Nearly a third of triplets are born very premature and triplets are 12 times more likely to die during the first year than
singletons. But when it comes to counseling a woman pregnant with triplets on her risks for a very premature delivery, one
size does not fit all. If certain maternal factors and assessments of nutritional status, chorionicity, and amnionicity point to heightened
odds for a very premature birth, the couple may need to wrestle with a wrenching decision like multifetal pregnancy reduction
(MFPR). On the other hand, if your assessment shows that the woman's chances are far smaller, that more reassuring information
can give the couple a more upbeat picture of their specific risks. An important decision like this should not be based on
general risk factors, but rather on as much specific information as you can possibly determine.
At age 34, Dina Brennan has had two children by her first husband (a 7-year-old daughter and a 5-year-old son, both spontaneous
vaginal deliveries at term) and a third pregnancy that ended in abortion. Divorced and seeking to start a second family with
her second husband, she underwent in vitro fertilization and has recently been told that she's carrying triplets. Mrs. Brennan
is a Caucasian stay-at-home mom. She is 5 ft 6 in, weighs 148 lb (BMI 23.9), and is physically fit, with a negative medical
history. Both deliveries were uncomplicated, resulting in an 8 lb and an 8 lb, 3 oz infant, respectively. She gained between
30 and 35 lb in each of those pregnancies and after her second delivery had both "tubes tied."
After her IVF procedure, in which two fresh blastocysts were transferred, pregnancy was confirmed by an appropriately rising
beta hCG titer. Just over a month following the transfer, Mrs. Brennan experienced some vaginal spotting. An ultrasound confirmed
a viable triamniotic, dichorionic triplet gestation, each with a crown-rump length consistent with 6 weeks' gestation.
An infertility specialist previously counseled the family about MFPR in light of the perinatal risks associated with triplet
pregnancies. The family now needs more specific information on her prognosis for carrying her three babies to at least 32
weeks' gestation.
Defining the term "very premature" Short-term and life-long morbidity, as well as mortality, in multiple gestations are chiefly related to the gestational age
(GA) at delivery rather than the number of newborns. Statistics reveal that 1.2% of singletons, 11% of twins, and 31% of triplets
are born very premature—that is, prior to 32 weeks' gestation.1 On average, triplets are born 7 weeks earlier and at half the weight of the average singleton infant, and at least 25% are
very underweight at birth (<1,500 g).2 Because of this skewed birthweight and GA distribution, triplets are 12 times more likely to die during the first year of
life compared to a singleton and one of five triplet gestations (20%) results in at least one child in the sibship with a
long-term handicap.2,4
Being able to identify risk factors for very low birthweight (VLBW) delivery or very preterm delivery less than 32 weeks'
gestation would help this patient and others in deciding whether to continue a triplet pregnancy or to undergo MFPR.
Maternal demographics and obstetric history Factors that can be evaluated in the first trimester include maternal demographics (like race) and obstetric history. A retrospective
cohort analysis of 178 triplet pregnancies in which all triplets were born alive revealed that nulliparous women are at highest
risk for an adverse outcome.5 This is still true even after adjusting for a wide range of potential confounding variables like pre-gravid weight, height,
gestational weight gain, and preeclampsia. Women who've had a good outcome in earlier pregnancies (birthweight >2,500 g and
at ≥ 37 weeks' gestation) had triplets with an average birthweight 153 g heavier than that of nulliparous women and an average
length of gestation almost 8 days longer. Even women with a previous poor obstetrical outcome (birthweight <2,500 g or <37
weeks of gestation) were at a lesser risk for an adverse outcome than were nulliparous women. A previous good obstetrical
outcome was associated with an adjusted odds ratio (AOR) of 0.26 (95% CI; 0.09–0.75; P<0.01) for delivery ≤30 weeks' gestation—meaning these women had about a 75% reduced risk of delivery before 30 weeks, when compared to nulliparous women.Nulliparity was associated with an almost fourfold greater risk (AOR 3.98; 95% CI; 1.39–11.34; P<0.009) of delivery before 30 weeks.
