Twins: prevalence, problems, and preterm births

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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

O

n October 10, 2009, there was an article entitled, “21st Century Babies: 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 concern. Thus, a review of antepartum complications with twin pregnancies is useful 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 seconds; a PubMed search with the words “twin pregnancy” found 24,982 publications (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, and preterm births, which are the bane of modern obstetrics.

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 abnormalities. Compared with singleton births, genetic amniocentesis–related loss at ⬍24 weeks of gestation for twin births is higher (0.9% vs 2.9%, respectively). Selective termination 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 membranes. 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 (⬍48 hours) in twin births. Administration of antenatal corticosteroids is an evidence-based recommendation. Key words: amniocentesis, perinatal mortality rate, preterm birth, twins

Twin birth rate In the United States, between 1980 and 2006, the twin rate climbed 101% (Figure 1). There were 68,339 twins born in 1980; 27 years later, 137,085 twins were born.2 The twinning rates have also increased 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 reproductive techniques (ARTs) and nonART procedures,4 maternal age, ethnicity, variation among the 50 states, and a decreasing rate of triplets and higher order 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 conventional in vitro fertilization and intracytoplasmic 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 ⬍20 years (compared with 80% for women in their 30s) and 190% for mothers who were ⱖ40 years old. In 2006, 20% of births to women 45-54 years old were twins, compared 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 varies among the states (Figure 3). In 20042006, the rate of twin pregnancies in the United States was 32.2 per 1000 live births, with ⬍25% being 29.5 per 1000 live births; median, 31.8 per 1000 live births, and ⬎75% being 34.0 per 1000 live births. In Connecticut, Massachusetts, and New Jersey, 4% of all births were twins. In contrast, ⬍2.5% of births to New Mexico residents were twin pregnancies.2 The likelihood of twin pregnancies is also increasing because the rate of trip-

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FIGURE 1

Twin deliveries and birth rate: United States, 1980-2006 Twins/year

Twins/1,000 births

150,000

35

100,000

25

Twins/1,000 births

# Twins/year

30

20

20

20

05

00

95 19

90 19

19

19

85

15

80

50,000

Years

Chauhan. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010.

lets and higher-order gestations is decreasing. Thus, twin pregnancies constitute a greater proportion of multiple pregnancies. In 1989, for example, there

were 110,670 twin deliveries, which constituted 93.6% of 118,296 multiple births; in 2006, the corresponding numbers were 137,085 twin pregnancies and

FIGURE 2

Twin birth rate, based on maternal ethnicity and age 250

Non-Hispanic white

Twins /1,000 live births

200

150 All races 100

Non-Hispanic black

50

Hispanic 0 < 15

15-17

18-19

20-24

25-29

30-34

35-39

40-44

45-54

Years of age

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.

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95.4%. During these 9 years, the rate of triplets and higher-order gestations decreased 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 pregnancies varies in the United States for several reasons and has stabilized, despite 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 center,6 the sensitivity, specificity, and positive and negative predictive values of prediction of monochorionicity at ⱕ14 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 visualized, the absence of an extension of chorionic tissue into the intertwin membrane suggests monochorionicity. In monochorionic twin pregnancies, the absence of an intertwin membrane suggests monoamniotic gestation. Monochorionic diamniotic twin gestation is associated with a 10-15% risk of twin-totwin transfusion syndrome.7 Although monoamnionicity is somewhat protective against the development of twin-totwin transfusion syndrome, monoamniotic 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, associations, or management of unique aspects of monochorionic gestations, namely

