphology. For example, one study of 39 sets oftriplets found that 28% included at least 1 fetus with avelamentous cord insertion site that was likely to begrowth restricted as a result (108). Depending on thenumber of fetuses, a diminution in fetal growth may bediscernible as early as 22 weeks of gestation (68). Thelong held theory that low-birth-weight infants from amultiple gestation do better than low-birth-weight sin-gleton infants is not correct. Because infants of multiplegestations are likely to be both preterm and low birthweight, their outcome may actually be worse (109).

Abnormally slow fetal growth in a multiple gesta-tion may be easier to recognize when not all of the fetus-es are affected equally. Discordant fetal growth is common in multiple gestation and usually is defined bya 15–25% reduction in the estimated fetal weight of thesmaller fetus when compared with the largest (110).Most published studies examine discordance in twins;twin weight discordance is associated with structuralmalformations, stillbirth, IUGR, preterm delivery,cesarean delivery for nonreassuring fetal heart tracing,umbilical arterial pH less than 7.1, admission to theNICU, respiratory distress syndrome, and neonatal deathwithin 7 days of delivery (6, 8, 9). The threshold atwhich discordant growth is most strongly associatedwith adverse outcomes is still a matter of debate, even intwin gestations (1, 6, 7).

Some discordance is expected in multiple gesta-tions, especially those resulting from ovulation inductionor the implantation of 3 or more embryos, when thefetuses are not genetically identical and may be of dif-

ferent sexes. They would not be expected to be moresimilar in weight than any other siblings. If 2 fetuses arediscordant but both have normal estimated weights andgrow appropriately on their own growth curves, the dis-cordance may not indicate a pathologic process (111).Conversely, concordance would not be desirable if bothfetuses are growth restricted. One study of 279 twin pairsshowed that when birth weight and gestational age atdelivery were evaluated separately, discordance itselfwas not a strong predictor of neonatal outcome (112).However, attribution of fetal weight differences tozygosity should only be considered once other more seri-ous etiologies have been ruled out.

Discordance can be caused by structural or geneticfetal anomalies; discordant infection; an unfavorableplacental implantation or umbilical cord insertion site;placental damage (ie, partial abruption); or complica-tions related to monochorionic placentation, such astwin–twin transfusion syndrome. All of these complica-tions occur more frequently in high-order multiple ges-tations. The workup should include a review of all prenatal exposures, a specialized ultrasound examina-tion, and, depending on the gestational age, a test of fetalwell-being.

Because of the inherent difficulty in fully evaluatingeach fetus, the ultrasound examination should be per-formed by someone with skill and experience in scan-ning multiple gestations. If an anomaly is identified, thepatient should receive counseling, and testing should beoffered, if applicable. In rare cases (for example,twin–twin transfusion syndrome), therapy may be avail-able. Before performing a preterm delivery to benefit thegrowth-restricted fetus, the well-being of the other fetus-es needs to be considered. A consultation with an obste-trician–gynecologist with expertise in the managementof high-risk pregnancies, such as a maternal–fetal medi-cine specialist, may be helpful.

How is the death of one fetus managed?

Multiple gestations, especially high-order multiple ges-tations, are at increased risk of losing 1 or more fetusesremote from delivery. One report described the outcomeof every twin, triplet, and higher order multiple gestationdelivered 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 onefetus, a loss rate of 6%. Six losses occurred in the firsttrimester and 13 in the second or third trimester; an addi-tional 9 pregnancies underwent fetal reduction, and oneof these pregnancies was miscarried afterward. Thecauses of the first-trimester losses could not be deter-mined, but the later losses were caused by twin–twin


▲

▲

transfusion syndrome (n = 4), severe IUGR (n = 3), pla-cental insufficiency (n = 4), and placental abruption (n = 1); the cause of 1 loss was unknown. Because high-order multiple gestations are significantly more likely tosustain the complications causing fetal demise in thisstudy and others, the loss rates for high-order multiplegestations may be considerably higher than 6%.

No fetal monitoring protocol has been shown to pre-dict most of these losses. In addition, authorities disagreeabout the preferred antepartum surveillance method andmanagement once a demise has occurred. Some investi-gators have advocated immediate delivery of the remain-ing fetuses (114). However, if the death is the result of anabnormality of the fetus itself rather than maternal oruteroplacental pathology, and the pregnancy is remotefrom term, expectant management may be appropriate.The most difficult cases are those in which the fetaldemise occurs in 1 fetus of a monochorionic twin pair.Because virtually 100% of monochorionic placentascontain vascular anastomoses that link the circulations ofthe 2 fetuses, the surviving fetus is at significant risk ofsustaining damage caused by the sudden, severe, andprolonged hypotension that occurs at the time of thedemise or by embolic phenomena that occurs later (115,116). By the time the demise is discovered, the greatestharm has most likely already been done, and there maynot be any benefit in immediate delivery, especially if thesurviving fetuses are very preterm and otherwise healthy.In such cases, allowing the pregnancy to continue mayprovide the most benefit.

Although maternal disseminated intravascular coag-ulopathy (DIC) remains a theoretical risk, it rarelyoccurs. One series of 28 multiple gestations complicatedby the demise of one fetus remote from term included nocases of DIC (113). Fibrinogen and fibrin degradationproduct levels can be monitored serially until delivery,and delivery can be expedited if DIC develops.

Is there a role for routine antepartum fetalsurveillance?

Multiple gestations are at increased risk of stillbirth. Therisk in multifetal pregnancies is higher than the risk insingleton pregnancies at each week of gestation, and theloss is likely to occur at a much earlier gestational agethan in singleton or twin pregnancies (117). The mosteffective fetal surveillance system for such pregnanciesis not known. Because of the increased risk, cliniciansfrequently initiate fetal heart rate testing. Both the non-stress test and the fetal biophysical profile have beenshown to be effective in identifying the compromisedtwin or triplet gestation (118–122). However, none ofthese data are based on prospective study and none per-

tain to high-order multiple gestations. Additionally, sev-eral issues have not been resolved. For example, it is notknown at what gestational age testing should be initiat-ed, whether testing should be performed once or twiceper week, or whether there is a need to test normallygrowing dichorionic twins. At present, antepartum fetalsurveillance in multiple gestations is recommended in allsituations in which surveillance would ordinarily be per-formed in a singleton pregnancy (eg, IUGR, maternaldisease, decreased fetal movement). Further studies areneeded to determine whether routine antepartum fetalsurveillance provides objective benefit in the absence ofother high-risk conditions.

