Triplet and Higher-Order Pregnancy

Special Considerations

Ann McHugh and Fergal Malone

Introduction

The rate of triplet and higher-order multiple (HOM) pregnancies increased more than 400% during the 1980s and 1990s, peaking at 193.5 per 100,000 births in 1998.

The Facts

Higher-order multiple births are naturally conceived in approximately one-fifth of cases, one- to two-thirds are a consequence of ovulation induction or superovulation and 13-44% are associated with ART.² Assisted reproductive technology itself does not appear to increase the risk of composite neonatal morbidity (culture-proven sepsis, respiratory distress syndrome or Apgar Score < 7 at 5 minutes) or perinatal death in triplet pregnancies,³ despite the fact that mothers undergoing ART are older and tend to deliver at an earlier gestational age.⁴ Triplet pregnancies resulting from ART are most likely to be trizygotic and therefore trichorionic. However, monochor- ionic placentation is more common in spontaneously conceived triplets. Multifetal pregnancies carry significant risks for both mother and fetus (Tables 22.1 and 22.2).

Table 22.1 Incidence (%) of maternalcomplications in triplet and quadruplet pregnancies^{6 9}

PIH: pregnancy-induced hypertension; PET: preeclampsia; GDM: gestationaldiabetes mellitus; Hb: haemoglobin; g/L: grams per litre; PPH: post-partum haemorrhage

Table 22.2 Incidence (%) of perinatalcomplications in triplet and quadruplet pregnancies^1,2,10,11

GA: gestationalage; BW: birthweight; NICU: neonatal intensive care unit *Quadruplet and quintuplet data combined

The Issues

Prenatal Care

Triplet and HOM pregnancies should be offered first-trimester ultrasonography to estimate gestational age and importantly, to determine chorionicity and amnionicity.

If chorionicity cannot be determined, the pregnancy should be managed as a monochorionic pregnancy until proven otherwise due to the potential adverse effect of chorionicity on perinatal outcome.¹² A systematic review and meta-analysis of nine studies of 1,373 triplet pregnancies (1,062 trichorionic (TC), 261 dichorionic-triamniotic (DCTA) and 50 monochorionic- triamniotic (MCTA)) reported a higher risk of perinatal death (OR 3.3, 95% CI 1.3-8.0) and intrauterine demise (OR 4.6,95% C11.8-11.7) in DCTA compared with TC triplet pregnancies, even when controlling for a difference in gestational age at birth between the two groups (mean difference, 1.1 weeks (95% CI -0.3 to 2.5 weeks), P = 0.12). The incidence of composite morbidity in TC and DCTA triplets was 30% (95% CI 21.1-38.9%) and 34% respectively (95% CI 22-48%), with the risk of neurological morbidity (OR 5.4, 95% CI 1.6-18.3) signifi­cantly higher in DCTA compared with TC triplets. Only one study reported on outcomes of MCTA pregnancies and therefore no formal comparison can be made with the other groups.¹³

Prenatal Screening

All women with triplet and HOM pregnancies are candidates for aneuploidy screening, regard­less of maternal age. However, several limitations must be considered when screening for aneuploidy in triplet and HOM pregnancies. Serum screening tests are not useful in women with triplet gestations compared with singleton gestations because of the inability to differentiate which feto-placental unit contributed to the overall serum marker level.¹ The use of second- trimester serum screening for trisomy 21 in triplet pregnancies is no longer recommended for the same reason and also because other, more reliable options exist, such as nuchal translucency measurement.³ While non-invasive prenatal testing (NIPT) using cell-free fetal DNA from the plasma of pregnant women is a useful screening tool for fetal aneuploidy in singleton and twin pregnancies, there are limited data on its use in women with triplet and HOM pregnancies.¹ Owing to the low fetal fraction for each fetus, NIPT for multiple pregnancies is more difficult.

Prenatal Diagnosis

Amniocentesis and chorionic villous sampling (CVS) can be performed in women with triplet or HOM pregnancies who desire definitive testing. Amniocentesis and CVS have similar procedure-associated pregnancy loss rates of between 1.0 and 1.8%, which are slightly increased when compared to singleton pregnancies.¹ However, technical difficulties may be encountered when performing amniocentesis and CVS in women with triplet or HOM pregnancies, with a sampling error rate for CVS of approximately 1%. Sampling error can be reduced in triplet pregnancies by using both transabdominal and transcervical approaches in the same patient. The sampling error rate can be reduced with amniocentesis by using indigo carmine. Indigo carmine can be injected into the gestational sac being sampled before removing the needle. When a second needle is then inserted into the second sac the appear­ance of a clear sample of amniotic fluid can confirm that two separate sacs have been sampled.