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FIGURE 3

Twin births (2004-2006) by state by percentile Washington Montana Oregon

Maine

North Dakota Minnesota

Vermont New Hampshire

Idaho Wisconsin

South Dakota

New York Massachusetts Michigan

Wyoming

Nebraska

Nevada

Connecticut PennsylvaniaNew Jersey

Iowa Ohio

Utah California

Illinois

West Virginia Kansas

Virginia

Missouri

Kentucky Tennessee

Arizona

MarylandDelaware

Indiana

Colorado

North Carolina

Oklahoma Arkansas

New Mexico

South Carolina

MississippiAlabama

Georgia

Texas Louisiana

Florida

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

Alaska

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 monoamnionicity. In addition to the determination of chorionicity and amnionicity, the goal of sonographic examination with twin gestations 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 identify risk factors that may suggest a need for active or prophylactic therapy to decrease the likelihood of adverse pregnancy outcome. Depending on the severity and/or lethality of the identified anomalies or syndromes, pregnancy management options include (1) continued conservative management, (2) termination of pregnancy in efforts to decrease maternal morbidity and death, especially in cases in which lethal syndromes are suspected, (3) selective reduction 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 pregnancies with structural, chromosomal, and Mendelian anomalies are known for centers with experience. Evans et al9 reported on 345 cases of selective termination with twins, of whom 7% delivered at ⬍24 weeks of gestation and 93% ended in a viable singleton. Unlike multifetal reduction for multifetal pregnancies, in which outcomes are related to experience,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 the gestational age of the procedure, even when done at ⬎24 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 dizygotic 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 pregnancies. Because ARTs are often used in older women, the risk of aneuploidy should be approximately twice her agerelated risk, unless donor oocytes are used. In monozygous twins, the risk of both twins being affected should be similar to that of a singleton gestation. First-trimester screening for aneuploidy in twin pregnancies has many nuances that limit its capabilities as a screening tool.11 Although monochorionicity has been associated with increased

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nuchal translucency,12 nuchal translucency alone has been shown to be an effective marker for aneuploidy in twin gestations.11,12 The addition of serum biochemistry to age and nuchal translucency measurement in twin gestation has a very high sensitivity for detecting trisomy 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 translucency 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 ⬍100%.11 As alluded to earlier, early diagnosis is important to minimize the complications that are associated with intervention. Chorionic villus sampling (CVS) is the standard first-trimester approach to the confirmation of suspected aneuploidy. CVS is performed by 2 general approaches: transabdominal vs transcervical, depending on operator experience and placental location/accessibility. In the hands of experienced clinicians, firsttrimester CVS has been found to be at least as safe and effective as second-trimester amniocentesis for prenatal diagnosis in twin gestations. De Catte et al13 summarized the outcomes of CVS with 3 earlier studies14-16 and their own experience 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 pregnancy loss rate before multifetal pregnancy reduction. Compared with singleton pregnancies, twin pregnancy is associated with an increased incidence of anomalies,18,19 although 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 singleton pregnancies. They categorized cardiac anomalies into 16 groups; twins had a higher incidence for all 16 catego308

www.AJOG.org ries. For 7 of the cardiovascular categories, 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). Ventricular septal defects are the most frequent heart defects. Fortunately, detection of anomalies in twin gestation does not seem to be compromised by its multifetal nature. Edwards et al20 confirmed a sensitivity of 82% and negative predictive value of 98% for anatomic surveys among 245 consecutive twins, with a 4.9% prevalence of anomalies. Among 495 monochorionic twins, Sperling et al21 reported severe structural abnormalities in 2.6%; two-thirds of the abnormalities were cardiac. With first-trimester nuchal translucency and anatomy scan at ⬍20 weeks of gestation, 83% of anomalies and aneuploidy were detected. Earlier reports on detection of congenital anomalies in twin pregnancies noted a lower detection 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 noncardiac anomalies, and 69% of major anomalies for which routine prenatal management would be altered. For detection of cardiac anomalies, their ultrasound protocol was limited to a 4-chamber view, and they detected no major cardiac lesions. Thus, it is understandable 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 assisted reproduction.25 Importantly, if discordant anomaly is noted, the likelihood of adverse outcome for the normal twin is increased. Sun et

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al26 used the 1995-1997 matched multiple 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 increased the risk of (1) preterm birth at ⬍32 weeks of gestation (odds ratio [OR], 1.85; 95% CI, 1.65–2.07), (2) birthweight ⬍1500 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 chorionicity, first trimester screening should be done to identify fetuses with aneuploidy, targeted ultrasound should be done for the detection of major anomalies, and fetal echocardiography should be done for identification of congenital heart defect. As recommended by the ACOG practice bulletin on ultrasonography in pregnancy,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 abnormality, 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 syndrome as a 35-year-old woman with a singleton infant. Thus, the importance of genetic amniocentesis with twins can be seen. Among the 6 publications that reported on loss rate after genetic amniocentesis with twins, the needle gauge varied, but all investigators used 2 separate needle insertions (Table 1).28-33 Although the rate of loss at ⬍24 weeks of gestation varied from 0.4-4.1%, the cumulative experience with ⬎1700 amnio-