How is delayed delivery of the second twinmanaged?

Rarely, preterm labor results in expulsion of a singlefetus followed by cessation of uterine contractions anduterine quiescence. Often, the placenta remains in situ,with the umbilical cord visibly protruding through thecervical os. Whether such an event should prompt deliv-ery of the remaining fetuses is controversial. In view ofthe paucity of objective, prospective, randomized dataand the risk involved, consultation with individuals withtraining, experience, and expertise in maternal–fetalmedicine and neonatology is indicated.

How are problems caused by monochorionicplacentation managed?

Twin–Twin Transfusion SyndromeTwin–twin transfusion syndrome is believed to occur asthe result of uncompensated arteriovenous anastomosesin a monochorionic placenta, which lead to greater netblood flow going to one twin at the expense of the other(123). The donor twin usually is anemic and growthrestricted and appears “stuck” to one spot in the uterusbecause the lack of amniotic fluid in its sac precludesmovement; the recipient twin usually is plethoric andmuch larger, and hydramnios is evident. The syndromeusually becomes apparent in the second trimester andcan rapidly lead to premature rupture of membranes,preterm labor, or early mortality because of heart failurein either of the fetuses (124–126). A variety of therapieshave been attempted, but serial therapeutic amniocente-ses of the recipient twin’s amniotic sac is most frequent-ly used. This therapy is believed to work by favorablychanging intraamniotic pressure and, thus, placentalintravascular pressure, allowing redistribution of placen-tal blood flow and normalization of amniotic fluid vol-umes in each sac (123–127). More aggressive therapies,which usually are considered only for very early, severe


▲

▲▲

cases, include abolishing the placental anastomoses byendoscopic laser coagulation or selective feticide byumbilical cord occlusion (128–131). Because both twinsare at significantly increased risk of sudden death result-ing from either hypovolemic or hypervolemic heart fail-ure, these pregnancies should be monitored closely.Death of one fetus has been reported to result in the sud-den transfusion of blood from the viable fetus to the lowpressure system of the dead fetus, resulting in exsan-guination of the viable twin (132, 133). If the gestation-al age is such that survival is likely, immediate deliveryshould be considered, recognizing that damage to theremaining viable fetus may already have occurred.

Rare ComplicationsAn acardiac or acephalus twin is a monozygotic fetuswithout a normally developed heart or brain, respective-ly, as the result of abnormal division of the zygote at thetime of twinning. These “fetuses” are nonviable and sur-vive antenatally only because they receive blood flowfrom their monochorionic co-twin. Because the “pump”twin is supplying blood flow to both its own body andthat of its abnormal twin, death from heart failure is acommon complication (134). Such pregnancies requireclose monitoring, with consideration of early delivery orselective feticide of the abnormal co-twin by umbilicalcord occlusion if heart failure develops (135).

When division of the embryonic disc is not com-plete, twins can be joined at the head, thorax, abdomen,or spine and often share organs. Management of con-joined twins is directed by their chance of long-term survival. If postnatal separation or survival without sep-aration is possible, the twins should be monitored close-ly for heart failure or other signs of stress and be delivered atraumatically, usually by cesarean delivery(136). Pregnancies in which survival of either fetus isunlikely can be managed expectantly but also mayrequire cesarean delivery for dystocia.

Are there special considerations for timing ofdelivery in multiple gestations?

The nadir of perinatal mortality for twin pregnanciesoccurs at approximately 38 completed weeks of gesta-tion and at 35 completed weeks of gestation for triplets;the nadir for quadruplet and other high-order multiplegestations is not known (137). Fetal and neonatal mor-bidity and mortality begin to increase in twin and tripletpregnancies extended beyond 37 and 35 weeks of gesta-tion, respectively (137, 138). However, no prospectiverandomized trials have tested the hypothesis that electivedelivery at these gestational ages improves outcomes inthese pregnancies. If the fetuses are appropriate in size

for gestational age with evidence of sustained growthand there is normal amniotic fluid volume and reassuringantepartum fetal testing in the absence of maternal com-plications, such as preeclampsia or gestational diabetes,the pregnancy can be continued. Alternatively, if thewoman is experiencing morbidities that would improvewith delivery but do not necessarily mandate delivery(eg, worsening dyspnea, inability to sleep, severedependent edema, painful superficial varicosities), deliv-ery may be considered at these gestational ages.

Determination of fetal pulmonary maturity beforedelivery may be necessary for twin and other multiplegestations if prenatal care was late, if the woman desiresa scheduled delivery, or if the pregnancy is complicatedby preterm labor or preterm premature rupture of membranes. Several reports have noted that beyond31–32 weeks of gestation, the biochemical markers ofpulmonary maturity (lecithin/sphingomyelin ratio or flu-orescence polarization immunoassay) are higher in twinpregnancies than in singleton pregnancies at comparablegestational ages (139, 140). Recent publications notethat asynchronous pulmonary maturity occurs in morethan 5% of twins, regardless of fetal sex and size. Before32 weeks of gestation, 25% of twin pairs have a signifi-cant disparity, usually resulting from one twin having alecithin/sphingomyelin ratio that is more mature thanexpected for gestational age (141). Accordingly, someauthorities recommend that the gestational sac of eachtwin be sampled if technically feasible. There are insuf-ficient data to make a similar recommendation for preg-nancies with 3 or more fetuses.

Are there special considerations for route ofdelivery for multiple gestations?

The route of delivery for twins should be determined bythe position of the fetuses, the ease of fetal heart ratemonitoring, and maternal and fetal status. Data are insuf-ficient to determine the best route of delivery for high-order multiple gestations. There are retrospective caseseries that validate vaginal delivery as a potential mode ofdelivery, especially for triplet gestations. However, mostsuch pregnancies are delivered by cesarean delivery.

