Twins: Prevalence, Problems, and Preterm Births Suneet P

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Twins: prevalence, problems, and preterm births Suneet P. Chauhan, MD; James A. Scardo, MD; Edward Hayes, MD; Alfred Z. Abuhamad, MD; Vincenzo Berghella, MD

n October 10, 2009, there was an Oarticle entitled, “21st Century Ba- The rate of twin pregnancies in the United States has stabilized at 32 per 1000 births in bies: The Gift of Life, and Its Price,” 2006. Aside from determining chorionicity, first-trimester screening and second-trimester which started with 2 succinct sentences: ultrasound scanning should ascertain whether there are structural or chromosomal ab- “Scary. Like aliens.” The article could normalities. Compared with singleton births, genetic amniocentesis–related loss at Ͻ24 have been dismissed easily were it not weeks of gestation for twin births is higher (0.9% vs 2.9%, respectively). Selective termi- published in The New York Times and nation for an anomalous fetus is an option, although the pregnancy loss rate is 7% at were the topic something other than experienced centers. For singleton and twin births for African American and white women, twins.1 Because this article is the first in a approximately 50% of preterm births are indicated; approximately one-third of these births are spontaneous, and 10% of the births occur after preterm premature rupture of mem- series called “21st Century Babies: The branes. From 1989-2000, the rate of preterm twin births increased, for African American Twins Dilemma,” twinning will be a part and white women alike, although the perinatal mortality rate has actually decreased. As of patient lexicon and a source of con- with singleton births, tocolytics should be used judiciously and only for a limited time (Ͻ48 cern. Thus, a review of antepartum com- hours) in twin births. Administration of antenatal corticosteroids is an evidence-based plications with twin pregnancies is useful recommendation. not only for the concerned patient but also because recent publications on the Key words: amniocentesis, perinatal mortality rate, preterm birth, twins topic may influence our practice. A Google search with the word “twin” yields 116,000,000 results in 0.21 sec- Twin birth rate The rate of twin pregnancies varies by onds; a PubMed search with the words In the United States, between 1980 and maternal age and ethnicity (Figure 2). “twin pregnancy” found 24,982 publica- 2006, the twin rate climbed 101% (Fig- Between 1980 and 2006, twin birth rates Ͻ tions (November 12, 2009). Therefore, ure 1). There were 68,339 twins born in rose 27% for mothers 20 years (com- although it is not feasible to summarize 1980; 27 years later, 137,085 twins were pared with 80% for women in their 30s) 2 Ն the voluminous literature on this topic, born. The twinning rates have also in- and 190% for mothers who were 40 this review article will focus on: twin creased in Austria, Finland, Norway, years old. In 2006, 20% of births to birth rate, common antenatal problems, Sweden, Canada, Australia, Hong Kong, women 45-54 years old were twins, com- 3 pared with approximately 2% of births and preterm births, which are the bane of Israel, Japan, and Singapore. There are multiple causes for the change in the rate to women 20-24 years old. Twin birth modern obstetrics. of twin pregnancies: use of assisted re- rates were essentially unchanged among productive techniques (ARTs) and non- the 3 largest racial groups for 2005-2006: ART procedures,4 maternal age, ethnic- non-Hispanic white (36.0 per 1000 ity, variation among the 50 states, and a births in 2006), non-Hispanic black From the Aurora Health Care and Center for decreasing rate of triplets and higher or- (36.8 per 1000 births), and Hispanic Urban Population Health, Milwaukee, WI der multiple gestation.2 (21.8 per 1000 births). Since 1990, rates (Dr Chauhan); Spartanburg Regional Approximately 1% of infants born in have risen 57% for non-Hispanic white Medical Center, Spartanburg, SC (Dr the United States in 2006 were conceived and 38% and 21% for non-Hispanic black Scardo); Women’s Center at Aurora Bay with the use of ARTs and account for and Hispanic women, respectively.2 Care Medical Center, Greenbay, WI (Dr Hayes); Eastern Virginia Medical School, 18% of the multiple births nationwide. The rate of twin pregnancies also var- Norfolk, VA (Dr Abuhamad); Thomas Of 54,566 infants who were born with ies among the states (Figure 3). In 2004- Jefferson Medical School, Philadelphia, PA the use of ARTs, 48% were multiple birth 2006, the rate of twin pregnancies in the (Dr Berghella). deliveries. The International Committee United States was 32.2 per 1000 live Received Jan. 12, 2010; revised April 12, for Monitoring Assisted Reproductive births, with Ͻ25% being 29.5 per 1000 2010; accepted April 19, 2010. Technology5 analyzed ARTs for the year live births; median, 31.8 per 1000 live Reprints not available from the authors. 2002 from 53 countries. For conven- births, and Ͼ75% being 34.0 per 1000 Authorship and contribution to the article is tional in vitro fertilization and intracyto- live births. In Connecticut, Massachu- limited to the 5 authors indicated. There was plasmic sperm injection, the overall twin setts, and New Jersey, 4% of all births no outside funding or technical assistance with rate was 26%. In the United States, the were twins. In contrast, Ͻ2.5% of births the production of this article. twin rate was 32%; in Latin America, it to New Mexico residents were twin 0002-9378/$36.00 was 25%; in Europe, it was 23%; in Asia pregnancies.2 © 2010 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.04.031 and the Middle East, it was 22%, and in The likelihood of twin pregnancies is Australia/New Zealand, it was 21%. also increasing because the rate of trip-

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95.4%. During these 9 years, the rate of FIGURE 1 triplets and higher-order gestations de- Twin deliveries and birth rate: United States, 1980-2006 creased by 29%.2 Twins/year Twins/1,000 births The rapid rise, however, in twin rates 150,000 35 over the last several decades may have ended. From 1935-1980, the twinning rate declined. After that, there has been a

30 steady increase: in 1980, the twin rate was 18.9 per 1000 births; in 1990, it was 22.6 per 1000 births, and in 2000, it was 29.3 per 1000 births (Figure 1). The rate 100,000 25 reached 32 per 1000 births in 2004 and

# Twins/year has stabilized since then; the rate was 2 Twins/1,000 births 32.1 per 1000 births in 2006. 20 To summarize, the rate of twin pregnancies varies in the United States for several reasons and has stabilized, de- 1 50,000 15 spite the recent alarm by public press.