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TABLE 1

Amniocentesis with twin pregnancies Variable

Country

Yukobowich et al28b

Israel

Tóth-Pál et al29

Hungary

Millaire et al30

Canada

Delisle et al31

British Columbia

Cahill et al32

United States

Daskalakis et al33

Greece

Twin pregnancy amniocentesis 476

Needle size

Second puncture

Loss at <24 wk gestation, n

Loss rate, %a

20

Yes

13

2.7 (1.6–4.6)

Twin pregnancy with no amniocentesis, n 477

Loss with no amniocentesis, n 3

Loss rate, %a 0.6 (0.2–1.8)

................................................................................................................................................................................................................................................................................................................................................................................

155

22

Yes

6

3.9 (1.8–9.1)

292

7

2.4 (1.1–4.8)

................................................................................................................................................................................................................................................................................................................................................................................

134

22

Yes

4

3.0 (1.1–7.4)

248

2

0.8 (0.2–2.8)

................................................................................................................................................................................................................................................................................................................................................................................

233

No mention

Yes

1

0.4 (0.1–2.3)

—

—

—

................................................................................................................................................................................................................................................................................................................................................................................

311

22

Yes

9

2.9 (1.5–5.4)

—

—

—

................................................................................................................................................................................................................................................................................................................................................................................

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.

centeses indicates that the fetal loss rate is 2.9% (95% CI, 2.3–3.8) or 1 per 34 (95% CI, 26 – 43). It is noteworthy that a systematic review that summarized the results of 29 articles calculated that, for singleton pregnancies who undergo genetic amniocentesis, the loss rate at ⬍24 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 result from the fact that the spontaneous loss rate at ⬍24 weeks of gestation is higher with multiples. Only 3 of these reports provided data for twins who were treated at a similar time who did not have a genetic amniocentesis.28-30 For the twins who did not have the invasive procedure, 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 conceived 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 (⬍37

weeks of gestation) than singleton pregnancies, 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 ⬍2500 g (82,799 infants). Approximately 1 in 10 twins was born at ⬍32 weeks of gestation (n ⫽ 16,597 infants) or weighed ⬍1500 g (n ⫽ 13,983; Figure 4). As Ananth et al36 noted that, with the exception of France and Finland, most industrialized countries have noted a temporal increase in prematurity. The increase in preterm births is multifactorial but can be categorized into 3 groups: medically indicated because 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 Statistics, Ananth et al36,37 provided such data (singleton pregnancies for the year 2000 and twin pregnancies for the years 19992002). For singleton and twin pregnancies 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). Perhaps because the data do not lend themselves to detailed information on the cause of indicated delivery, the investigators 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 plurality, ethnicity, and the subtypes of prematurity (Figure 6). With the exception of singleton and white pregnancies, the PNM rate is highest when preterm delivery follows premature rupture of membranes. Consistently for singleton and twin pregnancies for African American and white women, the PNM rate is lowest when preterm birth results from spontaneous labor. Within the same ethnicity, the total preterm PNM rate is significantly less for twin than for singleton pregnancies. The remarkable finding by Ananth et 36,37 is that, despite the increase in the al rate of prematurity in the United States, there is a concomitant decrease in PNM rates among African American and white women among twin and singleton pregnancies. 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

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www.AJOG.org medically indicated preterm births are associated with a favorable reduction in PNM rates.