Summary ofRecommendationsThe following recommendations are based on lim-ited or inconsistent scientific evidence (Level B):

Tocolytic agents should be used judiciously in mul-tiple gestations.


▲

▲▲

Women with high-order multiple gestations shouldbe queried about nausea, epigastric pain, and otherunusual third-trimester symptoms because they areat increased risk to develop HELLP syndrome, inmany cases before symptoms of preeclampsia haveappeared.

The higher incidence of gestational diabetes and hypertension in high-order multiple gestationswarrants screening and monitoring for these complications.

The following recommendations are based primar-ily on consensus and expert opinion (Level C):

The National Institutes of Health recommends thatwomen in preterm labor with no contraindication tosteroid use be given one course of steroids, regard-less of the number of fetuses.

Cerclage, hospitalization, bed rest, or home uterineactivity monitoring have not been studied in high-order multiple gestations, and, therefore, should notbe ordered prophylactically. There currently is noevidence that their prophylactic use improves out-come in these pregnancies.

Because the risks of invasive prenatal diagnosis pro-cedures, such as amniocentesis and chorionic villussampling, are inversely proportional to the experi-ence of the operator, only experienced cliniciansshould perform these procedures in high-order mul-tiple gestations.

Women should be counseled about the risks of high-order multiple gestation before beginning ART.

Management of discordant growth restriction ordeath of one fetus in a high-order multiple gestationshould be individualized, taking into considerationthe welfare of the other fetus(es).

References1. Martin JA, Hamilton BE, Sutton PD, Ventura SJ,

Menacker F, Munson ML. Births: final data for 2002.Natl Vital Stat Rep 2003;52(10):1–102. (Level II-3)

2. Jewell SE, Yip R. Increasing trends in plural births in the United States. Obstet Gynecol 1995;85:229–32.(Level III)

3. Ho ML, Chen JY, Ling UP, Chen JH, Huang CM, ChangCC, et al. Changing epidemiology of triplet pregnancy:etiology and outcome over twelve years. Am J Perinatol1996;13:269–75. (Level III)

4. Westergaard T, Wohlfahrt J, Aaby P, Melbye M. Popula-tion based study of rates of multiple pregnancies inDenmark, 1980–94. BMJ 1997;314:775–9. (Level II-3)

5. Platt MJ, Marshall A, Pharoah PO. The effects of assist-ed reproduction on the trends and zygosity of multiplebirths in England and Wales 1974–99. Twin Res2001;4:417–21. (Level II-2)

6. Roberts CL, Raynes-Greenow CH, Algert CS, Peat B.Higher order multiple pregnancies in New South Wales1990–1999. Aust N Z J Obstet Gynaecol 2002;42:51–4.(Level III)

7. Stevenson DK, Wright LL, Lemons JA, Oh W, KoronesSB, Papile LA, et al. Very low birth weight outcomes ofthe National Institute of Child Health and HumanDevelopment Neonatal Research Network, January 1993through December 1994. Am J Obstet Gynecol 1998;179:1632–9. (Level II-3)

8. Powers WF, Kiely JL. The risk confronting twins: anational perspective. Am J Obstet Gynecol 1994;170:456–61. (Level II-2)

9. Donovan EF, Ehrenkranz RA, Shankaran S, StevensonDK, Wright LL, Younes N, et al. Outcomes of very lowbirth weight twins cared for in the National Institute ofChild Health and Human Development NeonatalResearch Network’s intensive care units. Am J ObstetGynecol 1998;179:742–9. (Level II-2)

10. Yokoyama Y, Shimizu T, Hayakawa K. Incidence of hand-icaps in multiple births and associated factors. Acta GenetMed Gemellol (Roma) 1995;44:81–91. (Level II-2)

11. Petterson B, Nelson KB, Watson L, Stanley F. Twins,triplets, and cerebral palsy in births in Western Australiain the 1980’s. BMJ 1993;307:1239–43 (Level II-3)

12. Grether JK, Nelson KB, Cummins SK. Twinning andcerebral palsy: experience in four northern Californiacounties, births 1983 through 1985. Pediatrics 1993;92:854–8. (Level II-3)

13. Mauldin JG, Newman RB. Neurologic morbidity associ-ated with multiple gestation. Female Pat 1998;23(4):27–8, 30, 35–6, passim. (Level III)

14. Skrablin S, Kuvacic I, Pavicic D, Kalafatic D, Goluza T.Maternal neonatal outcome in quadruplet and quintupletversus triplet gestations. Eur J Obstet Gynecol ReprodBiol 2000;88:147–52. (Level II-2)

15. Kilpatrick SJ, Jackson R, Croughan-Minihane MS.Perinatal mortality in twins and singletons matched forgestational age at delivery at > or = 30 weeks. Am JObstet Gynecol 1996;174:66–71. (Level II-2)

16. Luke B, Minogue J, Witter FR. The role of fetal growthrestriction in gestational age on length of hospital stay in twin infants. Obstet Gynecol 1993;81:949–53. (Level II-2)

17. Wolf EJ, Vintzileos AM, Rosenkrantz TS, Rodis JF,Lettieri L, Mallozzi A. A comparison of pre-dischargesurvival and morbidity in singleton and twin very lowbirth weight infants. Obstet Gynecol 1992;80:436–9.(Level II-2)

18. Low JA, Handley-Derry MH, Burke SO, Peters RD,Pater EA, Killen HL, et al. Association of intrauterinefetal growth retardation and learning deficits at age 9 to11 years. Am J Obstet Gynecol 1992;167:1499–505.(Level II-2)


▲▲

▲▲

▲▲

▲

19. McCormick MD, Brooks-Gunn J, Workman-Daniels K,Turner J, Peckham GJ. The health and developmental sta-tus of very low-birth-weight children at school age.JAMA 1992;267:2204–8. (Level II-2)

20. Chelmow D, Penzias AS, Kaufman G, Cetrulo C. Costsof triplet pregnancy. Am J Obstet Gynecol 1995;172:677–82. (Level III)

21. Peaceman AM, Dooley SL, Tamura RK, Socol ML.Antepartum management of triplet gestations. Am JObstet Gynecol 1992;167:1117–20. (Level II-3)

