Twins prevalence, problems, and preterm births ajog2010
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Twins prevalence, problems, and preterm births ajog2010 Twins prevalence, problems, and preterm births ajog2010 Document Transcript

  • Twins: prevalence, problems, and preterm births Suneet P. Chauhan, MD; James A. Scardo, MD; Edward Hayes, MD; Alfred Z. Abuhamad, MD; Vincenzo Berghella, MD On October 10, 2009, there was an article entitled, “21st Century Ba- bies: The Gift of Life, and Its Price,” which started with 2 succinct sentences: “Scary. Like aliens.” The article could have been dismissed easily were it not published in The New York Times and were the topic something other than twins.1 Because this article is the first in a series called “21st Century Babies: The Twins Dilemma,” twinning will be a part of patient lexicon and a source of con- cern. Thus, a review of antepartum com- plicationswithtwinpregnanciesisuseful not only for the concerned patient but also because recent publications on the topic may influence our practice. A Google search with the word “twin” yields 116,000,000 results in 0.21 sec- onds; a PubMed search with the words “twin pregnancy” found 24,982 publica- tions (November 12, 2009). Therefore, although it is not feasible to summarize the voluminous literature on this topic, this review article will focus on: twin birth rate, common antenatal problems, andpretermbirths,whicharethebaneof modern obstetrics. Twin birth rate In the United States, between 1980 and 2006, the twin rate climbed 101% (Fig- ure 1). There were 68,339 twins born in 1980; 27 years later, 137,085 twins were born.2 The twinning rates have also in- creased in Austria, Finland, Norway, Sweden, Canada, Australia, Hong Kong, Israel, Japan, and Singapore.3 There are multiple causes for the change in the rate of twin pregnancies: use of assisted re- productive techniques (ARTs) and non- ART procedures,4 maternal age, ethnic- ity, variation among the 50 states, and a decreasing rate of triplets and higher or- der multiple gestation.2 Approximately 1% of infants born in the United States in 2006 were conceived with the use of ARTs and account for 18% of the multiple births nationwide. Of 54,566 infants who were born with the use of ARTs, 48% were multiple birth deliveries. The International Committee for Monitoring Assisted Reproductive Technology5 analyzed ARTs for the year 2002 from 53 countries. For conven- tional in vitro fertilization and intracyto- plasmic sperm injection, the overall twin rate was 26%. In the United States, the twin rate was 32%; in Latin America, it was 25%; in Europe, it was 23%; in Asia and the Middle East, it was 22%, and in Australia/New Zealand, it was 21%. The rate of twin pregnancies varies by maternal age and ethnicity (Figure 2). Between 1980 and 2006, twin birth rates rose 27% for mothers Ͻ20 years (com- pared with 80% for women in their 30s) and 190% for mothers who were Ն40 years old. In 2006, 20% of births to women 45-54 years old were twins, com- pared with approximately 2% of births to women 20-24 years old. Twin birth rates were essentially unchanged among the 3 largest racial groups for 2005-2006: non-Hispanic white (36.0 per 1000 births in 2006), non-Hispanic black (36.8 per 1000 births), and Hispanic (21.8 per 1000 births). Since 1990, rates have risen 57% for non-Hispanic white and 38% and 21% for non-Hispanic black and Hispanic women, respectively.2 The rate of twin pregnancies also var- ies among the states (Figure 3). In 2004- 2006, the rate of twin pregnancies in the United States was 32.2 per 1000 live births, with Ͻ25% being 29.5 per 1000 live births; median, 31.8 per 1000 live births, and Ͼ75% being 34.0 per 1000 live births. In Connecticut, Massachu- setts, and New Jersey, 4% of all births were twins. In contrast, Ͻ2.5% of births to New Mexico residents were twin pregnancies.2 The likelihood of twin pregnancies is also increasing because the rate of trip- From the Aurora Health Care and Center for Urban Population Health, Milwaukee, WI (Dr Chauhan); Spartanburg Regional Medical Center, Spartanburg, SC (Dr Scardo); Women’s Center at Aurora Bay Care Medical Center, Greenbay, WI (Dr Hayes); Eastern Virginia Medical School, Norfolk, VA (Dr Abuhamad); Thomas Jefferson Medical School, Philadelphia, PA (Dr Berghella). Received Jan. 12, 2010; revised April 12, 2010; accepted April 19, 2010. Reprints not available from the authors. Authorship and contribution to the article is limited to the 5 authors indicated. There was no outside funding or technical assistance with the production of this article. 0002-9378/$36.00 © 2010 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.04.031 The rate of twin pregnancies in the United States has stabilized at 32 per 1000 births in 2006. Aside from determining chorionicity, first-trimester screening and second-trimester ultrasound scanning should ascertain whether there are structural or chromosomal ab- normalities. Compared with singleton births, genetic amniocentesis–related loss at Ͻ24 weeks of gestation for twin births is higher (0.9% vs 2.9%, respectively). Selective termi- nation for an anomalous fetus is an option, although the pregnancy loss rate is 7% at experienced centers. For singleton and twin births for African American and white women, 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- branes. From 1989-2000, the rate of preterm twin births increased, for African American and white women alike, although the perinatal mortality rate has actually decreased. As with singleton births, tocolytics should be used judiciously and only for a limited time (Ͻ48 hours) in twin births. Administration of antenatal corticosteroids is an evidence-based recommendation. Key words: amniocentesis, perinatal mortality rate, preterm birth, twins www.AJOG.org Obstetrics Reviews OCTOBER 2010 American Journal of Obstetrics & Gynecology 305
