REFUND AMOUNT LESS THAN P1,000

Obstetrics
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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.
306
American Journal of Obstetrics & Gynecology OCTOBER 2010
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
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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
American Journal of Obstetrics & Gynecology OCTOBER 2010
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-
Obstetrics
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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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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.
310
American Journal of Obstetrics & Gynecology OCTOBER 2010
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
Obstetrics
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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
Reviews
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.
OCTOBER 2010 American Journal of Obstetrics & Gynecology
311
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Obstetrics
www.AJOG.org
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
Obstetrics
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
OCTOBER 2010 American Journal of Obstetrics & Gynecology
313
Reviews
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
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