22. Haas JS, Berman S, Goldberg AB, Lee LW, Cook EF.Prenatal hospitalization and compliance with guidelinesfor prenatal care. Am J Public Health 1996;86:815–9.(Level II-2)

23. Luke B, Bigger HR, Leurgans S, Sietsema D. The cost ofprematurity: a case-control study of twins vs singletons.Am J Public Health 1996;86:809–14. (Level II-2)

24. Albrecht JL, Tomich PG. The maternal and neonatal out-come of triplet gestations. Am J Obstet Gynecol1996;174:1551–6. (Level III)

25. Newman RB, Hamer C, Miller MC. Outpatient tripletmanagement: a contemporary review. Am J ObstetGynecol 1989;161:547–53; discussion 553–5. (Level III)

26. Gardner MO, Goldenberg RL, Cliver SP, Tucker JM,Nelson KG, Copper RL. The origin and outcome ofpreterm twin pregnancies. Obstet Gynecol 1995;85:553–7. (Level II-2)

27. Seoud MA, Toner JP, Kruithoff C, Muasher SJ. Outcomeof twin, triplet, and quadruplet in vitro fertilization preg-nancies: the Norfolk experience. Fertil Steril 1992;57:825–34. (Level II-2)

28. Elliott JP, Radin TG. Quadruplet pregnancy: contempo-rary management and outcome. Obstet Gynecol 1992;80:421–4. (Level III)

29. Ettner SL, Christiansen CL, Callahan TL, Hall JE. Howlow birthweight and gestational age contribute toincreased inpatient costs for multiple births. Inquiry1997–98;34:325–39. (Level II-2)

30. Contribution of assisted reproductive technology andovulation-inducing drugs to triplet and higher-order mul-tiple births—United States, 1980–1997. MMWR MorbMortal Wkly Rep 2000;49:535–8. (Level II-3)

31. Wenstrom KD, Syrop CH, Hammitt DG, van Voorhis BJ.Increased risk of monochorionic twinning associatedwith assisted reproduction. Fertil Steril 1993;60:510– 4.(Level III)

32. Sutcliffe AG, D’Souza SW, Cadman J, Richards B,McKinlay IA, Lieberman B. Outcome in children fromcryopreserved embryos. Arch Dis Child 1995;72:290–3.(Level II-2)

33. Schachter M, Raziel A, Friedler S, Strassburger D, BernO, Ron-El R. Monozygotic twinning after assisted repro-ductive techniques: a phenomenon independent of micro-manipulation. Hum Reprod 2001;16:1264–9. (Level III)

34. Edwards RG, Mettler L, Walters DE. Identical twins andin vitro fertilization. J In Vitro Fert Embryo Transf1986;3:114–7. (Level III)

35. Bressers WM, Eriksson AW, Kostense PJ, Parisi P.Increasing trend in the monozygotic twinning rate. Acta Genet Med Gemellol (Roma) 1987;36:397–408.(Level II-3)

36. Meyers C, Adam R, Dungan J, Prenger V. Aneuploidy intwin gestations: when is maternal age advanced? ObstetGynecol 1997;89:248–51. (Level II-2)

37. van den Berg C, Braat AP, van Opstal D, Halley DJ,Kleijer WJ, den Hollander NS, et al. Amniocentesis orchorionic villus sampling in multiple gestations?Experience with 500 cases. Prenat Diagn 1999;19:234–44. (Level II-2)

38. Wapner RJ, Johnson A, Davis G, Urban A, Morgan P,Jackson L. Prenatal diagnosis in twin gestations: a com-parison between second-trimester amniocentesis andfirst-trimester chorionic villus sampling. Obstet Gynecol1993:82:49–56. (Level II-2)

39. Pergament E, Schulman JD, Copeland K, Fine B, BlackSH, Ginsberg NA, et al. The risk and efficacy of chori-onic villus sampling in multiple gestations. Prenat Diagn1992;12:377–84. (Level III)

40. Brambati B, Tului L, Guercilena S, Alberti E. Outcomeof first-trimester chorionic villus sampling for geneticinvestigation in multiple pregnancy. Ultrasound ObstetGynecol 2001;17:209–16. (Level II-2)

41. De Catte L, Liebaers I, Foulon W, Bonduelle M, VanAssche E. First trimester chorionic villus sampling in twin gestations. Am J Perinatol 1996;13:413–7. (Level II-2)

42. Casals G, Borrell A, Martinez JM, Soler A, Cararach V,Fortuny A. Transcervical chorionic villus sampling inmultiple pregnancies using a biopsy forceps. PrenatDiagn 2002;22:260–5. (Level II-2)

43. Schwartz DB, Daoud Y, Zazula P, Goyert G, BronsteenR, Wright D, et al. Gestational diabetes mellitus: meta-bolic and blood glucose parameters in singleton versustwin pregnancies. Am J Obstet Gynecol 1999;181:912–4. (Level II-2)

44. Sivan E, Maman E, Homko CJ, Lipitz S, Cohen S, SchiffE. Impact of fetal reduction on the incidence of gestational diabetes. Obstet Gynecol 2002;99:91–4.(Level II-1)

45. Roach VJ, Lau TK, Wilson D, Rogers MS. The incidenceof gestational diabetes in multiple pregnancy. Aust N Z JObstet Gynaecol 1998;38:56–7. (Level II-3)

46. Sibai BM, Hauth J, Caritis S, Lindheimer MD, MacPherson C, Klebanoff M, et al. Hypertensive disorders intwin versus singleton gestations. National Institute ofChild Health and Human Development Network ofMaternal-Fetal Medicine Units. Am J Obstet Gynecol2000;182:938–42. (Level I)

47. Mastrobattista JM, Skupski DW, Monga M, Blanco JD,August P. The rate of severe preeclampsia is increased intriplet as compared to twin gestations. Am J Perinatol1997;14:263–5. (Level II-2)

48. Krotz S, Fajardo J, Ghandi S, Patel A, Keith LG.Hypertensive disease in twin pregnancies: a review. TwinRes 2002;5:8–14. (Level III)