  • lets and higher-order gestations is de- creasing. Thus, twin pregnancies consti- tute a greater proportion of multiple pregnancies. In 1989, for example, there were 110,670 twin deliveries, which con- stituted 93.6% of 118,296 multiple births; in 2006, the corresponding num- bers were 137,085 twin pregnancies and 95.4%. During these 9 years, the rate of triplets and higher-order gestations de- creased by 29%.2 The rapid rise, however, in twin rates over the last several decades may have ended. From 1935-1980, the twinning rate declined. After that, there has been a 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 reached 32 per 1000 births in 2004 and has stabilized since then; the rate was 32.1 per 1000 births in 2006.2 To summarize, the rate of twin preg- nancies varies in the United States for several reasons and has stabilized, de- spite the recent alarm by public press.1 Identification of chorionicity and anomaly Because of risks that are associated with monochorionicity, an important aspect of first-trimester ultrasound scans in twin gestation is the determination of chorionicity. It has been demonstrated that chorionicity is best determined by sonography in the first or early second trimester. In a single large tertiary cen- ter,6 the sensitivity, specificity, and posi- tive and negative predictive values of prediction of monochorionicity at Յ14 weeks was found to be 89.8%, 99.5%, 97.8%, and 97.5%, respectively. If only 1 placenta is visualized, the presence of an extension of chorionic tissue from the fused dichorionic placentas suggests dichorionicity. If only 1 placenta is visu- alized, the absence of an extension of chorionic tissue into the intertwin mem- brane suggests monochorionicity. In monochorionic twin pregnancies, the absence of an intertwin membrane sug- gests monoamniotic gestation. Mono- chorionic diamniotic twin gestation is associated with a 10-15% risk of twin-to- twin transfusion syndrome.7 Although monoamnionicity is somewhat protec- tive against the development of twin-to- twin transfusion syndrome, monoamni- otic gestations are associated with a 6% incidence of twin-to-twin transfusion.8 Because of the breadth of the topic, this article will not address risks, associa- tions, or management of unique aspects of monochorionic gestations, namely FIGURE 1 Twin deliveries and birth rate: United States, 1980-2006 50,000 100,000 150,000 1980 1985 1990 1995 2000 2005 Years #Twins/year 15 20 25 30 35 Twins/1,000births Twins/year Twins/1,000 births Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. FIGURE 2 Twin birth rate, based on maternal ethnicity and age 0 50 100 150 200 < 15 15-17 18-19 20-24 25-29 30-34 35-39 40-44 45-54 Years of age Twins/1,000livebirths 250 Non-Hispanic white All races Hispanic Non-Hispanic black Open circles denote non-Hispanic African American; light gray line denotes non-Hispanic white; solid black line denotes all races; and open squares denote Hispanic. Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. Reviews Obstetrics www.AJOG.org 306 American Journal of Obstetrics & Gynecology OCTOBER 2010
  • twin-to-twin transfusion syndrome and monoamnionicity. In addition to the determination of chorionicity and amnionicity, the goal of sonographic examination with twin ges- tations is to identify anomalies and/or syndromes. This should allow for the modification of pregnancy management in efforts to optimize outcome for mother and newborn infants or to iden- tify risk factors that may suggest a need for active or prophylactic therapy to de- crease the likelihood of adverse preg- nancy outcome. Depending on the se- verity and/or lethality of the identified anomalies or syndromes, pregnancy managementoptionsinclude(1)contin- ued conservative management, (2) ter- mination of pregnancy in efforts to de- crease maternal morbidity and death, especially in cases in which lethal syn- dromes are suspected, (3) selective re- duction to prevent the birth of an ad- versely affected child and/or to optimize likelihood of survival for an apparently normal fetal sibling, or (4) placental (vascular) and/or fetal and/or neonatal therapy in efforts to optimize outcome for 1 or both the neonates. Risks that are associated with selective termination of dichorionic twin preg- nancies with structural, chromosomal, and Mendelian anomalies are known for centers with experience. Evans et al9 re- ported on 345 cases of selective termina- tion with twins, of whom 7% delivered at Ͻ24 weeks of gestation and 93% ended in a viable singleton. Unlike multifetal reduction for multifetal pregnancies, in which outcomes are related to experi- ence,10 over 15 years, termination for an anomalous fetus was not associated with improvement in losses or prematurity. The loss rate also was not influenced by thegestationalageoftheprocedure,even when done at Ͼ24 weeks of gestation, and by the indication for selective termination.9 For many reasons, the likelihood of aneuploidy is higher in twin pregnancies than in singleton pregnancies. In dizy- gotic gestations, the background risk for each twin is the same as it would be in a singleton gestation for that mother; however, the number of fetuses results in a 2-fold increase in risk for that gestation when compared with singleton pregnan- cies. Because ARTs are often used in older women, the risk of aneuploidy should be approximately twice her age- related risk, unless donor oocytes are used. In monozygous