Risks with Triplet and Higher-Order Multiple Pregnancies

Miscarriage

The rate of miscarriage increases with HOM pregnancy and approaches 11% for triplet pregnan­cies. The true rate of miscarriage in HOM pregnancy is unknown as most are not reported.

Medical Complications of Pregnancy

Medical complications of pregnancy are more common in women with triplet and HOM pregnancies than with singleton gestations.

Spontaneous Preterm Birth

Women with triplet and HOM pregnancies have a higher risk of spontaneous preterm birth (PTB) compared to women with a singleton pregnancy, with up to 75% of triplet pregnan­cies experiencing spontaneous birth before 35 weeks of gestational age. This risk is amplified if other risk factors for preterm birth exist.¹² Fetuses that reach viability carry a significant chance of delivery at an extremely preterm gestational age (< 28 weeks). Triplet pregnancies carry an 8-14% risk of extreme preterm delivery whereas quadruplets carry a risk of up to 30% (Table 22.2). Extreme preterm delivery is associated with significant risks of neonatal morbidity and mortality.

It is not recommended that predictive tests such as fetal fibronectin testing be used to predict the risk of spontaneous PTB in triplet pregnancy. The use of progesterone, pessaries, bed rest, tocolytics and cervical cerclage for the prevention of spontaneous PTB in triplet and HOM pregnancies is not routinely recommended.^1,12 Cervical length measurement assessed in mid-gestation is a poor predictor of PTB at less than 28, 30 and 32 weeks of gestational age, respectively, in asymptomatic triplet pregnancy¹⁸ and there is a limited predictive value for cervical length measurement before 25 + 0 weeks in triplet pregnancy.¹⁹ In symptomatic women the positive predictive value of fetal fibronectin or short cervical length is also poor, and use of these tests is not recommended to direct management in this setting.¹ The lack of utility of such screening tests for spontaneous PTB for triplets or HOMs is likely because such pregnancies are already at such increased risk that the incremental value of an abnormal fibronectin or short cervix is minimal.

Selective Growth Restriction

Antenatal care of patients with HOM pregnancy should occur in a tertiary-level medical institution. Not uncommonly, selective fetal growth restriction can occur with HOM pregnancies. Clinically important indicators of selective growth restriction include an estimated fetal weight (EFW) discordance of 25% or more in TC pregnancies or if the EFW of any of the fetuses is below the 10th centile for gestational age.¹² Additionally, women with DCTA and MCTA triplet pregnancy should be monitored for feto-fetal transfusion syndrome. Twin anaemia-polycythaemia sequence (TAPS) is a complication affecting monochorionic pregnancies and can occur in an MC pair of a triplet or HOM pregnancy. When TAPS occurs the recipient twin develops polycythaemia and the donor twin develops anaemia, but without the polyhydramnios-oligohydramnios sequence observed in feto-fetal transfusion syndrome.¹² Although routine screening for TAPS is not recommended, regular monitoring for all other complications of monochorionicity, which can occur at any gestational age, is important.

Management Options

Expert clinical recommendations suggest that continuing an uncomplicated TC or a DCTA triplet pregnancy beyond 35+6 weeks of pregnancy is associated with an increased risk of fetal demise.¹² Therefore, some experts recommend that planned birth should be offered to uncomplicated TC and DCTA pregnancies at 35 weeks of gestational age. However, in an MCTA triplet pregnancy or a triplet pregnancy that involves a shared amnion, the timing of birth should be individualised in each case.¹² One course of antenatal corticosteroids should be administered to all patients who are between 24 and 34 weeks of gestation, provided that they have an increased risk of delivery within seven days, irrespective of the fetal number.¹ We do not recommend routine prophylactic administration of antenatal corticosteroids at an arbitrary gestational age to all asymptomatic triplet or HOM gestations in the absence of a specific added risk.

The optimal route of delivery for women with triplet pregnancy remains unknown. Although there are no absolute contraindications to vaginal birth, there is limited and very low quality evidence in this area with only retrospective cohort studies identified. Small observational studies have suggested that similar perinatal outcomes can be obtained for women undergoing a planned trial of labour compared with those who undergo a planned caesarean delivery with an uncomplicated triplet pregnancy, provided that the leading triplet is in a vertex presentation.^20,21 There were no differences in adverse maternal or neonatal outcomes by either planned delivery approach.²¹ However, although case series of successful vaginal triplet delivery exist, there remains no large prospective studies to demonstrate the safety of this route. Given the practical difficulties involved in accurately monitoring each fetus with confidence in a triplet or HOM gestation throughout labour and delivery, caesarean section is the favoured mode of delivery in most centres. The optimal type of uterine incision has not been established.