FIGURE 4

Preterm births in 2006: twin vs singleton Singletons OR, 10.83 (95% CI, 10.71-10.95)

Twins OR, 21.94 (95% CI, 21.68-22.19)

60%

58%

OR, 7.68 (95% CI, 7.51-7.78)

OR, 10.21 (95% CI, 10.01-10.41)

12%

11%

10%

7% 2% Del <37 weeks

1%

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.

perinatal mortality rates (Figure 7). For their analysis, they had 1,172,405 preterm twin live births and 46,375,578 preterm singleton pregnancies. Over 11 years, the rate of preterm births increased 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 during the 11 years (Figure 7). The reason for the decrease in the PNM rate is that

FIGURE 5

Data are based on ethnicity and subtypes of preterm births: singleton vs twin Med Indicated

Sp PTB

PROM

9%

10%

9%

35%

32%

38%

56%

58%

53%

Singletons (AA)

Twins (AA)

Singletons (W)

8%

30%

62%

Twins (W)

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.

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Preterm labor: prediction, 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 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 results of in vitro fertilization, the rate of birth at ⬍37 weeks of gestation was 53%, at ⬍34 weeks of gestation was 16%, and ⬍28 weeks of gestation was 4%. The rate of spontaneous preterm birth was significantly higher when either fFN was positive or cervical length was ⬍20 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 ⬎34 weeks of gestation. Conversely, if both fFN and cervical length are abnormal, ⬎50% of the pregnancies will deliver at ⬍34 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 antepartum admission without concomitant 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 ⫽ .35), delivery at ⬍28 weeks of gestation (8.2% vs 3.9%; P ⫽ .21), or delivery at ⬍34 weeks of gestation (26.1% vs 25.6%; P ⫽ .94); however, 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 ⬍ .001). It is uncertain

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FIGURE 6

Data are based on ethnicity and perinatal mortality rates with preterm births: singleton vs twin PROM

Med Ind

Sp PTB

100 76

71 51

53

49 43

41

PNM/1000 births

whether their findings would have been valid had they obtained fFN measurements in conjunction with cervical length. So, fFN and cervical length can be used to ascertain which twin pregnancies will deliver prematurely, although improvement 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 symptomatic patients should be to identify those who will deliver prematurely. Such identification avoids unnecessary therapeutic interventions like unwarranted 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 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 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 pregnancies within a week of the onset of symptoms: 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 cervical length was 11-15 mm; 21% of the pregnancies delivered when the cervical length was 16-20 mm; 7% of the pregnancies 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 determine whether the knowledge of fFN and cervical length influences outcome among twin pregnancies, as it did in the trial reported by Ness et al.42 While awaiting the results of these randomized trials, we should be cognizant of the ACOG practice bulletin on the management of preterm labor.43 They recommend that either cervical ultrasound examination or fFN or both diagnostic tests should be

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44 33

31

29 25

10 Singletons (AA)

Twins (AA)

Singletons (W)

Twins (W)

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 AA

White

30% 22% 14% 10%

9%

-10% -15%

-30%

-27%

-30%

-37% -41% -50%

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.

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TABLE 2

Spontaneous preterm birth among twin pregnancies Gestational week Variable Negative fetal fibronectin level: 135 births, %

<28

<30

<32

2.1

2.9

4.5

27.3

21.4

<34

<37

⬍11.5

46

55

95

................................................................................................................................................................................................................................................................................................................................................................................

Positive fetal fibronectin level: 20 births, %

35

................................................................................................................................................................................................................................................................................................................................................................................

P value

.005

.017

⬍ .001

.001

⬍ .001

................................................................................................................................................................................................................................................................................................................................................................................

Transvaginal cervical length ⱖ20 mm: 129 births, %

2.3

3

4.7

15.8

26.9

11.9

46.8

36

83.3

................................................................................................................................................................................................................................................................................................................................................................................

Transvaginal cervical length ⬍20 mm: 26 births, %

25

................................................................................................................................................................................................................................................................................................................................................................................

P value

.008

.42

.002

.006

.001

................................................................................................................................................................................................................................................................................................................................................................................

Negative fetal fibronectin level and transvaginal cervical length ⱖ20 mm: 120 births, %

1.6

2.4

4.2

10.3

43

................................................................................................................................................................................................................................................................................................................................................................................

Either positive fetal fibronectin level or transvaginal cervical length ⬍20 mm: 24 births, %

13.3

Positive fetal fibronectin level and transvaginal cervical length ⬍20 mm: 11 births, %

50

P value

⬍ .001

9.5

8.3

26.1

77.3

................................................................................................................................................................................................................................................................................................................................................................................