1980 1985 1990 1995 2000 2005 Identification of chorionicity Years and anomaly Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. Because of risks that are associated with monochorionicity, an important aspect of first-trimester ultrasound scans in lets and higher-order gestations is de- were 110,670 twin deliveries, which con- twin gestation is the determination of creasing. Thus, twin pregnancies consti- stituted 93.6% of 118,296 multiple chorionicity. It has been demonstrated tute a greater proportion of multiple births; in 2006, the corresponding num- that chorionicity is best determined by pregnancies. In 1989, for example, there bers were 137,085 twin pregnancies and sonography in the first or early second trimester. In a single large tertiary center,6 the sensitivity, specificity, and positive and negative predictive values of FIGURE 2 prediction of monochorionicity at Յ14 Twin birth rate, based on maternal ethnicity and age weeks was found to be 89.8%, 99.5%, 250 Non-Hispanic white 97.8%, and 97.5%, respectively. If only 1 placenta is visualized, the presence of an extension of chorionic tissue from the 200 fused dichorionic placentas suggests dichorionicity. If only 1 placenta is visualized, the absence of an extension of

150 chorionic tissue into the intertwin membrane suggests monochorionicity. In All races monochorionic twin pregnancies, the absence of an intertwin membrane sug- 100 gests monoamniotic gestation. Mono-

Twins /1,000 live births chorionic diamniotic twin gestation is associated with a 10-15% risk of twin-to- 50 Non-Hispanic black twin transfusion syndrome.7 Although monoamnionicity is somewhat protec- Hispanic tive against the development of twin-to- 0 twin transfusion syndrome, monoamni- < 15 15-17 18-19 20-24 25-29 30-34 35-39 40-44 45-54 otic gestations are associated with a 6% 8 Years of age incidence of twin-to-twin transfusion. Open circles denote non-Hispanic African American; light gray line denotes non-Hispanic white; solid Because of the breadth of the topic, this black line denotes all races; and open squares denote Hispanic. article will not address risks, associa- Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. tions, or management of unique aspects of monochorionic gestations, namely

306 American Journal of Obstetrics & Gynecology OCTOBER 2010 www.AJOG.org Obstetrics Reviews

FIGURE 3 Twin births (2004-2006) by state by percentile

Washington

Maine Montana North Dakota

Oregon Minnesota Vermont Idaho New Hampshire Wisconsin South Dakota New YorkMassachusetts Wyoming Michigan Connecticut

Iowa PennsylvaniaNew Jersey Nebraska Nevada Ohio MarylandDelaware Utah Illinois Indiana California Colorado West Virginia Virginia Kansas Missouri Kentucky

North Carolina Te n n e s s e e Oklahoma Arizona New Mexico Arkansas South Carolina

MississippiAlabama Georgia

Te x a s Louisiana

Florida

Alaska Twin births by percentile (Number per 1,000 live births)

Hawaii

< 25th percentile (24.3-28.9) 26-74th percentile (29.5-33.9) > 75th percentile (34-44.2) Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. twin-to-twin transfusion syndrome and versely affected child and/or to optimize and by the indication for selective monoamnionicity. likelihood of survival for an apparently termination.9 In addition to the determination of normal fetal sibling, or (4) placental For many reasons, the likelihood of chorionicity and amnionicity, the goal of (vascular) and/or fetal and/or neonatal aneuploidy is higher in twin pregnancies sonographic examination with twin ges- therapy in efforts to optimize outcome than in singleton pregnancies. In dizy- tations is to identify anomalies and/or for 1 or both the neonates. gotic gestations, the background risk for syndromes. This should allow for the Risks that are associated with selective each twin is the same as it would be in a modification of pregnancy management termination of dichorionic twin preg- singleton gestation for that mother; in efforts to optimize outcome for nancies with structural, chromosomal, however, the number of fetuses results in mother and newborn infants or to iden- and Mendelian anomalies are known for a 2-fold increase in risk for that gestation tify risk factors that may suggest a need centers with experience. Evans et al9 re- when compared with singleton pregnan- for active or prophylactic therapy to de- ported on 345 cases of selective termina- cies. Because ARTs are often used in crease the likelihood of adverse preg- tion with twins, of whom 7% delivered at older women, the risk of aneuploidy nancy outcome. Depending on the se- Ͻ24 weeks of gestation and 93% ended should be approximately twice her age- verity and/or lethality of the identified in a viable singleton. Unlike multifetal related risk, unless donor oocytes are anomalies or syndromes, pregnancy reduction for multifetal pregnancies, in used. In monozygous twins, the risk of management options include (1) contin- which outcomes are related to experi- both twins being affected should be sim- ued conservative management, (2) ter- ence,10 over 15 years, termination for an ilar to that of a singleton gestation. mination of pregnancy in efforts to de- anomalous fetus was not associated with First-trimester screening for aneu- crease maternal morbidity and death, improvement in losses or prematurity. ploidy in twin pregnancies has many nu- especially in cases in which lethal syn- The loss rate also was not influenced by ances that limit its capabilities as a dromes are suspected, (3) selective re- the gestational age of the procedure, even screening tool.11 Although monochorio- duction to prevent the birth of an ad- when done at Ͼ24 weeks of gestation, nicity has been associated with increased