twins, the risk of both twins being affected should be sim- ilar to that of a singleton gestation. First-trimester screening for aneu- ploidy in twin pregnancies has many nu- ances that limit its capabilities as a screening tool.11 Although monochorio- nicity has been associated with increased FIGURE 3 Twin births (2004-2006) by state by percentile Texas Utah Montana California Arizona Idaho Nevada Oregon Iowa Colorado Kansas Wyoming New Mexico Illinois Ohio Missouri Florida Minnesota Nebraska Georgia Oklahoma Alabama Washington Arkansas South Dakota Wisconsin North Dakota Virginia Maine New York Indiana Louisiana Michigan Kentucky Tennessee Pennsylvania North Carolina Mississippi South Carolina West Virginia Vermont Maryland New Jersey New Hampshire Massachusetts Connecticut Delaware Hawaii Alaska Twin births by percentile (Number per 1,000 live births) < 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. www.AJOG.org Obstetrics Reviews OCTOBER 2010 American Journal of Obstetrics & Gynecology 307 View slide
  • nuchal translucency,12 nuchal translu- cency alone has been shown to be an ef- fective marker for aneuploidy in twin gestations.11,12 The addition of serum biochemistry to age and nuchal translu- cency measurementintwingestationhas a very high sensitivity for detecting tri- somy 18 or 21. In that series of 535 sets, maternal (or egg donor) age alone was associated with a 33% detection rate for trisomy 18 or 21. The addition of nuchal translucency increased the sensitivity to 83%; combined age and nuchal translu- cency and biochemistry (free or total beta human chorionic gonadotropin and pregnancy-associated pregnancy protein A) increased sensitivity to 100%. The authors did acknowledge that, with larger numbers, the combined detection rate would be Ͻ100%.11 As alluded to earlier, early diagnosis is important to minimize the complica- tions that are associated with interven- tion. Chorionic villus sampling (CVS) is the standard first-trimester approach to the confirmation of suspected aneu- ploidy. CVS is performed by 2 general approaches: transabdominal vs transcer- vical, depending on operator experience and placental location/accessibility. In the hands of experienced clinicians, first- trimester CVS has been found to be at least as safe and effective as second-tri- mester amniocentesis for prenatal diag- nosis in twin gestations. De Catte et al13 summarized the outcomes of CVS with 3 earlier studies14-16 and their own experi- ence with 262 cases. Overall outcomes of 614 twins who had CVS were known. The likelihood of total loss was 4.6% (95% confidence interval [CI], 3.5–6.0). Furthermore, Ferrara et al17 confirmed that CVS does not increase the preg- nancy loss rate before multifetal preg- nancy reduction. Compared with singleton pregnan- cies, twin pregnancy is associated with an increased incidence of anomalies,18,19 al- though the rate of anomalies in dizygotic twins is not likely increased per twin. Hardin et al,18 for example, compared the prevalence of cardiovascular defects in 56,709 California twin pairs with sin- gleton pregnancies. They categorized cardiac anomalies into 16 groups; twins had a higher incidence for all 16 catego- ries. For 7 of the cardiovascular catego- ries, the prevalence was 2 times higher for twin pregnancies than singleton pregnancies. Like-sex twins, a proxy for monozygosity, had a higher prevalence of cardiac defects than unlike sex twins. Bahtiyar et al19 reviewed the literature and noted that congenital heart defects were prevalent significantly more among monochorionic, diamniotic twins than the general population (relative risk [RR], 9.18; 95% CI, 5.51–15.29). Ven- tricular septal defects are the most fre- quent heart defects. Fortunately, detection of anomalies in twin gestation does not seem to be com- promised by its multifetal nature. Ed- wards et al20 confirmed a sensitivity of 82% and negative predictive value of 98% for anatomic surveys among 245 consecutive twins, with a 4.9% preva- lence of anomalies. Among 495 mono- chorionic twins, Sperling et al21 reported severe structural abnormalities in 2.6%; two-thirdsoftheabnormalitieswerecar- diac.Withfirst-trimesternuchaltranslu- cency and anatomy scan at Ͻ20 weeks of gestation, 83% of anomalies and aneu- ploidy were detected. Earlier reports on detection of congenital anomalies in twinpregnanciesnotedalowerdetection rate. In 1991, Allen et al22 reported that, among 157 pair of twins (314 newborn infants), anomalies occurred in 9.5%. Antenatal ultrasonography detected only 39% of all major anomalies, 55% of non- cardiac anomalies, and 69% of major anomalies for which routine prenatal management would be altered. For de- tection of cardiac anomalies, their ultra- sound protocol was limited to a 4-cham- ber view, and they detected no major cardiac lesions. Thus, it is understand- able why the American College of Obstetrics and Gynecology (ACOG) practice bulletin23 on ultrasonography recommends that, as part of cardiac screening examination, the views of the outflow tracts should be obtained, if technically feasible. Twins should have fetal echocardiograms, especially if they are monochorionic24 or a result of as- sisted reproduction.25 Importantly, if discordant anomaly is noted, the likelihood of adverse outcome for the normal twin is increased. Sun et al26 used the 1995-1997 matched multi- ple births dataset from the United States and noted that 1 fetus had an anomaly in 2.5% of the cases and both fetuses had anomalies in 1.0%. They identified 3307 twins and matched them with 12,813 nonanomalous twins. Compared with the control subject, the presence of an anomalous cotwin significantly