49. Long PA, Oats JN. Preeclampsia in twin pregnancy—severity and pathogenesis. Aust N Z J Obstet Gynaecol1987;27:1–5. (Level II-2)

50. Lynch A, McDuffie R Jr, Murphy J, Faber K, Orleans M.Preeclampsia in multiple gestation: the role of assistedreproductive technologies. Obstet Gynecol 2002;99:445–51. (Level II-2)

51. Heller CS, Elliott JP. High-order multiple pregnanciescomplicated by HELLP syndrome. A report of four caseswith corticosteroid therapy to prolong gestation. JReprod Med 1997;42:743–6. (Level III)

52. Hardardottir H, Kelly K, Bork MD, Cusick W, CampbellWA, Rodis JF. Atypical presentation of preeclampsia inhigh-order multifetal gestations. Obstet Gynecol 1996;87:370–4. (Level III)

53. Smith-Levitin M, Kowalik A, Birnholz J, Skupski DW,Hutson JM, Chervenak FA, et al. Selective reduction ofmultifetal pregnancies to twins improves outcome overnonreduced triplet gestations. Am J Obstet Gynecol1996;175:878–82. (Level II-2)

54. Andrews WW, Leveno KJ, Sherman ML, Mutz J,Gilstrap LC 3rd, Whalley PJ. Elective hospitalization inthe management of twin pregnancies. Obstet Gynecol1991;77:826–31. (Level II-1)

55. Davidson KM, Simpson LL, Knox TA, D’Alton ME.Acute fatty liver of pregnancy in triplet gestation. ObstetGynecol 1998;91:806–8. (Level III)

56. Castro MA, Fassett MJ, Reynolds TB, Shaw KJ,Goodwin TM. Reversible peripartum liver failure: a newperspective on the diagnosis, treatment, and cause ofacute fatty liver of pregnancy, based on 28 consecu-tive cases. Am J Obstet Gynecol 1999;181:389–95.(Level III)

57. Malone FD, Kaufman GE, Chelmow D, Athanassiou A,Nores JA, D’Alton ME. Maternal morbidity associatedwith triplet pregnancy. Am J Perinatol 1998;15:73–7.(Level II-2)

58. Sims HF, Brackett JC, Powell CK, Treem WR, Hale DE,Bennett MJ, et al. The molecular basis of pediatric longchain 3-hydroxyacyl-CoA dehydrogenase deficiencyassociated with maternal acute fatty liver of pregnancy.Proc Natl Acad Sci U S A 1995;92:841–5. (Level III)

59. Isaacs JD Jr, Sims HF, Powell CK, Bennett MJ, Hale DE,Treem WR, et al. Maternal acute fatty liver of pregnancyassociated with fetal trifunctional protein deficiency:molecular characterization of a novel maternal mutantallele. Pediatr Res 1996;40:393–8. (Level III)

60. Chang J, Elam-Evans LD, Berg DJ, Herndon J, FlowersL, Seed KA, et al. Pregnancy-related mortality surveil-lance—United States, 1991–1999. MMWR 2003;52(SS-2):1–8. (Level II-3)

61. de Swiet M. Maternal mortality: confidential enquiriesinto maternal deaths in the United Kingdom. Am J ObstetGynecol 2000;182:760–6. (Level II-3)

62. Simpson EL, Lawrenson RA, Nightingale AL, FarmerRD. Venous thromboembolism in pregnancy and thepuerperium: incidence and additional risk factors from aLondon perinatal database. BJOG 2001;108:56–60.(Level II-2)

63. Elling SV, McKenna P, Powell FC. Pruritic urticarialpapules and plaques of pregnancy in twin and tripletpregnancies. J Eur Acad Dermatol Venereol 2000;14:378–81. (Level III)

64. Bianchi DW. Fetal cells in the mother: from genetic diag-nosis to diseases associated with fetal cell micro-chimerism. Euro J Obstet Gynecol Reprod Biol 2000;92:103–8. (Level III)

65. Evans MI, Dommergues M, Wapner RJ, Goldberg JD,Lynch L, Zador IE, et al. International, collaborativeexperience of 1789 patients having multifetal pregnancyreduction: a plateauing of risks and outcomes. J SocGynecol Investig 1996;3:23–6. (Level II-3)

66. Kadhel P, Olivennes F, Fernandez H, Vial M, Frydman R.Are there still obstetric and perinatal benefits for selec-tive embryo reduction of triplet pregnancies? HumReprod 1998;13:3555–9. (Level II-2)

67. Depp R, Macones GA, Rosenn MF, Turzo E, Wapner RJ,Weinblatt VJ. Multifetal pregnancy reduction: evalua-tion of fetal growth in the remaining twins. Am J Obstet Gynecol 1996;174:1233–8; discussion 1238–40. (Level II-2)

68. Alexander GR, Kogan M, Martin J, Papiernik E. Whatare the fetal growth patterns of singletons, twins, andtriplets in the United States? Clin Obstet Gynecol 1998;41:114–25. (Level III)

69. Berkowitz RL, Lynch L, Lapinski R, Bergh P. Firsttrimester transabdominal multifetal pregnancy reduction:a report of two hundred completed cases. Am J ObstetGynecol 1993;169:17–21. (Level II-3)

70. Torok O, Lapinski R, Salafia CM, Bernasko J, BerkowitzRL. Multifetal pregnancy reduction is not associated withan increased risk of intrauterine growth restriction,except for very-high-order multiples. Am J ObstetGynecol 1998;179:221–5. (Level II-2)

71. Benson CB, Doubilet PM, Acker D, Heffner LJ.Multifetal pregnancy reduction of both fetuses of amonochorionic pair by intrathoracic potassium chlorideinjection of one fetus. J Ultrasound Med 1998;17:447–9.(Level II-3)

72. Berkowitz RL, Lynch L, Stone J, Alvarez M. The currentstatus of multifetal pregnancy reduction. Am J ObstetGynecol 1996;174:1265–72. (Level III)

73. Lynch L, Berkowitz RL, Stone J, Alvarez M, Lapinski R.Preterm delivery after selective termination in twin preg-nancies. Obstet Gynecol 1996;87:366–9. (Level II-2)