Maternal factors that had no significant impact on either birthweight or gestational length in this particular model included:
maternal age, ethnicity, height, pre-gravid weight, BMI, smoking, or use of infertility treatments. Although it is frequently
stated that taller women with multiples are at less risk of preterm birth, this anecdotal observation could not be confirmed
in either this investigation or in other reports.6
What about race? As with most other aspects of obstetrics, race is a significant prognostic factor. In the above cited investigation
by Luke and colleagues,5 African-American race did not affect obstetric outcome among the live-born triplets but was associated with an increased
risk of fetal death. In a much larger retrospective cohort study of triplets delivered in the United States between 1995 and
1997, Salihu and colleagues identified a significant racial disparity in triplet perinatal outcomes.7 Comparing 14,364 white and 1,317 black triplet gestations, the investigators noted significantly higher rates of preterm birth
less than 33 weeks (43.1% vs. 55.1%; P<0.0001) and delivery of VLBW infants (33.5% vs. 51%; P<0.0001) among black women. Adjusted odds ratios were generated after controlling for the confounding effects of maternal
age, parity, mother's education, marital status, maternal smoking, alcohol consumption during pregnancy, level of prenatal
care utilization, and birth order.
The likelihood of stillbirth and perinatal mortality was not significantly different between black and white triplets. However,
the AOR for neonatal, postneonatal, and infant mortality were significantly different. Black triplets were at least twice
as likely to experience a neonatal death or infant mortality as white triplets. The widest disparity was observed in postneonatal
deaths; black triplets had an almost fourfold increased risk compared to whites.7
In a follow-up study using the same cohort of triplets delivered in the US between 1995 and 1998, Salihu and colleagues showed
the positive association between maternal age and perinatal outcome.8 They found that both mean birthweight and GA at delivery increased with maternal age. Triplets born to women age 40 or older
had about a 50% lower risk of LBW, 42% for VLBW, and 33% for preterm birth at less than 33 weeks.
The researchers also found a significant improvement in outcome for women between ages 30 and 39 who were carrying triplets.
They obtained these estimates after adjusting for maternal race, education, marital status, adequacy of prenatal care, and
smoking, highlighting the fact that the interaction between maternal age and perinatal outcome remains poorly understood.
This retrospective cohort did not assess the impact of maternal prepregnancy BMI (greater in older mothers), parity, maternal
nutrition, and weight gain, which likely would have been helpful in explaining this apparent paradox of advanced maternal
age being linked with better triplet growth and perinatal outcomes.
Numerous studies have suggested increased morbidity and mortality among triplets resulting from assisted conception as compared
to their naturally conceived counterparts. Much of these data, however, come from large registries or national databases that
lack sufficient depth to consider pertinent confounding variables. In an analysis of twin gestations, as well as in the above
cited triplet analysis, Luke and colleagues could not identify a significant impact of the mode of conception on multifetal
pregnancy outcome.5,9 Rather, specific factors that are more common among pregnancies resulting from assisted conception, such as older age, nulliparity,
preeclampsia, and fetal reduction, are associated with the increased risk of early preterm birth, VLBW, and impaired fetal
growth in these gestations.
Mother's diet greatly impacts length of pregnancy Maternal nutrition also substantially affects both birthweight and length of gestation. Although you can't prospectively evaluate
this factor during a first-trimester consultation, you can retrospectively assess it from a patient's previous pregnancies.
The rate of maternal weight gain in triplets prior to 24 weeks' gestation has a three- to fivefold greater effect on the rate
of fetal growth and birthweight than does weight gain after 24 weeks.5 In one study, maternal weight gain of less than 36 lb by 24 weeks' gestation adversely affected both the rate of triplet growth
and reduced birthweight by almost 0.5 lb compared to women who gained 36 or more lb by 24 weeks.5 This adverse impact was present in all BMI categories but was greater in the underweight (BMI <19.8) and normal-weight (BMI
19.8–26.0) triplet mothers compared to the overweight mothers (BMI >26.0). Aggressively treat hyperemesis in the first trimester—especially
in women who are already underweight. Hyperemesis associated with a more than 5% weight loss has been linked to an increased
risk of intrauterine growth restriction.
