Follow-up issues with multiples

Abstract

The rate of multiple pregnancy has increased in developed countries, a finding usually attributed to more widespread use of assisted reproductive technologies. Multiple pregnancies are associated with a greater risk of pregnancy complications, including intrauterine growth restriction of one or more of the fetuses, vascular communications within a shared monochorionic placenta and premature delivery. Surviving infants are at significantly greater risk of developing cerebral palsy due to a combination of a higher proportion of them being preterm or of low birth weight, and complications associated with chorionicity. These infants are also at greater risk for abnormal cognitive development and learning disabilities for the same reasons. Parenting styles and family dynamics may also differ with multiples compared with singletons, which may affect long-term behaviour and development.

Thus, infants of multiple pregnancies should receive careful neurodevelopmental follow-up. For larger, lower risk infants, this follow-up may be provided by general paediatricians within the community. However, for infants with birth weights of less than 1000 g or with a complicated antenatal or neonatal course, follow-up should be in a high-risk neonatal follow-up clinic with appropriate multidisciplinary support.

Canada, similar to other industrialized countries, has seen an increase in multiple births over the past decade, an increase generally attributed to assisted reproductive technologies (ARTs) (1,2). The rate of multiple births in Canada is now 2.7 per 100 total births, a figure two to four times higher than the natural rate (1,3). Twins, triplets and higher-order multiples are at increased risk of preterm delivery and, subsequently, higher morbidity and mortality (3). Multiple pregnancies have long been associated with increased rates of cerebral palsy (CP) due to the combination of prematurity and low birth weight, but these long-term adverse outcomes may also be due to specific fetal and maternal complications (3,4). The present article reviews the literature on the neurodevelopmental outcomes associated with multiple births and makes some recommendations for the follow-up of these infants.

PREMATURITY, LOW BIRTH WEIGHT AND MORTALITY IN MULTIPLE GESTATIONS

Multiple births, compared with singletons, are at increased risk for premature delivery. In a recent study (5), the average gestational ages at delivery for twins, triplets and quadruplets were reported to be 35.3, 32.2 and 29.9 weeks, respectively, with correspondingly low birth weights.

Many studies (2,4) have shown that infant mortality is closely linked to plurality, but it also appears that multiple gestation, as well as prematurity, is an independent risk factor for infant mortality. Preterm babies may be less well able to compensate for hypoxic-ischemic events occurring either pre- or postnatally (3). Synnes et al (6) reported a higher mortality for twins versus singletons born at 24 to 27 weeks’ gestation, but there was no difference between the groups by 28 weeks; others have failed to show this (7,8).

ASSISTED REPRODUCTION

Up to 10% of couples may require some form of fertility treatment, the simplest being ovarian hormonal stimulation. Multiple pregnancies conceived by ovarian stimulation alone have not been shown to adversely affect long-term infant outcomes (9). ARTs now include in vitro fertilization and intracytoplasmic sperm injection, and are associated with an increased risk of multiple gestations and the associated risk of premature delivery. The literature is still unclear as to whether there is an increased risk of congenital malformations in these infants. A study by Hansen et al (10) found a 25% or greater risk of birth defects in ART infants, while a systematic review and meta-analysis by McDonald et al (11) showed no difference in incidences of congenital malformations in ART pregnancies compared with spontaneously conceived twins matched for maternal age.

Assisted reproduction information is not always available to follow-up personnel; however, when these cohorts were followed, an independent effect of in vitro fertilization on growth and neurological outcomes was not seen (12). It is estimated that because of the increased numbers of multiples associated with ARTs, they now contribute 8% to the annual number of CP cases.

GROWTH RESTRICTION AND MULTIPLES

Fetal growth abnormalities are common in multiple pregnancies, with more than one-half of all triplet and higher-order gestations being complicated by intrauterine growth restriction (IUGR) of one or more of the fetuses (3,9). Growth-restricted infants have significantly higher risks of morbidity and mortality, regardless of their plurality. The intrauterine growth of twins is similar to that of singletons until approximately 28 weeks’ gestation. A matched study (9) of discordant IUGR infants as part of a twin or triplet set showed that the growth-restricted infant often remained smaller and had more behavioural problems, as well as visual and speech difficulties. Goyen et al (13) reported the developmental outcomes at three years of age of 21 discordant twin pairs (greater than 15% growth discordance) born preterm and at a very low birth weight. Using Griffiths developmental quotient, the smaller twins scored less well, and this was more marked when there was a discordance of greater than 30% in the birth weights. This study indicates a small but significant influence of growth restriction on neurodevelopmental outcome. Growth in utero is also a predictor of postnatal growth: a significant proportion of growth-restricted co-twins or co-triplets who failed to show catch-up growth, as well as some who did, remained shorter and lighter, suggesting a long-term stunting effect of IUGR (9).