74. Goldenberg RL, Iams JD, Miodovnik M, Van Dorsten JP,Thurnau G, Bottoms S, et al. The preterm predictionstudy: risk factors in twin gestations. National Institute ofChild Health and Human Development Maternal-FetalMedicine Units Network. Am J Obstet Gynecol 1996;175:1047–53. (Level II-2)

75. Souka AP, Heath V, Flint S, Sevastopoulou I, NicolaidesKH. Cervical length at 23 weeks in twins in predictingspontaneous preterm delivery. Obstet Gynecol 1999;94:450–4. (Level II-2)

76. Imseis HM, Albert TA, Iams JD. Identifying twin gesta-tions at low risk for preterm birth with a transvaginal


ultrasonographic cervical measurement at 24 to 26 weeks’gestation. Am J Obstet Gynecol 1997;177:1149–55.(Level II-2)

77. Ramin KD, Ogburn PL Jr, Mulholland TA, Breckle RJ,Ramsey PS. Ultrasonographic assessment of cervicallength in triplet pregnancies. Am J Obstet Gynecol1999;180:1442–5. (Level II)

78. Houlton MC, Marivate M, Philpott RH. Factors associat-ed with preterm labour and changes in the cervix beforelabour in twin pregnancy. Br J Obstet Gynaecol 1982;89:190–4. (Level II-2)

79. Neilson JP, Verkuyl DA, Crowther CA, Bannerman C.Preterm labor in twin pregnancies: prediction by cer-vical assessment. Obstet Gynecol 1988;72:719–23. (Level II-2)

80. Wennerholm UB, Holm B, Mattsby-Baltzer I, Nielsen T,Platz-Christensen J, Sundell G, et al. Fetal fibronectin,endotoxin bacterial vaginosis, and cervical length as pre-dictors of preterm birth and neonatal morbidity in twinpregnancies. Br J Obstet Gynaecol 1997;104:1398–404.(Level II-2)

81. Oliveira T, de Souza E, Mariani-Neto C, Camano L. Fetalfibronectin as a predictor of preterm delivery in twin gestations. Int J Gynaecol Obstet 1998;62:135–9. (Level II-2)

82. Tolino A, Ronsini S, Zullo F, Pellicano M, Regine V,Nappi C. Fetal fibronectin as a screening test for prema-ture delivery in multiple pregnancies. Int J GynaecolObstet 1996;52:3–7. (Level II-2)

83. Dyson DC, Crites YM, Ray DA, Armstrong MA.Prevention of preterm birth in high-risk patients: the roleof education and provider contact versus home uterinemonitoring. Am J Obstet Gynecol 1991;164:756–62.(Level I)

84. Branum AM, Schoendorf KC. Changing patterns of low birthweight and preterm birth in the United States,1981-98. Paediatr Perinat Epidemiol 2002;16:8–15.(Level II-2)

85. Dor J, Shalev J, Mashiach S, Blankstein J, Serr DM.Elective cervical suture of twin pregnancies diagnosedultrasonically in the first trimester following induced ovu-lation. Gynecol Obstet Invest 1982;13:55–60. (Level I)

86. Interim report of the Medical Research Council/RoyalCollege of Obstetricians and Gynaecologists multicenterrandomized trial of cervical cerclage. MRC/RCOGWorking Party on Cervical Cerclage. Br J ObstetGynaecol 1988;95:437–45. (Level I)

87. Crowther CA, Verkuyl DA, Neilson JP, Bannerman C,Ashurst HM. The effects of hospitalization for rest onfetal growth, neonatal morbidity and length of gestationin twin pregnancy. Br J Obstet Gynaecol 1990;97:872–7.(Level I)

88. MacLennan AH, Green RC, O’Shea R, Brookes C,Morris D. Routine hospital admission in twin pregnancybetween 26 and 30 weeks’ gestation. Lancet 1990;335:267–9. (Level I)

89. Saunders MC, Dick JS, Brown IM, McPherson K,Chalmers I. The effects of hospital admission for bed rest

on duration of twin pregnancy: a randomised trial. Lancet1985;2:793–5. (Level I)

90. Hartikainen-Sorri AL, Jouppila P. Is routine hospitaliza-tion needed in antenatal care of twin pregnancy? J PerinatMed 1984;12:31–4. (Level II-1)

91. Crowther CA, Verkuyl DA, Ashworth MF, Bannerman C,Ashurst HM. The effects of hospitalization for bed reston duration of gestation, fetal growth and neonatal mor-bidity in triplet pregnancy. Acta Genet Med Gemellol(Roma) 1991;40:63–8. (Level II-1)

92. Adams DM, Sholl JS, Haney EI, Russell TL, Silver RK.Perinatal outcome associated with outpatient manage-ment of triplet pregnancy. Am J Obstet Gynecol 1998;178:843–7. (Level II-2)

93. Jeffrey RL, Bowes WA Jr, Delaney JJ. Role of bed rest in twin gestation. Obstet Gynecol 1974;43:822–6. (Level II-3)

94. Syrop CH, Varner MW. Triplet gestation: maternal andneonatal implications. Acta Genet Med Gemellol (Roma)1985;34:81–8. (Level III)

95. Ron-el R, Caspi E, Schreyer P, Weintraub Z, Arieli S,Goldberg MD. Triplet and quadruplet pregnancies and management. Obstet Gynecol 1981;57:458–63.(Level III)

96. O’Connor MC, Murphy H, Dalrymple IJ. Double blindtrial of ritodrine and placebo in twin pregnancy. Br JObstet Gynaecol 1979;86:706–9. (Level I)

97. Marivate M, de Vilhers KQ, Fairbrother P. The effect ofprophylactic outpatient administration of fenoterol on thetime of onset of spontaneous labor and fetal growth ratein twin pregnancy. Am J Obstet Gynecol 1977;128:707–8. (Level I)

98. Skjaerris J, Aberg A. Prevention of prematurity in twinpregnancy by orally administered terbutaline. ActaObstet Gynecol Scand Suppl 1982;108:39–40. (Level I)