Table 1: Nutritional guidelines for a triplet pregnancy
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The early rates of fetal growth are important, as they have significant and opposite effects on the length of gestation. Fetal
growth rates in the lowest quartile (<45 g/wk) were associated with gestations shorter than average by more than 5 weeks (–36.7
2.9 d) while growth at ≥ 75th percentile (>61 g per wk) was associated with triplet gestations 2 to 3 weeks longer than
average (+ 18.9 3.9 d).5 Optimal maternal nutrition, early weight gain, and an appropriate maternal pre-gravid BMI may be critical for normal placental
growth and function and have the potential to significantly improve outcomes for these high-risk pregnancies (Table 1). Ideally,
efforts to improve a mother's nutritional status (including nutritional consultation) should get under way prior to pregnancy—before
or during infertility treatment.
Table 2: Complications of dichorionic (monochorionic twin pair) vs. trichorionic triplet gestations
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How well do chorionicity and amnionicity predict outcome? Chorionicity and amnionicity of the triplet gestation is another factor that may help predict outcome. Assisted reproductive
technologies like IVF and intracytoplasmic sperm injection have been linked with increased risks of monozygotic twinning,
especially when the embryo culture is prolonged to the blastocyst stage in an effort to increase implantation rates.10 In a series of 35 triplet pregnancies at one perinatal center, 17 included a monochorionic twin pair.11 Among the 16 triplet sets resulting from IVF, six included a monochorionic twin pair and each of these followed replacement
of only two embryos. Triplet pregnancies that include monochorionic twins appear to be at higher risk than trichorionic triplets.
In the above cited series, 27 of 51 dichorionic triplets (52.9%) delivered prior to 32 weeks while only 15 of 54 trichorionic
triplets (28%) experienced this same degree of prematurity (Table 2).11 The increased risk of early preterm birth appeared to be related to other complications encountered more often among fetuses
with a shared placental circulation. Of the 17 dichorionic triplets, twin-to-twin transfusion syndrome (TTTS) was suspected
in three, while three mothers had preeclampsia/HELLP syndrome compared with only one trichorionic triplet. In addition, four
infants from dichorionic triplet gestations had anomalies compared to only one trichorionic infant, and two sets of dichorionic
triplets were also monoamniotic; both were complicated by cord entanglement.
In another single-center series, investigators identified 17 dichorionic triplet pregnancies (11.3%) among 151 women with
triplets evaluated between 1993 and 2000.12 Two of these women conceived spontaneously while the remaining 15 conceived following IVF or ovulation induction. Two of the
17 pregnancies were spontaneously lost before viability (11.8%). In three other pregnancies severe, early onset TTTS with
a "stuck twin" was diagnosed in the monochorionic pair (17.6%). Two of these patients elected to terminate the entire pregnancy
while the third underwent serial amniotic fluid reduction. In that case, intrauterine fetal death of the donor occurred at
22 weeks and selective termination of the recipient was performed at 23 weeks. The remaining triplet was delivered at 32 weeks.
Overall, of the 17 dichorionic/triamniotic triplet pregnancies, nearly a third were complicated by either pregnancy loss prior
to viability or severe TTTS in the second trimester.12
Using cervical length to detect or exclude preterm birth risk Although not accessible at the time of a first-trimester consultation, it's important to inform a patient of the availability
of second-trimester transvaginal sonography (TVS) for examining the cervix. Cervical length assessment is a powerful tool
for detecting or excluding patients at risk for preterm birth. Ramin and colleagues performed TVS on 32 triplet gestations
to establish cervical length normograms for triplet pregnancies.13 They noted that cervical length shortened progressively with advancing gestation, and that the average cervical length was
significantly shorter than that reported for singletons at both 24 weeks (35.2 8.3 vs. 25.0 8.0 mm; P<0.001) and 28 weeks (33.7 8.5 vs. 28.0 11.0 mm; P<0.005). They also reported a nonsignificant trend toward a lower mean cervical length among triplet pregnancies delivered
before 33 weeks. Cervical funneling was noted in three women with triplets, and the average time from detection to delivery
was only 27 days.