in- creased the risk of (1) preterm birth at Ͻ32weeksofgestation(oddsratio[OR], 1.85; 95% CI, 1.65–2.07), (2) birth- weight Ͻ1500 g (OR, 1.88; 95% CI 1.67– 2.12), (3) small for gestational age (10% vs 12%; OR, 1.21; 95% CI, 1.07–1.36), (4) fetal death (OR, 3.75; 95% CI, 2.61– 5.38), (5) neonatal death (OR, 2.08; 95% CI 1.47–2.94), and (6) infant death (OR, 1.97; 95% CI,1.49–2.61). In summary, once twin pregnancies are detected, sonographic examination should be done to determine chorionic- ity, first trimester screening should be done to identify fetuses with aneuploidy, targeted ultrasound should be done for the detection of major anomalies, and fe- tal echocardiography should be done for identification of congenital heart defect. As recommended by the ACOG practice bulletin on ultrasonography in pregnan- cy,23 every patient should be informed about the limitation of the detection of all major birth defects. If 1 fetus has a major structural or chromosomal ab- normality, selective termination should be discussed. Genetic amniocentesis Compared with singleton pregnancies, twin pregnancies are at higher risk for fetal anomalies and for chromosomal abnormalities. Rodis et al27 calculated that a 33-year-old woman with twins has an equivalent risk of a child with Down syndromeasa35-year-oldwomanwitha singleton infant. Thus, the importance of genetic amniocentesis with twins can be seen. Among the 6 publications that re- ported on loss rate after genetic amnio- centesis with twins, the needle gauge var- ied, but all investigators used 2 separate needle insertions (Table 1).28-33 Al- though the rate of loss at Ͻ24 weeks of gestation varied from 0.4-4.1%, the cu- mulative experience with Ͼ1700 amnio- Reviews Obstetrics www.AJOG.org 308 American Journal of Obstetrics & Gynecology OCTOBER 2010 View slide
  • centesesindicatesthatthefetallossrateis 2.9% (95% CI, 2.3–3.8) or 1 per 34 (95% CI, 26–43). It is noteworthy that a sys- tematic review that summarized the re- sults of 29 articles calculated that, for sin- gleton pregnancies who undergo genetic amniocentesis, the loss rate at Ͻ24 weeks of gestation is 0.9% (95% CI, 0.6–1.3) or 1 per 111 procedures (95% CI, 76– 111).34 The differential loss rate between singleton and twin pregnancies may re- sult from the fact that the spontaneous loss rate at Ͻ24 weeks of gestation is higher with multiples. Only 3 of these re- ports provided data for twins who were treatedatasimilartimewhodidnothave a genetic amniocentesis.28-30 For the twins who did not have the invasive pro- cedure, the overall loss rate was 1.1% (95% CI, 0.6–2.0). A comparison of spontaneous loss rate vs after loss rate genetic amniocentesis indicates that the fetal losses are approximately 160% higher after the procedure (1.1% vs 2.9%; Table 1). It should be noted that loss subsequent to genetic amniocentesis is similar among twins who are con- ceived spontaneously or with ART and those who had undergone multifetal reduction.35 Subtypes of preterm birth and perinatal death Undeniably twin pregnancies are more likely to be delivered preterm (Ͻ37 weeks of gestation) than singleton preg- nancies, although its magnitude may be underappreciated.2 In 2006, of the 137,085 twins who were delivered in the United States, approximately 60% of the twins were preterm (78,824 infants) and weighed Ͻ2500 g (82,799 infants). Ap- proximately 1 in 10 twins was born at Ͻ32 weeks of gestation (n ϭ 16,597 in- fants) or weighed Ͻ1500 g (n ϭ 13,983; Figure 4). As Ananth et al36 noted that, with the exception of France and Fin- land, most industrialized countries have noted a temporal increase in prematu- rity. The increase in preterm births is multifactorial but can be categorized into 3 groups: medically indicated be- cause of maternal-neonatal outcomes, after spontaneous onset of preterm labor, and after premature rupture of membranes. A comparison of the causes of preterm births for singleton vs twin pregnancies is instructive, especially when the data are separated by ethnicity. Using the data from National Center for Health Statis- tics, Ananth et al36,37 provided such data (singleton pregnancies for the year 2000 and twin pregnancies for the years 1999- 2002). For singleton and twin pregnan- cies for African American and white women, approximately 50% of preterm births were indicated; one-third of the births were spontaneous, and 10% of the births occurred after preterm premature rupture of membranes (Figure 5). Per- haps because the data do not lend them- selves to detailed information on the cause of indicated delivery, the investiga- tors did not provide the specific reasons clinicians were compelled to perform the delivery prematurely. The perinatal mortality (PNM) rates with preterm birth vary based on plural- ity, ethnicity, and the subtypes of prema- turity (Figure 6). With the exception of singleton and white pregnancies, the PNM rate is highest when preterm deliv- ery follows premature rupture of mem- branes. Consistently for singleton and twin pregnancies for African American and white women, the PNM rate is low- est when preterm birth results from spontaneous labor. Within the same eth- nicity, the total preterm PNM rate is sig- nificantly less for twin than for singleton pregnancies. The remarkable finding by Ananth et al36,37 is that, despite the increase in the rate of prematurity in the United States, there is a concomitant decrease in PNM ratesamongAfricanAmericanandwhite women among twin and singleton preg- nancies. In 2 separate publications, Ananth et al36,37 reported the trends in preterm births for twin and singleton pregnancies in the United States from 1989-2000, along with its impact