Multifetal Pregnancy Reduction (MFPR)

In the first trimester a substantial number of women with HOM pregnancies undergo spontaneous reduction of one or more fetuses, commonly referred to as the ‘vanishing twin'. The probability of this spontaneous reduction increases with the number of gestational sacs with a rate of 53% for triplets and 65% for quadruplets. In the second and third trimesters up to 17% of triplets experience intrauterine demise of one or more fetuses.¹

Multifetal reduction is the practice of reducing the number of fetuses in a multifetal pregnancy. This topic is explored in detail in Chapter 4. The aim is to reduce the chances of preterm delivery and to improve the outcome for the remaining fetuses. The fetus or fetuses that are technically easiest to access are generally chosen for MFPR provided no obvious abnormalities are identified in the other remaining fetuses, such as an increased nuchal translucency. Aneuploidy testing can be performed before the reduction to assist patients in making decisions about interventions. Aneuploidy testing is recommended for the fetus(es) being retained so as to avoid the chance of retaining a genetically abnormal fetus. If there is a monochorionic pair within an HOM gestation, it is recommended that both fetuses in the MC pair are reduced, given the associated negative effects on the development of the remaining twin of an MC pair if only one is reduced.

In TC pregnancies, a meta-analysis has demonstrated that fetal reduction to twins was associated with a lower risk (17% versus 50%) of preterm birth before 34 weeks of gestational age (RR = 0.36, 95% CI 0.28-0.48), without a concomitant increase in the risk of miscarriage (8.1% vs 7.4%) (RR = 1.08, 95% CI 0.58-1.98). Expectant management of DCTA triplet pregnancies demonstrated rates of miscarriage and preterm birth of approxi­mately 9% and 52%, respectively. While this meta-analysis was inconclusive, it did suggest that in a DCTA triplet pregnancy, fetal reduction to twins was possibly associated with a lower risk of preterm birth without an increased risk of miscarriage.²²

A Cochrane review concluded that women who underwent pregnancy reduction from triplets to twins compared with those who continued with expectant management of a triplet pregnancy had lower frequencies of pregnancy loss, antenatal complications, preterm birth, low-birthweight infants, caesarean delivery and neonatal deaths. Post MFPR, the pregnancy outcomes were similar to those observed in women with spontan­eously conceived twin gestations.²³

Counselling patients in relation to MFPR, especially for couples who may have undertaken extensive fertility treatments to become pregnant in the first instance, can be challenging. Conveying the specific risks of a multifetal pregnancy to patients who are concerned that they may never have a child can be difficult. A multidisciplinary team approach should be adopted to support patients during their decision-making. The multidisciplinary team may include mental health professionals, social workers, neonat- ologists and obstetricians.

Fertility treatment and ART have contributed significantly to the numbers of multifetal pregnancies. Multifetal pregnancy reduction should not be a solution for the negative consequences of HOM pregnancies. A recent analysis of 15 years of European IVF Monitoring (EIM) Consortium activity demonstrated that the initial aims of the pro­gramme were met. These included collection and publication of regional European data on census and trends on ART utilisation, effectiveness, safety and quality. Over that period the number of triplet deliveries was reduced from 3.7% in 1997 to 0.6% in 2011 and clear trends towards transferring fewer embryos were observed.²⁴ The proportion of countries with a compulsory register increased over the 15 years and continued regulation in this area is crucial to reduce the number of HOM pregnancies. Appropriate standards of practice in ART and fertility treatment should be enforced to reduce the occurrence of multifetal pregnancy and the need for MFPR.

Key Points

• Triplet and higher-order multiple (HOM) pregnancies carry significant maternal and fetal risks. Women should be counselled regarding the possible complications of HOM pregnancy and offered close antenatal surveillance for such complications.

• Fetal risks in HOM pregnancy relate mainly to prematurity and intrauterine growth restriction. Monochorionicity in HOM pregnancy poses additional risks of feto-fetal transfusion syndrome or reversed arterial perfusion sequence.

• There remains limited guidance on appropriate surveillance and management of HOM pregnancies with many guidelines suggesting an individualised approach in relation to timing and mode of delivery.

• Challenges in relation to prenatal screening, sonographic assessment of growth and well-being and fetal monitoring increase with increasing fetal number.

• Multifetal pregnancy reduction (MFPR) to twins should be discussed with patients with HOM pregnancies (≥ 3). If selected, this should be performed in a specialist fetal medicine centre.

• Multifetal pregnancy reduction should not be considered as a solution for the complications and adverse outcomes of HOM pregnancies. Instead, primary prevention strategies should be followed in fertility clinics to reduce the need for MFPR.

• Long-term neurodevelopmental follow-up of survivors of HOM pregnancies, including those managed expectantly and those who have undergone MFPR, is required.

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