Other investigators undertook a second prospective cohort study that included 51 triplet pregnancies evaluated with serial
TVS cervical length measurements between 15 and 28 weeks' gestation.14 Notably, a cervical length of 25 mm or less between 15 and 20 weeks' gestation had both a specificity and a positive predictive
value of 100% and a sensitivity of 50% for delivery before 28 weeks. In contrast, a cervical length of less than 25 mm between
15 and 20 weeks of gestation had a negative predictive value of 91% for delivery before 28 weeks, 84% for delivery before
30 weeks, and 72% for delivery before 32 weeks. A cervical length of 25 mm or less between 21 and 24 weeks had a sensitivity
of 86% (six of seven cases identified) and a positive predictive value of 40% for predicting spontaneous delivery before 28
weeks' gestation. A cervical length of ≤20 mm between 25 and 28 weeks' gestation had both a sensitivity and negative predictive
value of 100% for delivery before 28 and before 30 weeks' gestation with positive predictive values of 18% and 32%, respectively.14
Once we identify preterm labor, can we successfully intervene? The obvious question is whether detecting a triplet gestation at risk for early preterm delivery allows any opportunity for
intervention to prolong pregnancy or to improve outcomes. Unfortunately, evidence-based data defining successful interventions
to prolong high-risk triplet pregnancies are sparse.
Once identified, a triplet pregnancy with a shortened cervix or other maternal risk factors frequently results in recommendations
to modify lifestyle factors, work, or other maternal activities. However, although bed rest, work, and activity restrictions
are often advised in multifetal gestations, there are no prospective, randomized data to support their effectiveness. Data
that are available are retrospective, not current, and confounded by late diagnosis. A recumbent position does take pressure
off the cervix, while walking and sexual intercourse are both associated with increased uterine contractility.
Of course, some advise cerclage placement to reduce the risk of early preterm birth in triplets, but at least two prospective,
randomized trials, including twin pregnancies and a large retrospective non-randomized cohort of triplet pregnancies, have
failed to demonstrate any benefit associated with prophylactic cerclage placement.15 Overall, there does not appear to be sufficient evidence to support the routine placement of a cervical cerclage in triplet
pregnancies. The potential role of cerclage in the presence of cervical shortening identified by second-trimester endovaginal
sonography demands prospective randomized investigation.
The value of early diagnosis of preterm labor using increased perinatal surveillance or electronic home uterine activity monitoring
is essentially unexplored among triplet gestations. However, because current tocolytic therapies can do little beyond prolonging
pregnancy for the short-term administration of antenatal corticosteroids, there's a frustrating lack of treatment options
to offer once preterm labor is identified.
Multifetal pregnancy reduction has now evolved as an option for reducing the complications of high-order multiple gestations.
Considering its associated loss rates and potential benefits, most clinicians and patients have accepted it when it comes
to quadruplets or more and have not considered it for twins. MFPR for triplet pregnancies remains controversial. The most
recent collaborative data show that triplets reduced to twins have rates of loss at 24 weeks or less (4.5%) and preterm delivery
between 25 and 28 weeks (3.5%) that are equivalent to naturally occurring twins.16
Table 3: Outcomes of twin gestations following MFPR from triplets compared to nonreduced triplets and two large spontaneous
twin cohorts
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Yaron and colleagues reviewed 143 triplet pregnancies that underwent MFPR to twins over a 10-year period at a single center
and compared them to 12 nonreduced triplet pregnancies and two large twin cohorts (Table 3).17 Severe prematurity (25- to 28-weeks' gestation) occurred in 25% of the nonreduced triplets compared with 4.9% after reduction—similar
to rates of 7.7% and 8.4% seen among the nonreduced twin cohorts. The mean GA at delivery and birthweights were significantly
worse for the expectantly managed triplets (32.9 4.7 weeks; 1,636 645 g) compared to the triplets reduced to twins (35.6
3.1 weeks; 2,381 602 g) or either of the nonreduced twin cohorts. Regardless of the data, however, many couples won't
even consider an invasive procedure or embryo reduction or both, especially when it comes to a monochorionic "twin" pair in
a triplet gestation where experts often recommend reducing to the "singleton."
What will Dina decide? Returning to our case history, the challenge of determining the specific risks facing Mrs. Brennan, the maternal-fetal medicine
specialist reviews specific maternal factors and assesses nutritional status, chorionicity, and amnionicity of the triplet
gestation to provide useful information about her individual risk of delivery prior to 32 weeks. In addition, he or she should
discuss the possibility of ongoing risk assessment using endovaginal ultrasonography for cervical length assessment and potential
interventions that might help prolong her pregnancy. To effectively balance the risks and potential benefits of reducing a
triplet gestation to either twins or a singleton, a patient must be fully informed of the likelihood of early preterm birth.