on TABLE 1 Amniocentesis with twin pregnancies Variable Country Twin pregnancy amniocentesis Needle size Second puncture Loss at <24 wk gestation, n Loss rate, %a Twin pregnancy with no amniocentesis, n Loss with no amniocentesis, n Loss rate, %a Yukobowich et al28b Israel 476 20 Yes 13 2.7 (1.6–4.6) 477 3 0.6 (0.2–1.8) ................................................................................................................................................................................................................................................................................................................................................................................ Tóth-Pál et al29 Hungary 155 22 Yes 6 3.9 (1.8–9.1) 292 7 2.4 (1.1–4.8) ................................................................................................................................................................................................................................................................................................................................................................................ Millaire et al30 Canada 134 22 Yes 4 3.0 (1.1–7.4) 248 2 0.8 (0.2–2.8) ................................................................................................................................................................................................................................................................................................................................................................................ Delisle et al31 British Columbia 233 No mention Yes 1 0.4 (0.1–2.3) — — — ................................................................................................................................................................................................................................................................................................................................................................................ Cahill et al32 United States 311 22 Yes 9 2.9 (1.5–5.4) — — — ................................................................................................................................................................................................................................................................................................................................................................................ Daskalakis et al33 Greece 442 21 Yes 18 4.1 (2.5–6.7) — — — ................................................................................................................................................................................................................................................................................................................................................................................ 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. www.AJOG.org Obstetrics Reviews OCTOBER 2010 American Journal of Obstetrics & Gynecology 309
  • perinatal mortality rates (Figure 7). For their analysis, they had 1,172,405 pre- term twin live births and 46,375,578 pre- term singleton pregnancies. Over 11 years, the rate of preterm births in- creased for African American and white twin pregnancies and for white singleton pregnancies; however, it decreased for African American twin singletons. The PNM rate decreased for all 4 groups dur- ing the 11 years (Figure 7). The reason for the decrease in the PNM rate is that medically indicated preterm births are associated with a favorable reduction in PNM rates. Preterm labor: prediction, prevention, and management Regardless of the temporal trend, the prediction, prevention, and manage- ment 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 to deliver prematurely. Fox et al38 described their experience with routinely obtaining, from 22-32 weeks, fFN and measuring transvaginal cervical length. Overall, among 155 twin pregnancies, of which 64% were the re- sults of in vitro fertilization, the rate of birth at Ͻ37 weeks of gestation was 53%, at Ͻ34 weeks of gestation was 16%, and Ͻ28 weeks of gestation was 4%. The rate of spontaneous preterm birth was signif- icantly higher when either fFN was pos- itive or cervical length was Ͻ20 mm, but it was the highest when both tests were abnormal (Table 2). It is noteworthy that, if the fFN is negative and cervical length is at least 20 mm, almost 90% of the pregnancies will deliver at Ͼ34 weeks of gestation. Conversely, if both fFN and cervical length are abnormal, Ͼ50% of the pregnancies will deliver at Ͻ34 weeks of gestation. Routine use of the diagnostic tests in twin pregnancies should not be expected to decrease the actual rate of preterm births. Matter of fact, the use of cervical length could increase the duration of an- tepartum admission without concomi- 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 the 2 groups, there was no difference in 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 ges- tation (26.1% vs 25.6%; P ϭ .94); how- ever, there was an increase in maternal antepartum length of stay (cervical length at 34.5 days vs no cervical length at 31.3 days; P Ͻ .001). It is uncertain FIGURE 4 Preterm births in 2006: twin vs singleton 11% 2% 7% 1% 58% 12% 60% 10% Del <37 weeks Singletons Twins OR, 7.68 (95% CI, 7.51-7.78) OR, 21.94 (95% CI, 21.68-22.19) OR, 10.21 (95% CI, 10.01-10.41) OR, 10.83 (95% CI, 10.71-10.95) Del <32 weeks BW <2500 g BW <1500 g BW, birthweight; CI, confidence interval; Del, delivery; OR, odds ratio. Data derived, with permission, from Martin et al.2 Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. FIGURE 5 Data are based on ethnicity and subtypes of preterm births: singleton vs twin 56% 58% 53% 62% 35% 32% 38% 30% 9% 10% 9% 8% Singletons (AA) Twins (AA) Singletons (W) Twins (W) Med Indicated Sp PTB PROM 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 Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. Reviews Obstetrics www.AJOG.org 310 American Journal of Obstetrics & Gynecology OCTOBER 2010