99. O’Leary JA. Prophylactic tocolysis of twins. Am J ObstetGynecol 1986;154:904–5. (Level II-1)

100. Mathews DD, Friend JB, Michael CA. A double-blindtrial of oral isoxuprine in the prevention of prematurelabour. J Obstet Gynaecol Br Commonw 1967;74:68–70.(Level I)

101. Cetrulo CL, Freeman RK. Ritodrine HCL for the preven-tion of premature labor in twin pregnancies. Acta GenetMed Gemellol (Roma) 1976;25:321–4. (Level I)

102. Ashworth MF, Spooner SF, Verkuyl DA, Waterman R,Ashurst HM. Failure to prevent preterm labour in twinpregnancy using prophylactic oral salbutamol. Br JObstet Gynaecol 1990;97:878–82. (Level I)

103. Fletcher SE, Fyfe DA, Case CL, Wiles HB, Upshur JK,Newman RB. Myocardial necrosis in a newborn afterlong-term subcutaneous terbutaline infusion for suppres-sion of preterm labor. Am J Obstet Gynecol 1991;165:1401–4. (Level III)

104. Gabriel R, Harika G, Saniez D, Durot S, Quereux C,Wahl P. Prolonged intravenous ritodrine therapy: a com-parison between multiple and singleton pregnancies.Eur J Obstet Gynecol Reprod Biol 1994;57:65–71.(Level II-1)


105. Perry KG Jr, Morrison JC, Rust OA, Sullivan CA, MartinRW, Naef RW 3rd. Incidence of adverse cardiopul-monary effects with low-dose continuous terbutalineinfusion. Am J Obstet Gynecol 1995;173:1273–7. (Level II-3)

106. Katz M, Robertson PA, Creasy RK. Cardiovascular com-plications associated with terbutaline treatment forpreterm labor. Am J Obstet Gynecol 1981;139:605–8.(Level II-3)

107. Effect of corticosteroids for fetal maturation on peri-natal outcomes. NIH Consens Statement 1994;12:1–24.(Level III)

108. Feldman DM, Borgida AF, Trymbulak WP, Barsoom MJ,Sanders MM, Rodis JF. Clinical implications of vela-mentous cord insertion in triplet gestations. Am J ObstetGynecol 2002;186:809–11. (Level III)

109. Kaufman GE, Malone FD, Harvey-Wilkes KB, ChelmauD, Penzias AS, D’Alton MD. Neonatal morbidity andmortality associated with triplet pregnancy. ObstetGynecol 1998;91:342–8. (Level II-2)

110. Talbot GT, Goldstein RF, Nesbitt T, Johnson JL, Kay HH.Is size discordancy an indication for delivery of pre-term twins? Am J Obstet Gynecol 1997;177:1050–4.(Level II-2)

111. Warner BB, Kiely JL, Donovan EF. Multiple births and outcome. Clin Perinatal 2000;27:347–61, ix. (Level III)

112. Hsieh TT, Chang TC, Chiu TH, Hsu JJ, Chao A. Growthdiscordancy, birth weight and neonatal adverse events inthird trimester twin gestations. Gynecol Obstet Invest1994;38:36–40. (Level III)

113. Petersen IR, Nyholm HC. Multiple pregnancies with sin-gle intrauterine demise. Description of twenty-eightpregnancies. Acta Obstet Gynecol Scand 1999;78:202–6.(Level III)

114. D’Alton ME, Newton ER, Cetrulo CL. Intrauterine fetaldemise in multiple gestation. Acta Genet Med Gemellol(Roma) 1984;33:43–9. (Level III)

115. Robertson EG, Neer KJ. Placental injection studies intwin gestation. Am J Obstet Gynecol 1983;147:170–4.(Level III)

116. Langer B, Boudier E, Gasser B, Christmann D, Messer J,Schlaeder G. Antenatal diagnosis of brain damage in thesurvivor after the second trimester death of a monochori-onic monoamniotic co-twin: case report and literaturereview. Fetal Diagn Ther 1997;12:286–91. (Level III)

117. Sairam S, Costeloe K, Thilaganathan B. Prospective riskof stillbirth in multiple-gestation pregnancies: a popula-tion-based analysis. Obstet Gynecol 2002;100:638–41.(Level III)

118. Bailey D, Flynn AM, Kelly J, O’Conor M. Antepartumfetal heart rate monitoring in multiple pregnancy. Br JObstet Gynaecol 1980;87:561–4. (Level II-3)

119. Blake GD, Knuppel RA, Ingardia CJ, Lake M, AumannG, Hanson M. Evaluation of nonstress fetal heart ratetesting in multiple gestations. Obstet Gynecol 1984;63:528–32. (Level II-3)

120. Devoe LD, Azor H. Simultaneous nonstress fetal heartrate testing in twin pregnancy. Obstet Gynecol 1981;58:450–5. (Level II-3)

121. Knuppel RA, Rattan PK, Scerbo JC, O’Brien WF.Intrauterine fetal death in twins after 32 weeks of gesta-tion. Obstet Gynecol 1985;65:172–5. (Level III)

122. Lodeiro JG, Vintzileos AM, Feinstein SJ, Campbell WA,Nochimson DJ. Fetal biophysical profile in twin gesta-tion. Obstet Gynecol 1986;67:824–7. (Level II-3)

123. Talbert DG, Bajoria R, Sepulveda W, Bower S, Fisk NM.Hydrostatic and osmotic pressure gradients producemanifestations of fetofetal transfusion syndrome in acomputerized model of monochorial twin pregnancy. AmJ Obstet Gynecol 1996;174:598–608. (Level III)

124. De Lia J, Fisk N, Hecher K, Machin G, Nicolaides K,Hyett J, et al. Twin-to-twin transfusion syndrome—debates on the etiology, natural history and management.Ultrasound Obstet Gynecol 2000;16:210–3. (Level III)

125. Mahony BS, Petty CN, Nyberg DA, Luthy DA, HickokDE, Hirsch JH. The “stuck twin” phenomenon: ultra-sonographic findings, pregnancy outcome, and manage-ment with serial amniocenteses. Am J Obstet Gynecol1990;163:1513–22. (Level III)