33.3

54.5

54.5

100

................................................................................................................................................................................................................................................................................................................................................................................

.001

⬍ .001

⬍ .001

⬍ .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 need tocolytics. Until there are publications to the contrary, this recommendation is applicable to twin and singleton pregnancies. Considering the increased likelihood of preterm births among twin pregnancies, 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 prophylactic 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 intervention has not been proved to reduce the incidence of birth at ⬍37 weeks of gestation (RR, 0.85; 95% CI, 0.65–1.10) or delivery at ⬍34 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 mortality 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 decrease the incidence of recurrent preterm delivery in a singleton gestation.45 A systematic review by Dodd et al46 iden312

tified only 2 randomized trials that assessed the use of progesterone vs placebo for multiple pregnancy. Depending on the outcome of interest, the number of participants varied between 154 and 1280. The authors concluded that the use of progesterone in multiple gestations does not decrease the likelihood of birth at ⬍37 weeks of gestation (RR, 1.01; 95% CI, 0.92–1.12), birthweight ⬍2500 g (RR, 0.94; 95% CI, 0.86 –1.02), respiratory distress (RR, 1.13; 95% CI, 0.86 –1.48), intraventricular hemorrhage 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 premature 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 ultrasound examination. The use of historyindicated (prophylactic) cerclage for ovulation-induced twin gestations (n ⫽ 50) in a randomized trial did not decrease the rate of prematurity significantly (45% with cerclage vs 48% without suture) or neonatal mortality (18%

American Journal of Obstetrics & Gynecology OCTOBER 2010

vs 15% for suture vs no suture, respectively).47 More importantly, when cerclage was used in asymptomatic woman with twin gestations and short cervical length on transvaginal ultrasound examination, it significantly increased the risk of delivery at ⬍35 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. Other prophylactic interventions, which have been examined in multiple gestations to prevent preterm delivery, are bed rest and home uterine monitoring. Crowther,49 in 2001, summarized the results of 6 trials with hospitalization and bed rest. The summary, which involved ⬎600 patients and 1400 newborn infants, 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 ⬍34 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 monitoring has not been shown to be beneficial in the prevention of preterm birth in

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www.AJOG.org multiple gestations, its use should be abandoned.50 Thus, the following treatment modalities have no role in the prevention 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 labor has been diagnosed. The use of tocolytics for the treatment of preterm labor has not been shown to decrease the incidence of delivery within 7 days of treatment, perinatal or neonatal death, or the neonatal complications of respiratory distress syndrome, necrotizing enterocolitis, 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 judiciously in this population.53 In contrast to the unproven efficacy of tocolytics, the use of antenatal corticosteroids (ACS) has been shown54 to decrease the incidence of neonatal death (RR, 0.69; 95% CI, 0.58 – 0.81), respiratory distress syndrome (RR, 0.66; 95% CI, 0.43– 0.69), intraventricular hemorrhage (RR, 0.54; 95% CI, 0.43– 0.69), necrotizing 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 Institutes 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 gestations beginning at 24 weeks of gestation and given every 2 weeks (n ⫽ 136) with the standard approach in women who were at immediate risk of preterm delivery (n ⫽ 902). The prophylactic approach was shown not to offer a significant reduction in respiratory distress syndrome (13% vs 11%; adjusted OR, 0.69; 95% CI, 0.33–1.46) and was associated with exposing a large number of ba-

bies to unnecessary treatment that adversely 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, intramuscularly, twice, 24 hours apart. If at least 14 days have elapsed and delivery is likely at ⬍33 weeks of gestation, then a single rescue dose should be administered. 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 received the rescue dosage had a significant reduction in composite perinatal neonatal morbidity (64% vs 44%; P ⫽ .02) and significantly decreased rate of respiratory distress syndrome, ventilator support, and surfactant use. In summary, although there are diagnostic 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 decrease the likelihood of preterm birth. Tocolytics should be used either to transfer a patient to a tertiary center or to ensure ACSs are administered. Prolonged 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 opportunities to the press,1 and challenge and trepidation to clinicians.58,59 Compared with singleton pregnancies, twin pregnancies are more likely to be complicated by hypertensive 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 anomalies,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