OCTOBER 2010 American Journal of Obstetrics & Gynecology 307 Reviews Obstetrics www.AJOG.org nuchal translucency,12 nuchal translu- ries. For 7 of the cardiovascular catego- al26 used the 1995-1997 matched multi- cency alone has been shown to be an ef- ries, the prevalence was 2 times higher ple births dataset from the United States fective marker for aneuploidy in twin for twin pregnancies than singleton and noted that 1 fetus had an anomaly in gestations.11,12 The addition of serum pregnancies. Like-sex twins, a proxy for 2.5% of the cases and both fetuses had biochemistry to age and nuchal translu- monozygosity, had a higher prevalence anomalies in 1.0%. They identified 3307 cency measurement in twin gestation has of cardiac defects than unlike sex twins. twins and matched them with 12,813 a very high sensitivity for detecting tri- Bahtiyar et al19 reviewed the literature nonanomalous twins. Compared with somy 18 or 21. In that series of 535 sets, and noted that congenital heart defects the control subject, the presence of an maternal (or egg donor) age alone was were prevalent significantly more among anomalous cotwin significantly in- associated with a 33% detection rate for monochorionic, diamniotic twins than creased the risk of (1) preterm birth at trisomy 18 or 21. The addition of nuchal the general population (relative risk Ͻ32 weeks of gestation (odds ratio [OR], translucency increased the sensitivity to [RR], 9.18; 95% CI, 5.51–15.29). Ven- 1.85; 95% CI, 1.65–2.07), (2) birth- 83%; combined age and nuchal translu- tricular septal defects are the most fre- weight Ͻ1500 g (OR, 1.88; 95% CI 1.67– cency and biochemistry (free or total quent heart defects. 2.12), (3) small for gestational age (10% beta human chorionic gonadotropin Fortunately, detection of anomalies in vs 12%; OR, 1.21; 95% CI, 1.07–1.36), and pregnancy-associated pregnancy twin gestation does not seem to be com- (4) fetal death (OR, 3.75; 95% CI, 2.61– protein A) increased sensitivity to 100%. promised by its multifetal nature. Ed- 5.38), (5) neonatal death (OR, 2.08; 95% The authors did acknowledge that, with wards et al20 confirmed a sensitivity of CI 1.47–2.94), and (6) infant death (OR, larger numbers, the combined detection 82% and negative predictive value of 1.97; 95% CI,1.49–2.61). rate would be Ͻ100%.11 98% for anatomic surveys among 245 In summary, once twin pregnancies As alluded to earlier, early diagnosis is consecutive twins, with a 4.9% preva- are detected, sonographic examination important to minimize the complica- lence of anomalies. Among 495 mono- should be done to determine chorionic- tions that are associated with interven- chorionic twins, Sperling et al21 reported ity, first trimester screening should be tion. Chorionic villus sampling (CVS) is severe structural abnormalities in 2.6%; done to identify fetuses with aneuploidy, the standard first-trimester approach to two-thirds of the abnormalities were car- targeted ultrasound should be done for the confirmation of suspected aneu- diac. With first-trimester nuchal translu- the detection of major anomalies, and fe- ploidy. CVS is performed by 2 general cency and anatomy scan at Ͻ20 weeks of tal echocardiography should be done for approaches: transabdominal vs transcer- gestation, 83% of anomalies and aneu- identification of congenital heart defect. vical, depending on operator experience ploidy were detected. Earlier reports on As recommended by the ACOG practice and placental location/accessibility. In detection of congenital anomalies in bulletin on ultrasonography in pregnan- the hands of experienced clinicians, first- twin pregnancies noted a lower detection cy,23 every patient should be informed trimester CVS has been found to be at rate. In 1991, Allen et al22 reported that, about the limitation of the detection of least as safe and effective as second-tri- among 157 pair of twins (314 newborn all major birth defects. If 1 fetus has a mester amniocentesis for prenatal diag- infants), anomalies occurred in 9.5%. major structural or chromosomal ab- nosis in twin gestations. De Catte et al13 Antenatal ultrasonography detected only normality, selective termination should summarized the outcomes of CVS with 3 39% of all major anomalies, 55% of non- be discussed. earlier studies14-16 and their own experi- cardiac anomalies, and 69% of major ence with 262 cases. Overall outcomes of anomalies for which routine prenatal Genetic amniocentesis 614 twins who had CVS were known. management would be altered. For de- Compared with singleton pregnancies, The likelihood of total loss was 4.6% tection of cardiac anomalies, their ultra- twin pregnancies are at higher risk for (95% confidence interval [CI], 3.5–6.0). sound protocol was limited to a 4-cham- fetal anomalies and for chromosomal Furthermore, Ferrara et al17 confirmed ber view, and they detected no major abnormalities. Rodis et al27 calculated that CVS does not increase the preg- cardiac lesions. Thus, it is understand- that a 33-year-old woman with twins has nancy loss rate before multifetal preg- able why the American College of an equivalent risk of a child with Down nancy reduction. Obstetrics and Gynecology (ACOG) syndrome as a 35-year-old woman with a Compared with singleton pregnan- practice bulletin23 on ultrasonography singleton infant. Thus, the importance cies, twin pregnancy is associated with an recommends that, as part of cardiac of genetic amniocentesis with twins can increased incidence of anomalies,18,19 al- screening examination, the views of the be seen. though the rate of anomalies in dizygotic outflow tracts should be obtained, if Among the 6 publications that re- twins is not likely increased per twin. technically feasible. Twins should have ported on loss rate after genetic amnio- Hardin et al,18 for example, compared fetal echocardiograms, especially if they centesis with twins, the needle gauge var- the prevalence of cardiovascular defects are monochorionic24 or a result of as- ied, but all investigators used 2 separate in 56,709 California twin pairs with sin- sisted reproduction.25 needle insertions (Table 1).28-33 Al- gleton pregnancies. They categorized Importantly, if discordant anomaly is though the rate of loss at Ͻ24 weeks of cardiac anomalies into 16 groups; twins noted, the likelihood of adverse outcome gestation varied from 0.4-4.1%, the cu- had a higher incidence for all 16 catego- for the normal twin is increased. Sun et mulative experience with Ͼ1700 amnio-

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TABLE 1 Amniocentesis with twin pregnancies Twin Loss at Twin pregnancy pregnancy Needle Second <24 wk Loss rate, with no Loss with no Loss rate, Variable Country amniocentesis size puncture gestation, n %a amniocentesis, n amniocentesis, n %a Yukobowich Israel 476 20 Yes 13 2.7 (1.6–4.6) 477 3 0.6 (0.2–1.8) et al28b ...... Tóth-Pál et Hungary 155 22 Yes 6 3.9 (1.8–9.1) 292 7 2.4 (1.1–4.8) al29 ...... Millaire et Canada 134 22 Yes 4 3.0 (1.1–7.4) 248 2 0.8 (0.2–2.8) al30 ...... Delisle et British Columbia 233 No mention Yes 1 0.4 (0.1–2.3) — — — al31 ...... Cahill et United States 311 22 Yes 9 2.9 (1.5–5.4) — — — al32 ...... Daskalakis Greece 442 21 Yes 18 4.1 (2.5–6.7) — — — et al33 ...... TOTAL 1751 51 2.9 (2.3–3.8) 1,017 12 1.1 (0.6–2.0) ...... a Data presented as percentage (95% confidence interval); b Reported loss rate within 4 weeks of birth. Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. centeses indicates that the fetal loss rate is weeks of gestation) than singleton preg- births occurred after preterm premature 2.9% (95% CI, 2.3–3.8) or 1 per 34 (95% nancies, although its magnitude may be rupture of membranes (Figure 5). Per- CI, 26–43). It is noteworthy that a sys- underappreciated.2 In 2006, of the haps because the data do not lend them- tematic review that summarized the re- 137,085 twins who were delivered in the selves to detailed information on the sults of 29 articles calculated that, for sin- United States, approximately 60% of the cause of indicated delivery, the investiga- gleton pregnancies who undergo genetic twins were preterm (78,824 infants) and tors did not provide the specific reasons amniocentesis, the loss rate at Ͻ24 weeks weighed Ͻ2500 g (82,799 infants). Ap- clinicians were compelled to perform the of gestation is 0.9% (95% CI, 0.6–1.3) proximately 1 in 10 twins was born at delivery prematurely. or 1 per 111 procedures (95% CI, 76– Ͻ32 weeks of gestation (n ϭ 16,597 in- The perinatal mortality (PNM) rates 34 111). The differential loss rate between fants) or weighed Ͻ1500 g (n ϭ 13,983; with preterm birth vary based on plural- singleton and twin pregnancies may re- Figure 4). As Ananth et al36 noted that, ity, ethnicity, and the subtypes of prema- sult from the fact that the spontaneous with the exception of France and Fin- turity (Figure 6). With the exception of Ͻ loss rate at 24 weeks of gestation is land, most industrialized countries have singleton and white pregnancies, the higher with multiples. Only 3 of these re- noted a temporal increase in prematu- PNM rate is highest when preterm deliv- ports provided data for twins who were rity. The increase in preterm births is ery follows premature rupture of mem- treated at a similar time who did not have multifactorial but can be categorized branes. Consistently for singleton and 28-30 a genetic amniocentesis. For the into 3 groups: medically indicated be- twin pregnancies for African American twins who did not have the invasive pro- cause of maternal-neonatal outcomes, and white women, the PNM rate is low- cedure, the overall loss rate was 1.1% after spontaneous onset of preterm est when preterm birth results from (95% CI, 0.6–2.0). A comparison of labor, and after premature rupture of spontaneous labor. Within the same eth- spontaneous loss rate vs after loss rate membranes. nicity, the total preterm PNM rate is sig- genetic amniocentesis indicates that the A comparison of the causes of preterm nificantly less for twin than for singleton fetal losses are approximately 160% births for singleton vs twin pregnancies pregnancies. higher after the procedure (1.1% vs is instructive, especially when the data The remarkable finding by Ananth et 2.9%; Table 1). It should be noted that are separated by ethnicity. Using the data al36,37 is that, despite the increase in the loss subsequent to genetic amniocentesis from National Center for Health Statis- rate of prematurity in the United States, is similar among twins who are con- tics, Ananth et al36,37 provided such data there is a concomitant decrease in PNM ceived spontaneously or with ART and (singleton pregnancies for the year 2000 rates among African American and white those who had undergone multifetal and twin pregnancies for the years 1999- women among twin and singleton preg- reduction.35 2002). For singleton and twin pregnan- nancies. In 2 separate publications, Subtypes of preterm birth cies for African American and white Ananth et al36,37 reported the trends in and perinatal death women, approximately 50% of preterm preterm births for twin and singleton Undeniably twin pregnancies are more births were indicated; one-third of the pregnancies in the United States from likely to be delivered preterm (Ͻ37 births were spontaneous, and 10% of the 1989-2000, along with its impact on