  • whether their findings would have been valid had they obtained fFN measure- ments in conjunction with cervical length. So, fFN and cervical length can be used to ascertain which twin pregnancies will deliver prematurely, although im- provement in peripartum outcomes should not be expected. Of twin gestations with symptoms of preterm labor, approximately 22-29% of the pregnancies will deliver within 7 days.39,40 Thus, the first goal with symp- tomatic patients should be to identify those who will deliver prematurely. Such identification avoids unnecessary thera- peutic interventions like unwarranted hospitalization and medical treatment. The usefulness of fFN in the evaluation of twin gestations with symptoms of pre- term labor is not related to its ability to predict who will deliver in the next 14 days (19% positive predictive value; 95% CI, 7–39%), but rather the test’s ability to determine who is not going to deliver during the timeframe (97% negative predictive value; 95% CI, 89–100). The negative predictive value of fFN is simi- lar 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- cies within a week of the onset of symp- toms: 80% of the pregnancies delivered when the cervical length was 0-5 mm; 46% of the pregnancies delivered when the cervical length was 6-10 mm; 29% of the pregnancies delivered when the cer- vical length was 11-15 mm; 21% of the pregnancies delivered when the cervical length was 16-20 mm; 7% of the preg- 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, randomized trials are needed to deter- mine whether the knowledge of fFN and cervical length influences outcome among twin pregnancies, as it did in the trial re- ported by Ness et al.42 While awaiting the results of these randomized trials, we should be cognizant of the ACOG prac- tice bulletin on the management of pre- term labor.43 They recommend that ei- ther cervical ultrasound examination or fFN or both diagnostic tests should be FIGURE 6 Data are based on ethnicity and perinatal mortality rates with preterm births: singleton vs twin 71 76 43 5351 49 44 33 41 31 29 25 10 100 Singletons (AA) Twins (AA) Singletons (W) Twins (W) PNM/1000births PROM Med Ind Sp PTB AA, African American; Med Ind, medically indicated; PNM, perinatal mortality rate; PROM, premature rupture of membranes; Sp PTB, spontaneous preterm birth; W, white. Data derived, with permission, from Ananth et al.36,37 Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. FIGURE 7 Trend in the rate of preterm births and perinatal mortality for twin and singleton births in the United States: 1989-2000 9% -15% -37% -27% 22% 14% -41% -30% -50% -30% -10% 10% 30% AA White PTB-Twins PTB-Singletons PNM-Twins PNM-Singletons AA, African American; PNM, perinatal mortality rate; PTB, preterm birth. Data derived, with permission, from Ananth et al.36,37 Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010. www.AJOG.org Obstetrics Reviews OCTOBER 2010 American Journal of Obstetrics & Gynecology 311
  • used to determine which patients do not need tocolytics. Until there are publica- tions to the contrary, this recommenda- tion is applicable to twin and singleton pregnancies. Considering the increased likelihood of preterm births among twin preg- nancies, it is reasonable to determine whether it can be prevented. One of the more common interventions that have been tried in the past was the use of pro- phylactic oral betamimetics to reduce the incidence of preterm birth in twin gestations. From a Cochrane database, Yamasmit et al44 reviewed 5 randomized trials with 344 twin pregnancies. This in- tervention has not been proved to reduce the incidence of birth at Ͻ37 weeks of gestation (RR, 0.85; 95% CI, 0.65–1.10) or delivery at Ͻ34 weeks of gestation (RR, 0.47; 95% CI, 0.15–1.50). It also has not been shown to change the neonatal outcomes of low birthweight (RR, 1.19; 95% CI, 0.77–1.85) or neonatal mortal- ity rates (RR, 0.80; 95% CI, 0.35–1.82). Therefore, in light of these findings, the use of prophylactic tocolysis should not be undertaken. Progesterone has been shown to de- crease the incidence of recurrent pre- term delivery in a singleton gestation.45 A systematic review by Dodd et al46 iden- tified only 2 randomized trials that as- sessed the use of progesterone vs placebo for multiple pregnancy. Depending on the outcome of interest, the number of participants varied between 154 and 1280.Theauthorsconcludedthattheuse of progesterone in multiple gestations does not decrease the likelihood of birth at Ͻ37 weeks of gestation (RR, 1.01; 95% CI, 0.92–1.12), birthweight Ͻ2500 g (RR, 0.94; 95% CI, 0.86–1.02), respira- tory distress (RR, 1.13; 95% CI, 0.86–1.48), intraventricular hemor- rhage grade 3 or 4 (RR, 1.20; 95% CI, 0.40–3.54), necrotizing enterocolitis (RR, 0.77; 95% CI, 0.17–3.42), neonatal sepsis (RR, 0.95; 95% CI, 0.55–1.63), and perinatal death (RR, 1.95; 95% CI, 0.37–10.33). Another approach to decrease prema- ture births is to reinforce the cervix with a cerclage in multiple gestations. The placement of a cerclage was examined both as a prophylactic intervention and when a short cervix is noted on ultra- sound examination. The use of history- indicated (prophylactic) cerclage for ovulation-induced twin gestations (n ϭ 50) in a randomized trial did not de- crease the