Reviews

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 stabilized 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 chorionicity but also aneuploidy with firsttrimester 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 clinicians who have experience in detecting these abnormalities evaluate these patients. If need be, parents who are expecting twins should be offered and referred for CVS, genetic amniocentesis, and selective reduction. Third, we found that the rate of preterm births is significantly higher for twin pregnancies than for singleton pregnancies (Figure 4). Although this has been known, findings from the national 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 (Figure 6). But what is most captivating is that, although the rate for preterm birth has increased, the associated perinatal mortality rate has actually decreased. The fact that this conclusion is based on a 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 future 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 decreased in the United States. Fourth, the findings focus on the management of preterm labor with twin gestations. Clinicians should be cognizant

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Obstetrics

of the facts that, with twins, preterm contractions are common, that the benefit of tocolytics is limited although the complications rate is higher, and that the preterm birth-related perinatal mortality rate has been lowered. Whenever feasible, 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 ⬍2.5 cm or fFN is positive or both, (2) the test results have been evaluated, (3) 48 hours have elapsed since the first dosage of corticosteroid was administered, or (4) the patient has been transferred to a tertiary center. As with singleton pregnancies,43 there is no justification for prolonged tocolytics with twin pregnancies. In conclusion, there are several reassuring findings with twin pregnancies. The rate of twin pregnancies is not increasing in the United States; although the preterm birth rate is high, the associated perinatal mortality rate is decreasing. Future studies should focus on improving the detection of birth defects and of abnormal growth and on antepartum testing to improve the outcomes for twin pregnancies with medical or obstetric 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?_r⫽1&scp⫽ 1&sq⫽The%20Gift%20of%20Life,%20and%20 Its%20Price&st⫽cse. 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 Gemellol (Roma) 1997;46:209-18. 4. Eriksson AW, Fellman J. Temporal trends in the rates of multiple maternities in England and Wales. Twin Res Hum Genet 2007;10:626-32. 5. De Mouzon J, Lancaster P, Nygren KG, et al. World collaborative report on assisted reproductive technology, 2002. Hum Reprod 2009; 1:1-11. 6. Lee YM, Cleary-Goldman J, Thaker HM, Simpson LL. Antenatal sonographic prediction of twin chorionicity. Am J Obstet Gynecol 2006;195:863-7. 7. Bermudez C, Becerra CH, Bornick PW, Allen MH, Arroyo J, Quintero RA. Placental types and twin-twin transfusion syndrome. Am J Obstet Gynecol 2002;187:489-94.