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medically indicated preterm births are FIGURE 4 associated with a favorable reduction in Preterm births in 2006: twin vs singleton PNM rates. Singletons Twins

OR, 10.83 (95% CI, 10.71-10.95) OR, 21.94 (95% CI, 21.68-22.19) Preterm labor: prediction, 60% 58% prevention, and management Regardless of the temporal trend, the prediction, prevention, and management of preterm birth are important and should be evidence based. Transvaginal cervical length or fetal ﬁbronectin (fFN) level can be used to differentiate those pregnancies that are likely to vs not likely

OR, 7.68 (95% CI, 7.51-7.78) OR, 10.21 (95% CI, 10.01-10.41) to deliver prematurely. 12% 38 11% 10% Fox et al described their experience 7% with routinely obtaining, from 22-32 2% 1% weeks, fFN and measuring transvaginal cervical length. Overall, among 155 twin Del <37 weeks Del <32 weeks BW <2500 g BW <1500 g pregnancies, of which 64% were the results of in vitro fertilization, the rate of BW, birthweight; CI, conﬁdence interval; Del, delivery; OR, odds ratio. Ͻ Data derived, with permission, from Martin et al.2 birth at 37 weeks of gestation was 53%, Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. at Ͻ34 weeks of gestation was 16%, and Ͻ28 weeks of gestation was 4%. The rate of spontaneous preterm birth was significantly higher when either fFN was pos- perinatal mortality rates (Figure 7). For twin pregnancies and for white singleton itive or cervical length was Ͻ20 mm, but their analysis, they had 1,172,405 pre- pregnancies; however, it decreased for it was the highest when both tests were term twin live births and 46,375,578 pre- African American twin singletons. The abnormal (Table 2). It is noteworthy term singleton pregnancies. Over 11 PNM rate decreased for all 4 groups dur- that, if the fFN is negative and cervical years, the rate of preterm births in- ing the 11 years (Figure 7). The reason length is at least 20 mm, almost 90% of creased for African American and white for the decrease in the PNM rate is that the pregnancies will deliver at Ͼ34 weeks of gestation. Conversely, if both fFN and cervical length are abnormal, Ͼ50% of FIGURE 5 the pregnancies will deliver at Ͻ34 weeks Data are based on ethnicity and subtypes of gestation. of preterm births: singleton vs twin Routine use of the diagnostic tests in Med Indicated Sp PTB PROM twin pregnancies should not be expected to decrease the actual rate of preterm 8% 9% 10% 9% births. Matter of fact, the use of cervical length could increase the duration of an- 30% tepartum admission without concomi- 32% 35% 38% tant improvement in neonatal outcome. A retrospective analysis by Gyamﬁ et al39 compared the outcome among 184 twin pregnancies with cervical length vs 78 pregnancies without this data. Between 62% the 2 groups, there was no difference in 56% 58% 53% gestational age at delivery (34.8 vs 35.3 weeks of gestation; P ϭ .35), delivery at Ͻ28 weeks of gestation (8.2% vs 3.9%; P ϭ .21), or delivery at Ͻ34 weeks of gestation (26.1% vs 25.6%; P ϭ .94); how- Singletons (AA) Twins (AA) Singletons (W) Twins (W) ever, there was an increase in maternal AA, African American; med, medically; PROM, premature rupture of membranes; Sp PTB, spontaneous preterm birth; W, white. Data derived, with permission, from Ananth et al.36,37 antepartum length of stay (cervical Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. length at 34.5 days vs no cervical length at 31.3 days; P Ͻ .001). It is uncertain