rate of prematurity signifi- cantly (45% with cerclage vs 48% with- out suture) or neonatal mortality (18% vs 15% for suture vs no suture, respec- tively).47 More importantly, when cer- clage was used in asymptomatic woman with twin gestations and short cervical length on transvaginal ultrasound exam- ination, it significantly increased the risk of delivery at Ͻ35 weeks of gestation (75% in the cerclage group and 36% without suture; RR, 2.15; 95% CI, 1.15– 4.01).48 Thus, cerclage of asymptomatic short cervical length should be avoided for twin gestations. Otherprophylacticinterventions,which have been examined in multiple gesta- tions to prevent preterm delivery, are bed rest and home uterine monitoring. Crowther,49 in 2001, summarized the re- sults of 6 trials with hospitalization and bed rest. The summary, which involved Ͼ600 patients and 1400 newborn in- fants, noted that the intervention did not decrease the rate of preterm birth or perinatal mortality. Paradoxically, bed rest significantly (OR, 1.84; 95% CI, 1.01–3.34) increased the risk of preterm birth at Ͻ34 weeks of gestation in asymptomatic twin gestations. Similarly a lack of efficacy was also shown with the use of home uterine monitoring for twin gestations. Because home uterine moni- toring has not been shown to be benefi- cial in the prevention of preterm birth in TABLE 2 Spontaneous preterm birth among twin pregnancies Variable Gestational week <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: 120 births, % 1.6 2.4 4.2 10.3 43 ................................................................................................................................................................................................................................................................................................................................................................................ Either positive fetal fibronectin level or transvaginal cervical length Ͻ20 mm: 24 births, % 13.3 9.5 8.3 26.1 77.3 ................................................................................................................................................................................................................................................................................................................................................................................ Positive fetal fibronectin level and transvaginal cervical length Ͻ20 mm: 11 births, % 50 33.3 54.5 54.5 100 ................................................................................................................................................................................................................................................................................................................................................................................ 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. Reviews Obstetrics www.AJOG.org 312 American Journal of Obstetrics & Gynecology OCTOBER 2010
  • multiple gestations, its use should be abandoned.50 Thus, the following treat- ment modalities have no role in the pre- vention of preterm births with twin gestations: bed rest and oral tocolytics; cerclage and progesterone injections. One of the most difficult aspects of caring for multiple gestations is the lack of proven intervention once preterm la- bor has been diagnosed. The use of toco- lytics for the treatment of preterm labor has not been shown to decrease the inci- dence of delivery within 7 days of treat- ment, perinatal or neonatal death, or the neonatal complications of respiratory distress syndrome, necrotizing entero- colitis, or cerebral palsy. This lack of proven efficacy,51 the amplification of side-effects, and the increased risk of pulmonary edema with tocolytics in multiple gestations52 lead ACOG to comment that they should be used judi- ciously in this population.53 In contrast to the unproven efficacy of tocolytics, the use of antenatal cortico- steroids (ACS) has been shown54 to de- crease the incidence of neonatal death (RR, 0.69; 95% CI, 0.58–0.81), respira- tory distress syndrome (RR, 0.66; 95% CI, 0.43–0.69), intraventricular hemor- rhage (RR, 0.54; 95% CI, 0.43–0.69), ne- crotizing enterocolitis (RR, 0.46; 95% CI, 0.29–0.74), and systemic infections within the first 48 hours of life (RR, 0.56; 95% CI, 0.38–0.58). Although none of the studies specifically addressed use in multiple gestations, the National Insti- tutes of Health recommends that all women in preterm labor, regardless of the number of fetuses, be given a course of ACS.55 Although ACS does improve neonatal outcome significantly, it should not be administered repeatedly. A retrospective study by Murphy et al56 compared the use of prophylactic ACS in twin gesta- tions beginning at 24 weeks of gestation and given every 2 weeks (n ϭ 136) with the standard approach in women who were at immediate risk of preterm deliv- ery (n ϭ 902). The prophylactic ap- proach was shown not to offer a signifi- cant reduction in respiratory distress syndrome (13% vs 11%; adjusted OR, 0.69; 95% CI, 0.33–1.46) and was associ- ated with exposing a large number of ba- bies to unnecessary treatment that ad- versely affects growth. Therefore, the repeated administration of ACS should be avoided in favor of those pregnancies that are at immediate risk for preterm births. One single rescue course of ACS should be given among twins who have received betamethasone 12 mg, intra- muscularly, twice, 24 hours apart. If at least 14 days have elapsed and delivery is likely at Ͻ33 weeks of gestation, then a single rescue dose should be adminis- tered. This recommendation is based on the