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www.AJOG.org 8. Hack KE, Derks JB, Schaap AH, et al. Perinatal outcome of monoamniotic twin pregnancies. Obstet Gynecol 2009;113:353-60. 9. Evans MI, Goldberg JD, Horenstein J, et al. Selective termination for structural, chromosomal, and Mendelian anomalies: international experience. Am J Obstet Gynecol 1999;181: 893-7. 10. Evans MI, Berkowitz RL, Wapner RJ, et al. Improvement in outcomes of multifetal pregnancy reduction with increased experience. Am J Obstet Gynecol 2001;184:97-103. 11. Chasen ST, Perni SC, Kalish RB, Chervenak FA. First-trimester risk assessment for trisomies 21 and 18 in twin pregnancy. Am J Obstet Gynecol 2007;197:374.e1-3. 12. Sebire NJ, Snijders RJ, Hughes K, Sepulveda W, Nicolaides KH. Screening for trisomy 21 in twin pregnancies by maternal age and fetal nuchal translucency thickness at 10-14 weeks of gestation. BJOG 1996;103: 999-1003. 13. De Catte L, Liebaers I, Foulon W. Outcome of twin gestations after first trimester chorionic villus sampling. Obstet Gynecol 2000;96:714-20. 14. Brambati B, Tului L, Lanzani A, Simoni G, Travi M. First trimester genetic diagnosis in multiple pregnancy: principles and potential pitfalls. Prenat Diagn 1991;11:767-74. 15. Pergament E, Schulman JD, Copeland K, et al. The risk and efficacy of chorionic villus sampling in multiple gestations. Prenat Diagn 1992;12:377-84. 16. Wapner RJ, Johnson A, Davis G, Urban A, Morgan P, Jackson L. Prenatal diagnosis in twin gestations: a comparison between second-trimester amniocentesis and first-trimester chorionic villus sampling. Obstet Gynecol 1993; 82;49-56. 17. Ferrara L, Gandhi M, Litton C, et al. Chorionic villus sampling and the risk of adverse outcome in patient undergoing multifetal pregnancy reduction. Am J Obstet Gynecol 2008; 199:408.e1-4. 18. Hardin J, Carmichael SL, Selvin S, Lammer EJ, Shaw GM. Increased prevalence of cardiovascular defects among 56,709 California twin pairs. Am J Med Genet A 2009;149A:877-86. 19. Bahtiyar MO, Dulay AT, Weeks BP, Friedman AH, Copel JA. Prevalence of congenital heart defects in monochorionic/diamniotic twin gestations: a systematic literature review. J Ultrasound Med 2007;26:1491-8. 20. Edwards MS, Ellings JM, Newman RB, Menard MK. Predictive value of antepartum ultrasound examination for anomalies in twin gestation. Ultrasound Obstet Gynecol 1995;6:43-9. 21. Sperling L, Kill C, Larsen LU, et al. Detection of chromosomal abnormalities, congenital abnormalities and transfusion syndrome in twins. Ultrasound Obstet Gynecol 2007;29:517-26. 22. Allen SR, Gray LG, Frentzen BH, Cruz AC. Ultrasonographic diagnosis of congenital anomalies in twins. Am J Obstet Gynecol 1991;165: 1056-60.

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23. Abuhamad AZ. ACOG practice bulletin: ultrasonography in pregnancy. Obstet Gynecol 2008;112:951-61. 24. Campbell KH, Copel JA, Ozan Bahtiyar M. Congenital heart defects in twin gestations. Minerva Ginecol 2009;61:239-44. 25. Abuhamad A, Chaoui R. Congenital heart disease: incidence, risk factors, and prevention. In: Abuhamad A, Chaoui R, eds. A practical guide to fetal echocardiography: normal and abnormal hearts. 2nd ed. Philadelphia: Lippincott, Williams & Wilkins; 2010:1-10. 26. Sun LM, Chen XK, Wen SW, Fung KF, Yang Q, Walker MC. Perinatal outcomes of normal cotwins in twin pregnancies with one structurally anomalous fetus: a population based retrospective study. Am J Perinatol 2009:26:51-6. 27. Rodis JF, Egan JF, Craffey A, Ciarleglio L, Greenstein RM, Scorza WE. Calculated risk of chromosomal abnormalities in twin gestations. Obstet Gynecol 1990;76:1037-41. 28. Yukobowich E, Anteby EY, Cohen SM, Lavy Y, Granat M, Yagel S. Risk of fetal loss in twin pregnancies undergoing second trimester amniocentesis. Obstet Gynecol 2001;98:231-4. 29. Tóth-Pál E, Papp C, Beke A, Bán Z, Papp Z. Genetic amniocentesis in multiple pregnancy. Fetal Diagn Ther 2004;19:138-44. 30. Millaire M, Bujold E, Morency AM, Gauthier RJ. Mid-trimester genetic amniocentesis in twin pregnancy and the risk of fetal loss. J Obstet Gynaecol Can 2006;28:512-8. 31. Delisle MF, Brosseuk L, Wilson RD. Amniocentesis for twin pregnancies: is alpha-fetoprotein useful in confirming that the two sacs were sampled? Fetal Diagn Ther 2007;22:221-5. 32. Cahill AG, Macones GA, Stamilio DM, Dicke JM, Crane JP, Odibo AO. Pregnancy loss rate after mid-trimester amniocentesis in twin pregnancies. Am J Obstet Gynecol 2009;200: 257.e1-6 33. Daskalakis G, Anastasakis E, Papantoniou N, Mesogitis S, Antsaklis A. Second trimester amniocentesis in assisted conception versus spontaneously conceived twins. Fertil Steril 2009;91:2572-7. 34. Mujezinovic F, Alfirevic Z. Procedure-related complications of amniocentesis and chorionic villous sampling: a systematic review. Obstet Gynecol 2007;110:687-94. 35. Antsaklis A, Daskalakis G, Papantoniou N, Mesogitis S, Michalas S. Genetic amniocentesis in multifetal pregnancies reduced to twins compared with nonreduced twin gestations. Fertil Steril 2000;74:1051-2. 36. Ananth CV, Joseph KS, Demissie K, Vintzileos AM. Trends in twin preterm birth subtypes in the United States, 1989 to 2000: impact of perinatal mortality. Am J Obstet Gynecol 2005; 193:1076-82. 37. Ananth CV, Joseph KS, Demissie K, Vintzileos AM. Trends in preterm birth and perinatal mortality among singletons: United States, 1989 through 2000. Obstet Gynecol 2005; 105:1084-91. 38. Fox NS, Saltzman DH, Klauser CK, Peress D, Gutierrez CV, Rebarber A. Prediction of