310 American Journal of Obstetrics & Gynecology OCTOBER 2010 www.AJOG.org Obstetrics Reviews whether their findings would have been FIGURE 6 valid had they obtained fFN measure- Data are based on ethnicity and perinatal mortality ments in conjunction with cervical rates with preterm births: singleton vs twin length. So, fFN and cervical length can be used to ascertain which twin pregnancies PROM Med Ind Sp PTB will deliver prematurely, although im- 100 provement in peripartum outcomes 76 should not be expected. 71 Of twin gestations with symptoms of 51 53 preterm labor, approximately 22-29% of 49 the pregnancies will deliver within 7 44 41 43 days.39,40 Thus, the first goal with symp- 33 tomatic patients should be to identify 31 those who will deliver prematurely. Such 29 identification avoids unnecessary thera- 25

peutic interventions like unwarranted PNM/1000 births hospitalization and medical treatment. The usefulness of fFN in the evaluation of twin gestations with symptoms of preterm labor is not related to its ability to predict who will deliver in the next 14 10 days (19% positive predictive value; 95% Singletons (AA) Twins (AA) Singletons (W) Twins (W) CI, 7–39%), but rather the test’s ability AA, African American; Med Ind, medically indicated; PNM, perinatal mortality rate; PROM, premature rupture of membranes; Sp PTB, to determine who is not going to deliver spontaneous preterm birth; W, white. during the timeframe (97% negative Data derived, with permission, from Ananth et al.36,37 predictive value; 95% CI, 89–100). The Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. negative predictive value of fFN is similar for singleton and twin pregnancies with symptoms of preterm labor.40 Fuchs et al41 reported on the inverse relationship between cervical length and likelihood of delivery of twin pregnan- FIGURE 7 cies within a week of the onset of symp- Trend in the rate of preterm births and perinatal mortality for twin toms: 80% of the pregnancies delivered and singleton births in the United States: 1989-2000 when the cervical length was 0-5 mm; AA White 46% of the pregnancies delivered when the cervical length was 6-10 mm; 29% of 30% the pregnancies delivered when the cer- 22% vical length was 11-15 mm; 21% of the 14% pregnancies delivered when the cervical 9% length was 16-20 mm; 7% of the preg- 10% nancies delivered when the cervical length was 21-25 mm, and none of the pregnancies delivered when the cervical length was at least 25 mm. Undeniably, -10% randomized trials are needed to deter- -15% mine whether the knowledge of fFN and cervical length inﬂuences outcome among -30% -27% twin pregnancies, as it did in the trial re- -30% ported by Ness et al.42 While awaiting the -37% results of these randomized trials, we -41% should be cognizant of the ACOG prac- -50% PTB-Twins PTB-Singletons PNM-Twins PNM-Singletons tice bulletin on the management of pre- 43 AA, African American; PNM, perinatal mortality rate; PTB, preterm birth. term labor. They recommend that ei- Data derived, with permission, from Ananth et al.36,37 ther cervical ultrasound examination or Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. fFN or both diagnostic tests should be

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TABLE 2 Spontaneous preterm birth among twin pregnancies Gestational week Variable <28 <30 <32 <34 <37 Negative fetal fibronectin level: 135 births, % 2.1 2.9 4.5 Ͻ11.5 46 ...... Positive fetal fibronectin level: 20 births, % 27.3 21.4 35 55 95 ...... P value .005 .017 Ͻ .001 .001 Ͻ .001 ...... Transvaginal cervical length Ն20 mm: 129 births, % 2.3 3 4.7 11.9 46.8 ...... Transvaginal cervical length Ͻ20 mm: 26 births, % 25 15.8 26.9 36 83.3 ...... P value .008 .42 .002 .006 .001 ...... Negative fetal fibronectin level and transvaginal cervical length Ն20 mm: 1.6 2.4 4.2 10.3 43 120 births, % ...... Either positive fetal fibronectin level or transvaginal cervical length Ͻ20 mm: 13.3 9.5 8.3 26.1 77.3 24 births, % ...... Positive fetal fibronectin level and transvaginal cervical length Ͻ20 mm: 11 50 33.3 54.5 54.5 100 births, % ...... P value Ͻ .001 .001 Ͻ .001 Ͻ .001 Ͻ .001 ...... Data derived, with permission, from Fox et al.38 Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. used to determine which patients do not tified only 2 randomized trials that as- vs 15% for suture vs no suture, respec- need tocolytics. Until there are publica- sessed the use of progesterone vs placebo tively).47 More importantly, when cer- tions to the contrary, this recommenda- for multiple pregnancy. Depending on clage was used in asymptomatic woman tion is applicable to twin and singleton the outcome of interest, the number of with twin gestations and short cervical pregnancies. participants varied between 154 and length on transvaginal ultrasound exam- Considering the increased likelihood 1280. The authors concluded that the use ination, it significantly increased the risk of preterm births among twin preg- of progesterone in multiple gestations of delivery at Ͻ35 weeks of gestation nancies, it is reasonable to determine does not decrease the likelihood of birth (75% in the cerclage group and 36% whether it can be prevented. One of the at Ͻ37 weeks of gestation (RR, 1.01; 95% without suture; RR, 2.15; 95% CI, 1.15– more common interventions that have CI, 0.92–1.12), birthweight Ͻ2500 g 4.01).48 Thus, cerclage of asymptomatic been tried in the past was the use of pro- (RR, 0.94; 95% CI, 0.86–1.02), respira- short cervical length should be avoided phylactic oral betamimetics to reduce tory distress (RR, 1.13; 95% CI, for twin gestations. the incidence of preterm birth in twin 0.86–1.48), intraventricular hemor- Other prophylactic interventions, which gestations. From a Cochrane database, rhage grade 3 or 4 (RR, 1.20; 95% CI, have been examined in multiple gesta- Yamasmit et al44 reviewed 5 randomized 0.40–3.54), necrotizing enterocolitis tions to prevent preterm delivery, are trials with 344 twin pregnancies. This in- (RR, 0.77; 95% CI, 0.17–3.42), neonatal bed rest and home uterine monitoring. tervention has not been proved to reduce sepsis (RR, 0.95; 95% CI, 0.55–1.63), and Crowther,49 in 2001, summarized the re- the incidence of birth at Ͻ37 weeks of perinatal death (RR, 1.95; 95% CI, sults of 6 trials with hospitalization and gestation (RR, 0.85; 95% CI, 0.65–1.10) 0.37–10.33). bed rest. The summary, which involved or delivery at Ͻ34 weeks of gestation Another approach to decrease prema- Ͼ600 patients and 1400 newborn in- (RR, 0.47; 95% CI, 0.15–1.50). It also has ture births is to reinforce the cervix with fants, noted that the intervention did not not been shown to change the neonatal a cerclage in multiple gestations. The decrease the rate of preterm birth or outcomes of low birthweight (RR, 1.19; placement of a cerclage was examined perinatal mortality. Paradoxically, bed 95% CI, 0.77–1.85) or neonatal mortal- both as a prophylactic intervention and rest significantly (OR, 1.84; 95% CI, ity rates (RR, 0.80; 95% CI, 0.35–1.82). when a short cervix is noted on ultra- 1.01–3.34) increased the risk of preterm Therefore, in light of these findings, the sound examination. The use of history- birth at Ͻ34 weeks of gestation in use of prophylactic tocolysis should not indicated (prophylactic) cerclage for asymptomatic twin gestations. Similarly be undertaken. ovulation-induced twin gestations (n ϭ a lack of efficacy was also shown with the Progesterone has been shown to de- 50) in a randomized trial did not de- use of home uterine monitoring for twin crease the incidence of recurrent pre- crease the rate of prematurity signifi- gestations. Because home uterine moni- term delivery in a singleton gestation.45 cantly (45% with cerclage vs 48% with- toring has not been shown to be benefi- A systematic review by Dodd et al46 iden- out suture) or neonatal mortality (18% cial in the prevention of preterm birth in