randomized trial by Garite et al57 that involved 437 patients, with 577 newborn infants, 24% of whom (141; 1 fetal death before randomization) were from twin gestations. Compared with the patients who received placebo, patients who re- ceived the rescue dosage had a significant reduction in composite perinatal neona- tal morbidity (64% vs 44%; P ϭ .02) and significantly decreased rate of respira- tory distress syndrome, ventilator sup- port, and surfactant use. In summary, although there are diag- nostic tests to identify those pregnancies that will deliver prematurely, these tests do not decrease the rate of preterm birth. There are no known treatments to de- crease the likelihood of preterm birth. Tocolyticsshouldbeusedeithertotrans- fer a patient to a tertiary center or to ensure ACSs are administered. Pro- longed tocolytic use should be avoided, as should repeated administration of corticosteroids. Comment Twins are a source of awe and delight to parents, fascination and photo opportuni- ties to the press,1 and challenge and trepi- dation to clinicians.58,59 Compared with singleton pregnancies, twin pregnancies are more likely to be complicated by hy- pertensive disorders, gestational diabetes mellitus, anemia, preterm birth, ante- and postpartum hemorrhage, and maternal death.60 The newborn infants from twin pregnancies are more likely to have anom- alies,26 intrauterine growth restriction,61 handicap, and cerebral palsy. The average cost for singleton deliveries is $9,845 and for twins is $37,947.60 Thus, continued understanding of twin pregnancies is important. This review of the literature on twin gestations, although limited to common problems, was notable for 4 findings. First, the rate for twin gestations has sta- bilized for now. For 2004, 2005, and 2006, there have been approximately 32 twin gestations per 1000 births (Figure 1). Second, the sonographic evaluations of twin gestations should be limited not only to the identification of the chorio- nicity but also aneuploidy with first- trimester screening and anomaly with first- and second-trimester ultrasound examinations. Because anomalies and aneuploidies are more common with twin pregnancies than with singleton pregnancies,26,27 it is important that cli- nicians who have experience in detecting these abnormalities evaluate these pa- tients. If need be, parents who are ex- pecting twins should be offered and re- ferred for CVS, genetic amniocentesis, and selective reduction. Third, we found that the rate of pre- term births is significantly higher for twin pregnancies than for singleton pregnancies (Figure 4). Although this has been known, findings from the na- tional data provide not only unequivocal evidence but also the magnitude to which this occurs. Data from the United States also are available for the analysis of causes for preterm birth (Figure 5) and associated perinatal mortality rates (Fig- ure 6). But what is most captivating is that, although the rate for preterm birth has increased, the associated perinatal mortality rate has actually decreased. Thefactthatthisconclusionisbasedona population-based, retrospective cohort study comprised of 46,375,578 women and 1,172,405 twins in the United States is staggering.36,37 It will be beneficial if other countries can confirm the findings reported by Ananth et al36,37 and if fu- ture studies can ascertain what precisely decreased the perinatal mortality rate. It will also be useful to understand whether the overall perinatal mortality rate, not just for preterm births, has also de- creased in the United States. Fourth, the findings focus on the man- agement of preterm labor with twin ges- tations. Clinicians should be cognizant www.AJOG.org Obstetrics Reviews OCTOBER 2010 American Journal of Obstetrics & Gynecology 313
  • ofthefactsthat,withtwins,pretermcon- tractions are common, that the benefit of tocolytics is limited although the com- plications rate is higher, and that the pre- term birth-related perinatal mortality rate has been lowered. Whenever feasi- ble, clinicians should use diagnostic tests (transvaginal cervical length or fFN) to differentiate true vs false preterm labor. The use of tocolytics should be limited to (1) either the cervical length is Ͻ2.5 cm or fFN is positive or both, (2) the test results have been evaluated, (3) 48 hours have elapsed since the first dosage of cor- ticosteroid was administered, or (4) the patient has been transferred to a tertiary center. As with singleton pregnancies,43 there is no justification for prolonged to- colytics with twin pregnancies. In conclusion, there are several reas- suring findings with twin pregnancies. The rate of twin pregnancies is not in- creasing in the United States; although the preterm birth rate is high, the associ- ated perinatal mortality rate is decreas- ing. Future studies should focus on im- proving the detection of birth defects and of abnormal growth and on antepar- tum testing to improve the outcomes for twin pregnancies with medical or obstet- ric complications. f REFERENCES 1. Saul S. 21st Century babies: the gift of life, and its price. The New York Times. Oct. 11, 2009. Available at: http://www.nytimes.com/ 2009/10/11/health/11fertility.html?_rϭ1&scpϭ 1&sqϭThe%20Gift%20of%20Life,%20and%20 Its%20Price&stϭcse. Accessed Oct. 19, 2009. 2. Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2006. Natl Vital Stat Rep 2009;57:1-102. 3. Imaizumi Y. Trends of twinning rates in ten countries, 1972-1996. Acta Genet Med Ge- mellol (Roma) 1997;46:209-18. 4. Eriksson AW, Fellman J. Temporal trends in the rates of multiple maternities in England and Wales. 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