In Mrs. Brennan's case, consultation reveals several factors that would be associated with a good likelihood for reaching
viability with her triplet pregnancy. These include her multiparity, previous good obstetrical outcomes, a normal BMI, and
history of appropriate weight gain in each of her previous singleton pregnancies. Clinicians should undertake careful surveillance
for the specific risks associated with a monochorionic twin pair. With this early pregnancy counseling, the patient and her
partner can now make a better decision about the potential bene-fit of MFPR in their particular circumstances.
REFERENCES1. Kiely JL. What is the population-based risk of preterm birth among twins and other multiples? Clin Obstet Gynecol. 1998;41:3-11.
2. Martin JA, MacDorman MF, Mathews TJ. Triplet births: trends and outcomes, 1971-94; Hyattsville, Md. US Dept. of Health and
Human Services, Public Health Service, Centers for Disese Control and Prevention, National Center for Health Statistics; 1977.
3. Yokoyama Y, Shimizu T, Hayakawa K. Incidence of handicaps in multiple births and associated factors. Acta Genet Med Gemellol (Roma). 1995;44:81-91.
4. Grether JK, Nelson KB, Cummins SK. Twinning and cerebral palsy: experience in four northern California counties, births 1983
through 1985. Pediatrics. 1993;92:854-858.
5. Luke B, Nugent C, van de Ven C, et al. The association between maternal factors and perinatal outcomes in triplet pregnancies.
Am J Obstet Gynecol. 2002;187:752-757.
6. Shah LP, Meier E. Are short women with multiple gestations at risk for preterm labor? Obstet Gynecol. 2001;95(suppl 1):S71.
7. Salihu HM, Williams AT, McCainey TN, et al. Early mortality among triplets in the United States: black-white disparity. Am J Obstet Gynecol. 2004;190:477-484.
8. Salihu HM, Bagchi S, Aliyu ZY, et al. Advanced maternal age and fetal growth inhibition in triplets. J Reprod Med. 2005;50:319-326.
9. Luke B, Brown MB, Nugent G, et al. Risk factors for adverse outcomes in spontaneous versus assisted conception twin pregnancies. Fertil Steril. 2004;81:315-319.
10. Peramo B, Ricciarelli E, Cuadros-Fernandez JM, et al. Blastocyst transfer and monozygotic twinning. Fertil Steril. 1999;72:1116-1117.
11. Arabin B, Merien A, van Eyck J. Prediction of preterm triplet birth by clinical assessment. In: Keith LG, Blickstein I, ed.
Triplet Pregnancies and Their Consequences. New York, NY: The Parthenon Publishing Group; 2002:133-148.
12. Chasen ST, Al-Kouatly HB, Ballabh P, et al. Outcomes of dichorionic triplet pregnancies. Am J Obstet Gynecol. 2002;186:765-767.
13. Ramin KD, Ogburn PL Jr., Mulholland TA, et al. Ultrasonographic assessment of cervical length in triplet pregnancies. Am J Obstet Gynecol. 1999;180:1442-1445.
14. Guzman ER, Walters C, O'Reilly-Green C, et al. Use of cervical ultrasonography in prediction of spontaneous preterm birth
in triplet gestations. Am J Obstet Gynecol. 2000;183:1108-1113.
15. Newman RB, Hamer C, Miller MC. Outpatient triplet management: a contemporary review. Am J Obstet Gynecol. 1989;161:547-555.
16. 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.
17. Yaron Y, Bryant-Greenwood PK, Dave N, et al. Multifetal pregnancy reduction of triplets to twins: comparison with nonreduced
triplets and twins. Am J Obstet Gynecol. 1999;80:268-271.
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Take-home messages- As much as possible, identify individual risk factors for very low birthweight (VLBW) delivery or very preterm delivery less
than 32 weeks—information that may help patients wrestling with the decision to continue a triplet pregnancy or to undergo
multifetal pregnancy reduction.
- One triplet study found that pregnancies at highest risk for adverse outcome were those among nulliparous women. Race is also
a significant prognostic factor.
- Although you can't prospectively evaluate maternal nutritional status during a first-trimester consultation, you can retrospectively
assess this factor from a patient's previous pregnancies.
- It's important to inform a patient of the availability of second-trimester transvaginal sonography for examining the cervix, which is a powerful tool for detecting or excluding patients
at risk for early preterm birth.