312 American Journal of Obstetrics & Gynecology OCTOBER 2010 www.AJOG.org Obstetrics Reviews multiple gestations, its use should be bies to unnecessary treatment that ad- understanding of twin pregnancies is abandoned.50 Thus, the following treat- versely affects growth. Therefore, the important. ment modalities have no role in the pre- repeated administration of ACS should This review of the literature on twin vention of preterm births with twin be avoided in favor of those pregnancies gestations, although limited to common gestations: bed rest and oral tocolytics; that are at immediate risk for preterm problems, was notable for 4 findings. cerclage and progesterone injections. births. First, the rate for twin gestations has sta- One of the most difficult aspects of One single rescue course of ACS bilized for now. For 2004, 2005, and caring for multiple gestations is the lack should be given among twins who have 2006, there have been approximately 32 of proven intervention once preterm la- received betamethasone 12 mg, intra- twin gestations per 1000 births (Figure bor has been diagnosed. The use of toco- muscularly, twice, 24 hours apart. If at 1). Second, the sonographic evaluations lytics for the treatment of preterm labor least 14 days have elapsed and delivery is of twin gestations should be limited not has not been shown to decrease the inci- likely at Ͻ33 weeks of gestation, then a only to the identification of the chorio- dence of delivery within 7 days of treat- single rescue dose should be adminis- nicity but also aneuploidy with first- ment, perinatal or neonatal death, or the tered. This recommendation is based on trimester screening and anomaly with neonatal complications of respiratory the randomized trial by Garite et al57 that first- and second-trimester ultrasound distress syndrome, necrotizing entero- involved 437 patients, with 577 newborn examinations. Because anomalies and colitis, or cerebral palsy. This lack of infants, 24% of whom (141; 1 fetal death aneuploidies are more common with proven efficacy,51 the amplification of twin pregnancies than with singleton before randomization) were from twin 26,27 side-effects, and the increased risk of gestations. Compared with the patients pregnancies, it is important that cli- pulmonary edema with tocolytics in nicians who have experience in detecting 52 who received placebo, patients who re- multiple gestations lead ACOG to ceived the rescue dosage had a significant these abnormalities evaluate these pa- comment that they should be used judi- tients. If need be, parents who are ex- 53 reduction in composite perinatal neona- ciously in this population. tal morbidity (64% vs 44%; P ϭ .02) and pecting twins should be offered and re- In contrast to the unproven efficacy of ferred for CVS, genetic amniocentesis, significantly decreased rate of respira- tocolytics, the use of antenatal cortico- and selective reduction. tory distress syndrome, ventilator sup- steroids (ACS) has been shown54 to de- Third, we found that the rate of pre- port, and surfactant use. crease the incidence of neonatal death term births is significantly higher for In summary, although there are diag- (RR, 0.69; 95% CI, 0.58–0.81), respira- twin pregnancies than for singleton nostic tests to identify those pregnancies tory distress syndrome (RR, 0.66; 95% pregnancies (Figure 4). Although this that will deliver prematurely, these tests CI, 0.43–0.69), intraventricular hemor- has been known, findings from the na- do not decrease the rate of preterm birth. rhage (RR, 0.54; 95% CI, 0.43–0.69), ne- tional data provide not only unequivocal There are no known treatments to de- crotizing enterocolitis (RR, 0.46; 95% evidence but also the magnitude to crease the likelihood of preterm birth. CI, 0.29–0.74), and systemic infections which this occurs. Data from the United within the first 48 hours of life (RR, 0.56; Tocolytics should be used either to trans- States also are available for the analysis of 95% CI, 0.38–0.58). Although none of fer a patient to a tertiary center or to causes for preterm birth (Figure 5) and the studies specifically addressed use in ensure ACSs are administered. Pro- associated perinatal mortality rates (Fig- multiple gestations, the National Insti- longed tocolytic use should be avoided, ure 6). But what is most captivating is tutes of Health recommends that all as should repeated administration of that, although the rate for preterm birth women in preterm labor, regardless of corticosteroids. has increased, the associated perinatal the number of fetuses, be given a course mortality rate has actually decreased. of ACS.55 Comment The fact that this conclusion is based on a Although ACS does improve neonatal Twins are a source of awe and delight to population-based, retrospective cohort outcome significantly, it should not be parents, fascination and photo opportuni- study comprised of 46,375,578 women 1 administered repeatedly. A retrospective ties to the press, and challenge and trepi- and 1,172,405 twins in the United States 58,59 study by Murphy et al56 compared the dation to clinicians. Compared with is staggering.36,37 It will be beneficial if use of prophylactic ACS in twin gesta- singleton pregnancies, twin pregnancies other countries can confirm the findings tions beginning at 24 weeks of gestation are more likely to be complicated by hy- reported by Ananth et al36,37 and if fu- and given every 2 weeks (n ϭ 136) with pertensive disorders, gestational diabetes ture studies can ascertain what precisely the standard approach in women who mellitus, anemia, preterm birth, ante- and decreased the perinatal mortality rate. It were at immediate risk of preterm deliv- postpartum hemorrhage, and maternal will also be useful to understand whether ery (n ϭ 902). The prophylactic ap- death.60 The newborn infants from twin the overall perinatal mortality rate, not proach was shown not to offer a signifi- pregnancies are more likely to have anom- just for preterm births, has also de- cant reduction in respiratory distress alies,26 intrauterine growth restriction,61 creased in the United States. syndrome (13% vs 11%; adjusted OR, handicap, and cerebral palsy. The average Fourth, the findings focus on the man- 0.69; 95% CI, 0.33–1.46) and was associ- cost for singleton deliveries is $9,845 and agement of preterm labor with twin ges- ated with exposing a large number of ba- for twins is $37,947.60 Thus, continued tations. Clinicians should be cognizant