126. Urig MA, Clewell WH, Elliott JP. Twin-twin transfusionsyndrome. Am J Obstet Gynecol 1990;163:1522–6.(Level III)

127. Dickinson JE. Severe twin-twin transfusion syndrome:current management concepts. Aust N Z J ObstetGynaecol 1995;35:16–21. (Level III)

128. De Lia JE, Kuhlmann RS, Harstad TW, Cruikshank DP.Fetoscopic laser ablation of placental vessels in severepreviable twin-twin transfusion syndrome. Am J ObstetGynecol 1995;172:1202–8; discussion 1208–11.(Level II-3)

129. Quintero RA, Comas C, Bornick PW, Allen MH, KrugerM. Selective versus non-selective laser photocoagulationof placental vessels in twin-to-twin transfusion syn-drome. Ultrasound Obstet Gynecol 2000;16:230–6.(Level II-1)

130. Quintero RA, Bornick PW, Allen MH, Johnson PK.Selective laser photocoagulation of communicating ves-sels in severe twin-twin transfusion syndrome in womenwith an anterior placenta. Obstet Gynecol 2001;97:477–81. (Level II-1)

131. Tanawattanacharoen S, Tantivatana J, Charoenvidhya D,Wisawasukmongchol W, Uerpairojkit B, Wacharaprech-anont T, et al. Occlusion of umbilical artery using aGuglielmi detachable coil for the treatment of TRAPsequence. Ultrasound Obstet Gynecol 2002; 19:313–5.(Level III)

132. Fusi L, Gordon H. Twin pregnancy complicated by sin-gle intrauterine death. Problems and outcome with con-servative management. Br J Obstet Gynaecol 1990;97:511–6. (Level III)

133. Ohkuchi A, Minakami H, Shiraishi H, Suzuki I, Ohki T,Sato I. Intrauterine death of one twin, with rescue of theother, in twin-twin transfusion syndrome. UltrasoundObstet Gynecol 2002;19:293–6. (Level III)


134. Moore TR, Gale S, Bernirschke K. Perinatal outcome offorty-nine pregnancies complicated by acardiac twin-ning. Am J Obstet Gynecol 1990;163:907–12. (Level III)

135. Quintero RA, Reich H, Puder KS, Bardicef M, Evans MI,Cotton DB, et al. Brief report: umbilical-cord ligation ofan acardiac twin by fetoscopy at 19 weeks of gestation.N Engl J Med 1994;330:469–71. (Level III)

136. van den Brand SF, Nijhuis JG, van Dongen PW. Prenatalultrasound diagnosis of conjoined twins. Obstet GynecolSurv 1994;49:656–62. (Level III)

137. Luke B. Reducing fetal deaths in multiple births: optimalbirthweights and gestational ages for infants of twin andtriplet births. Acta Genet Med Gemellol (Roma) 1996;45:333–48. (Level II-3)

138. Minakami H, Sato I. Reestimating date of delivery inmultifetal pregnancies [published erratum appears inJAMA 1996;276:452]. JAMA 1996;275:1432–4. (Level II-3)

139. Leveno KJ, Quirk JG, Whalley PJ, Herbert WN, TrubeyR. Fetal lung maturation in twin gestation. Am J ObstetGynecol 1984;148:405–11. (Level II-2)

140. McElrath TF, Norwitz ER, Robinson JN, Tanasijevic MJ,Lieberman ES. Differences in TDx fetal lung maturityassay values between twin and singleton gestations. AmJ Obstet Gynecol 2000;182:1110–2. (Level II-2)

141. Whitworth NS, Magann EF, Morrison JC. Evaluation offetal lung maturity in diamniotic twins. Am J ObstetGynecol 1999;180:1438–41. (Level II-2)


The MEDLINE database, the Cochrane Library, andACOG’s own internal resources and documents were usedto conduct a literature search to locate relevant articles pub-lished between January 1985 and March 2004. The searchwas restricted to articles published in the English language.Priority was given to articles reporting results of originalresearch, although review articles and commentaries alsowere consulted. Abstracts of research presented at sympo-sia and scientific conferences were not considered adequatefor inclusion in this document. Guidelines published byorganizations or institutions such as the National Institutesof Health and the American College of Obstetricians andGynecologists were reviewed, and additional studies werelocated by reviewing bibliographies of identified articles.When reliable research was not available, expert opinionsfrom obstetrician–gynecologists were used.

Studies were reviewed and evaluated for quality accordingto the method outlined by the U.S. Preventive Services TaskForce:

I Evidence obtained from at least 1 properly designedrandomized controlled trial.

II-1 Evidence obtained from well-designed controlledtrials without randomization.

II-2 Evidence obtained from well-designed cohort orcase–control analytic studies, preferably from morethan 1 center or research group.

II-3 Evidence obtained from multiple time series with orwithout the intervention. Dramatic results in uncon-trolled experiments also could be regarded as thistype of evidence.

III Opinions of respected authorities, based on clinicalexperience, descriptive studies, or reports of expertcommittees.

Based on the highest level of evidence found in the data,recommendations are provided and graded according to thefollowing categories:

Level A—Recommendations are based on good and consis-tent scientific evidence.

Level B—Recommendations are based on limited or incon-sistent scientific evidence.

Level C—Recommendations are based primarily on con-sensus and expert opinion.

Copyright © October 2004 by the American College of Obstetriciansand Gynecologists. All rights reserved. No part of this publication maybe reproduced, stored in a retrieval system, or transmitted, in any formor by any means, electronic, mechanical, photocopying, recording, orotherwise, without prior written permission from the publisher.

Requests for authorization to make photocopies should be directed toCopyright Clearance Center, 222 Rosewood Drive, Danvers, MA01923, (978) 750-8400.

The American College of Obstetricians and Gynecologists409 12th Street, SW, PO Box 96920, Washington, DC 20090-6920

12345/87654

Multiple gestation: complicated twin, triplet, and high-order multifetalpregnancy. ACOG Practice Bulletin No. 56. American College ofObstetricians and Gynecologists. Obstet Gynecol 2004;104:869–83.

Documents

ACOG SMFM Joint Practice Bulletin Multiple Gestation 2004