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www.AJOG.org spontaneous preterm birth in asymptomatic twin pregnancies with the use of combined fetal fibronectin and cervical length. Am J Obstet Gynecol 2009;201:313.e1-5. 39. Gyamfi C, Lerner V, Holzman I, Stone J. Routine cervical length in twins and perinatal outcomes. Am J Perinatol 2007;24:65-70. 40. Singer E, Pilpel S, Bsat F, Plevyak M, Healy A, Markenson G. Accuracy of fetal fibronectin to predict preterm birth in twin gestations with symptoms of labor. Obstet Gynecol 2007; 109:1083-7. 41. Fuchs I, Tsoi E, Henrich W, Dudenhausen JW, Nicolaides KH. Sonographic measurement of cervical length in twin pregnancies in threatened preterm labor. Ultrasound Obstet Gynecol 2004;23:42-5. 42. Ness A, Visintine J, Ricci E, Berghella V. Does knowledge of cervical length and fetal fibronectin affect management of women with threatened preterm labor? A randomized trial. Am J Obstet Gynecol 2007;197:426.e1-7. 43. American College of Obstetricians and Gynecologists. Management of preterm labor. Washington, DC: The College; 2003. 44. Yamasmit W, Chaithongwongwatthana S, Tolosa JE, Pereira L, Lumbiganon P. Prophylactic oral betamimetics for reducing preterm birth in woman with a twin pregnancy. Cochrane Database Syst Rev 2005;20:CD004733. 45. Meis PJ, Klebanoff M, Thom E, et al. Prevention of preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379-85.

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women at risk of preterm birth. Cochrane Database Syst Rev 2006;3:CD004454. 55. National Institutes of Health. Report of the Consensus Development Conference on the effect of corticosteroids for fetal maturation on perinatal outcomes. Pub no. 95-3784. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service; 1994. 56. Murphy DJ, Caukwell S, Joels LA, Wardle P. Cohort study of the neonatal outcome of twin pregnancies that were treated with prophylactic or rescue antenatal corticosteroids. Am J Obstet Gynecol 2002;187:483-8. 57. Garite TJ, Kurtzman J, Maurel K, et al. Impact of a “rescue course” of antenatal corticosteroids: a multicenter randomized placebocontrolled trial. Am J Obstet Gynecol 2009; 200:248.e1-9. 58. Baretta E, Boghi I, Fichera A, Mor E, Gregorini S, Frusca T. Twin pregnancy: not only a medical event. Minerva Ginecol 2007;59: 571-8. 59. Bryan E. The impact of multiple preterm birth on the family. BJOG 2003;20:24-8. 60. Kinzler WL, Ananth CV, Vintzileos AM. Medical and economic effects of twin gestations. J Soc Investig 2000;7:321-7. 61. Chauhan SP, Shields D, Parker D, Sanderson M, Scardo JA, Magann EF. Detecting fetal growth restriction or discordant growth in twin gestation stratified by placental chorionicity. J Repro Med 2004;49:279-84.

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