OCTOBER 2010 American Journal of Obstetrics & Gynecology 313 Reviews Obstetrics www.AJOG.org of the facts that, with twins, preterm con- 8. Hack KE, Derks JB, Schaap AH, et al. Peri- 23. Abuhamad AZ. ACOG practice bulletin: ul- tractions are common, that the benefit of natal outcome of monoamniotic twin pregnan- trasonography in pregnancy. Obstet Gynecol 2008;112:951-61. tocolytics is limited although the com- cies. Obstet Gynecol 2009;113:353-60. 9. Evans MI, Goldberg JD, Horenstein J, et al. 24. Campbell KH, Copel JA, Ozan Bahtiyar M. plications rate is higher, and that the pre- Selective termination for structural, chromo- Congenital heart defects in twin gestations. term birth-related perinatal mortality somal, and Mendelian anomalies: international Minerva Ginecol 2009;61:239-44. rate has been lowered. Whenever feasi- experience. Am J Obstet Gynecol 1999;181: 25. Abuhamad A, Chaoui R. Congenital heart ble, clinicians should use diagnostic tests 893-7. disease: incidence, risk factors, and prevention. 10. Evans MI, Berkowitz RL, Wapner RJ, et al. In: Abuhamad A, Chaoui R, eds. A practical (transvaginal cervical length or fFN) to guide to fetal echocardiography: normal and differentiate true vs false preterm labor. Improvement in outcomes of multifetal pregnancy reduction with increased experience. abnormal hearts. 2nd ed. Philadelphia: Lippin- The use of tocolytics should be limited to Am J Obstet Gynecol 2001;184:97-103. cott, Williams & Wilkins; 2010:1-10. Ͻ (1) either the cervical length is 2.5 cm 11. Chasen ST, Perni SC, Kalish RB, Cherve- 26. Sun LM, Chen XK, Wen SW, Fung KF, Yang Q, Walker MC. Perinatal outcomes of normal or fFN is positive or both, (2) the test nak FA. First-trimester risk assessment for tri- cotwins in twin pregnancies with one structur- results have been evaluated, (3) 48 hours somies 21 and 18 in twin pregnancy. Am J Ob- ally anomalous fetus: a population based retro- stet Gynecol 2007;197:374.e1-3. have elapsed since the first dosage of cor- spective study. Am J Perinatol 2009:26:51-6. 12. Sebire NJ, Snijders RJ, Hughes K, ticosteroid was administered, or (4) the 27. Rodis JF, Egan JF, Craffey A, Ciarleglio L, Sepulveda W, Nicolaides KH. Screening for tri- Greenstein RM, Scorza WE. Calculated risk of patient has been transferred to a tertiary somy 21 in twin pregnancies by maternal age 43 chromosomal abnormalities in twin gestations. center. As with singleton pregnancies, and fetal nuchal translucency thickness at there is no justification for prolonged to- Obstet Gynecol 1990;76:1037-41. 10-14 weeks of gestation. BJOG 1996;103: 28. Yukobowich E, Anteby EY, Cohen SM, Lavy colytics with twin pregnancies. 999-1003. Y, Granat M, Yagel S. Risk of fetal loss in twin In conclusion, there are several reas- 13. De Catte L, Liebaers I, Foulon W. Outcome of pregnancies undergoing second trimester am- suring findings with twin pregnancies. twin gestations after first trimester chorionic villus niocentesis. Obstet Gynecol 2001;98:231-4. sampling. Obstet Gynecol 2000;96:714-20. The rate of twin pregnancies is not in- 29. Tóth-Pál E, Papp C, Beke A, Bán Z, Papp Z. 14. Brambati B, Tului L, Lanzani A, Simoni G, creasing in the United States; although Genetic amniocentesis in multiple pregnancy. Travi M. First trimester genetic diagnosis in mul- Fetal Diagn Ther 2004;19:138-44. the preterm birth rate is high, the associ- tiple pregnancy: principles and potential pitfalls. 30. Millaire M, Bujold E, Morency AM, Gauthier ated perinatal mortality rate is decreas- Prenat Diagn 1991;11:767-74. RJ. Mid-trimester genetic amniocentesis in twin ing. Future studies should focus on im- 15. Pergament E, Schulman JD, Copeland K, et pregnancy and the risk of fetal loss. J Obstet proving the detection of birth defects al. The risk and efficacy of chorionic villus sam- Gynaecol Can 2006;28:512-8. and of abnormal growth and on antepar- pling in multiple gestations. Prenat Diagn 31. Delisle MF, Brosseuk L, Wilson RD. Amnio- 1992;12:377-84. centesis for twin pregnancies: is alpha-fetopro- tum testing to improve the outcomes for 16. Wapner RJ, Johnson A, Davis G, Urban A, tein useful in confirming that the two sacs were twin pregnancies with medical or obstet- Morgan P, Jackson L. Prenatal diagnosis in twin sampled? Fetal Diagn Ther 2007;22:221-5. ric complications. f gestations: a comparison between second-tri- 32. Cahill AG, Macones GA, Stamilio DM, Dicke mester amniocentesis and first-trimester chori- JM, Crane JP, Odibo AO. Pregnancy loss rate onic villus sampling. Obstet Gynecol 1993; after mid-trimester amniocentesis in twin preg- REFERENCES 82;49-56. nancies. Am J Obstet Gynecol 2009;200: 1. Saul S. 21st Century babies: the gift of life, 17. Ferrara L, Gandhi M, Litton C, et al. Chori- 257.e1-6 and its price. The New York Times. Oct. 11, onic villus sampling and the risk of adverse out- 33. Daskalakis G, Anastasakis E, Papantoniou 2009. Available at: http://www.nytimes.com/ come in patient undergoing multifetal preg- N, Mesogitis S, Antsaklis A. Second trimester ϭ ϭ 2009/10/11/health/11fertility.html?_r 1&scp nancy reduction. Am J Obstet Gynecol 2008; amniocentesis in assisted conception versus ϭ 1&sq The%20Gift%20of%20Life,%20and%20 199:408.e1-4. spontaneously conceived twins. Fertil Steril ϭ Its%20Price&st cse. Accessed Oct. 19, 2009. 18. Hardin J, Carmichael SL, Selvin S, Lammer 2009;91:2572-7. 34. Mujezinovic F, Alfirevic Z. Procedure-re- 2. Martin JA, Hamilton BE, Sutton PD, et al. EJ, Shaw GM. Increased prevalence of cardio- Births: final data for 2006. Natl Vital Stat Rep lated complications of amniocentesis and cho- vascular defects among 56,709 California twin 2009;57:1-102. rionic villous sampling: a systematic review. Ob- pairs. Am J Med Genet A 2009;149A:877-86. 3. Imaizumi Y. Trends of twinning rates in ten stet Gynecol 2007;110:687-94. 19. Bahtiyar MO, Dulay AT, Weeks BP, Fried- countries, 1972-1996. Acta Genet Med Ge- 35. Antsaklis A, Daskalakis G, Papantoniou N, man AH, Copel JA. Prevalence of congenital mellol (Roma) 1997;46:209-18. Mesogitis S, Michalas S. Genetic amniocente- heart defects in monochorionic/diamniotic twin 4. Eriksson AW, Fellman J. Temporal trends in sis in multifetal pregnancies reduced to twins gestations: a systematic literature review. J Ul- the rates of multiple maternities in England and compared with nonreduced twin gestations. Wales. Twin Res Hum Genet 2007;10:626-32. trasound Med 2007;26:1491-8. Fertil Steril 2000;74:1051-2. 5. De Mouzon J, Lancaster P, Nygren KG, et al. 20. Edwards MS, Ellings JM, Newman RB, Me- 36. Ananth CV, Joseph KS, Demissie K, Vintzi- World collaborative report on assisted repro- nard MK. Predictive value of antepartum ultra- leos AM. Trends in twin preterm birth subtypes ductive technology, 2002. Hum Reprod 2009; sound examination for anomalies in twin gesta- in the United States, 1989 to 2000: impact of 1:1-11. tion. Ultrasound Obstet Gynecol 1995;6:43-9. perinatal mortality. Am J Obstet Gynecol 2005; 6. Lee YM, Cleary-Goldman J, Thaker HM, 21. Sperling L, Kill C, Larsen LU, et al. Detection 193:1076-82. Simpson LL. Antenatal sonographic prediction of chromosomal abnormalities, congenital ab- 37. Ananth CV, Joseph KS, Demissie K, Vintzi- of twin chorionicity. Am J Obstet Gynecol normalities and transfusion syndrome in twins. leos AM. Trends in preterm birth and perinatal 2006;195:863-7. Ultrasound Obstet Gynecol 2007;29:517-26. mortality among singletons: United States, 7. Bermudez C, Becerra CH, Bornick PW, Allen 22. Allen SR, Gray LG, Frentzen BH, Cruz AC. 1989 through 2000. Obstet Gynecol 2005; MH, Arroyo J, Quintero RA. Placental types and Ultrasonographic diagnosis of congenital anoma- 105:1084-91. twin-twin transfusion syndrome. Am J Obstet lies in twins. Am J Obstet Gynecol 1991;165: 38. Fox NS, Saltzman DH, Klauser CK, Peress Gynecol 2002;187:489-94. 1056-60. D, Gutierrez CV, Rebarber A. Prediction of

314 American Journal of Obstetrics & Gynecology OCTOBER 2010 www.AJOG.org Obstetrics Reviews spontaneous preterm birth in asymptomatic 46. Dodd JM, Flenady VJ, Cincotta R, Crowther women at risk of preterm birth. Cochrane twin pregnancies with the use of combined fetal CA. Progesterone for the prevention of preterm Database Syst Rev 2006;3:CD004454. fibronectin and cervical length. Am J Obstet birth a systematic review. Obstet Gynecol 55. National Institutes of Health. Report of the Gynecol 2009;201:313.e1-5. 2008;112:127-34. Consensus Development Conference on the ef- 39. Gyamfi C, Lerner V, Holzman I, Stone J. 47. Dor J, Shalev J, Mashiach S, et al. Elective fect of corticosteroids for fetal maturation on Routine cervical length in twins and perinatal cervical suture of twin pregnancies diagnosed perinatal outcomes. Pub no. 95-3784. Be- outcomes. Am J Perinatol 2007;24:65-70. ultrasonically in the first trimester following in- thesda, MD: U.S. Department of Health and 40. Singer E, Pilpel S, Bsat F, Plevyak M, Healy duced ovulation. Gynecol Obstet Invest 1982; Human Services, Public Health Service; 1994. A, Markenson G. Accuracy of fetal fibronectin to 13:55-60. 56. Murphy DJ, Caukwell S, Joels LA, Wardle predict preterm birth in twin gestations with 48. Berghella V, Odibo A, To M, Rust O, Althui- P. Cohort study of the neonatal outcome of twin symptoms of labor. Obstet Gynecol 2007; sius S. Cerclage for short cervix on ultrasound pregnancies that were treated with prophylactic 109:1083-7. meta-analysis of trials using individual patient- or rescue antenatal corticosteroids. Am J Ob- 41. Fuchs I, Tsoi E, Henrich W, Dudenhausen level data. Obstet Gynecol 2005;106:181-9. stet Gynecol 2002;187:483-8. JW, Nicolaides KH. Sonographic measurement 49. Crowther CA. Hospitalization and bed rest of cervical length in twin pregnancies in threat- 57. Garite TJ, Kurtzman J, Maurel K, et al. Im- for multiple pregnancy. Cochrane Database ened preterm labor. Ultrasound Obstet Gynecol pact of a “rescue course” of antenatal cortico- Syst Rev 2001;1:CD000110. 2004;23:42-5. steroids: a multicenter randomized placebo- 50. Colton T, Kayne H, Zhang Y. A meta-anal- 42. Ness A, Visintine J, Ricci E, Berghella V. controlled trial. Am J Obstet Gynecol 2009; ysis of home uterine activity monitoring. Am J Does knowledge of cervical length and fetal fi- 200:248.e1-9. Obstet Gynecol 1995;173;1499-505. bronectin affect management of women with 58. Baretta E, Boghi I, Fichera A, Mor E, Gre- 51. threatened preterm labor? A randomized trial. Anotayanonth S, Subhedar NV, Garner P, gorini S, Frusca T. Twin pregnancy: not only Am J Obstet Gynecol 2007;197:426.e1-7. Neilson JP, Harigopal S. Betamimetics for in- a medical event. Minerva Ginecol 2007;59: 43. American College of Obstetricians and Gy- hibiting preterm labour. Cochrane Database 571-8. necologists. Management of preterm labor. Syst Rev 2004;4:CD004352. 59. Bryan E. The impact of multiple preterm 52. Pisani RJ, Rosenow EC 3rd. Pulmonary Washington, DC: The College; 2003. birth on the family. BJOG 2003;20:24-8. edema associated with tocolytic therapy. Ann 44. Yamasmit W, Chaithongwongwatthana S, 60. Kinzler WL, Ananth CV, Vintzileos AM. Med- Intern Med 1989:1:110:714-8. Tolosa JE, Pereira L, Lumbiganon P. Prophylactic ical and economic effects of twin gestations. J 53. American College of Obstetricians and Gy- oral betamimetics for reducing preterm birth in Soc Investig 2000;7:321-7. necologists; Society of Maternal-Fetal Medi- woman with a twin pregnancy. Cochrane Data- 61. Chauhan SP, Shields D, Parker D, Sander- cine. Multiple gestation: complicated twin, trip- base Syst Rev 2005;20:CD004733. son M, Scardo JA, Magann EF. Detecting fetal 45. Meis PJ, Klebanoff M, Thom E, et al. Pre- let, and higher-order multifetal pregnancy. growth restriction or discordant growth in twin vention of preterm delivery by 17 alpha-hy- Washington, DC: The College; 2004. gestation stratified by placental chorionicity. J droxyprogesterone caproate. N Engl J Med 54. Roberts D, Dalziel S. Antenatal corticoste- Repro Med 2004;49:279-84. 2003;348:2379-85. roids for accelerating fetal lung maturation for

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