ZYGOSITY, CHORIONICITY AND THE TWIN-TO-TWIN TRANSFUSION SYNDROME

Zygosity may be difficult to assess clinically but is very important when discussing outcomes in twin pregnancies. All dizygotic twins and about one-third of monozygotic twins are dichorionic, but much of the increased morbidity and mortality of twin pregnancies is associated with monochorionic placentation (4). In monochorionic twins, the placenta is shared and has intertwin vascular anastamoses, which produces various degrees of the twin-to-twin transfusion syndrome in 10% to 15% of cases. Left untreated, the twin-to-twin transfusion syndrome causes discordant twin growth and, sometimes, intrauterine demise of one twin. In utero death of one twin leads to fetal shunting with resulting anemia and a 20% risk of cognitive impairment in the surviving twin (14). With the advent of in utero therapies for severe twin-to-twin transfusion syndrome, survival and outcomes for these infants have improved. Current studies (3,15) following fetoscopic laser ablation of the intercommunicating vessels report at least one survivor in 70% of pregnancies. Sutcliffe et al (15) reported an overall CP rate of 9% in survivors, with 0% in the singleton survivors group and 13% in the twin survivors group. Detailed neurodevelopmental outcome data on these infants appears encouraging (16).

There are also a number of non-neurological abnormalities that are more common in monozygotic twins. Congenital anomalies such as agenesis of one or both kidneys (Potter syndrome), intestinal atresias and some cardiac defects are all more common in monozygotic twins, perhaps due to ischemia from hemodynamic imbalance in the twin-to-twin transfusion syndrome (4).

NEUROLOGICAL OUTCOMES IN MULTIPLE COMPARED WITH SINGLETON PREGNANCIES

Twinning has been recognized as a risk factor for CP for at least a century. Twins have approximately a fivefold risk of CP compared with singletons (4). There appears to be no significant difference in CP prevalence among twins and singletons in the lower birth weight groups (2500 g or less). The increase in CP prevalence with decreasing birth weight and extreme immaturity is clearly evident for both twins and singletons. Using a large data set from the National Institute of Child Health and Human Development Neonatal Research Network, Donovan et al (8) compared the outcomes of very low birth weight twins (1500 g or less or 28 weeks’ gestation or less) with those of matched singletons, and showed that twins and singletons had similar outcomes. Similarly, Asztalos et al (7) compared the outcomes, at 18 to 24 months, of twins versus singleton preterm infants of the same gestation and the outcomes of known monochorionic twins versus dichorionic twins. Fifty-two sets of twins were matched with 101 singletons. The incidence of death or severe disability was not different between the twins and the singleton preterm infants (29.7% versus 22.8%, respectively). When the outcome of death or severe neurodevelopmental disability was compared in monochorionic versus dichorionic twins, again, there was no statistically significant difference (38.9% versus 24.6%, respectively).

In contrast, the greater CP prevalence among the heavier twins (2500 g or greater) than among singletons, seen mostly in monozygotic/monochorionic twins as described above, is highly significant. The surviving twin of a co-twin fetal death is at particularly high risk (4,14). Thus, the difference in CP prevalence among twins and singletons is due to a combination of a higher proportion of low birth weight infants among twins and a significantly higher prevalence of CP in normal birth weight twins, probably related to chorionicity.

Moderate and severe learning disabilities are also significantly more common in twins than in singletons, even when corrected for lower birth weight and when those with CP are excluded (9). Ostfeld et al (17) found that the cognitive development of twins was less advanced than that of singleton control subjects, but this may also be confounded by parent-infant interactions. Despite older literature reporting an increased risk of speech delay in twins, more recent studies (4,9) are inconclusive but suggest a link with prematurity and/or growth restriction.

The prevalence of long-term neurological deficits increases with plurality: an analysis of Australian data showed that CP occurred 17 times more often in triplet than in singleton pregnancies, although this is complicated by the greater incidence of growth restriction (9). Feldman and Eidelman (18) recently reported the outcome of 23 sets of triplets compared with 23 sets of twins and 23 singletons. The infants were matched for gestational age, birth weight, and medical and demographic features. Infants with periventricular leukomalacia, severe intraventricular hemorrhage, perinatal asphyxia and central nervous system infection were excluded. Triplets scored less well on the Bayley Scales of Infant Development than did the twins and singletons at 24 months’ corrected age. This suggests that the triplet situation itself constitutes a risk condition for infants’ cognitive development. Triplets who were discordant for growth (greater than 15%) showed significantly poorer cognitive skills than did their larger co-triplets at 12 and 24 months.

FAMILY DYNAMICS AND PARENTING ISSUES

The parents of multiples may face many stresses both during pregnancy and after delivery. The risk of preterm delivery and pregnancy complications with more intensive fetal monitoring, as well as the enormous amount of time needed to care for these infants on discharge, is likely to alter the interaction between parents and infants. Mothers of twins tend to lift, hold, touch or pat their babies less often and talk to them less frequently than do mothers of singletons. In a study by Ostfield et al (17), mothers of premature twins showed fewer initiatives and responses to their offspring than did mothers of premature singletons. In this study, maternal behaviour was predictive of cognitive development. Feldman and Eidelman (18) studied mother-infant interaction variables and showed that there were more positive interactions in the singleton and twin groups than in the triplet group, and also that the maternal parenting style was less sensitive. They concluded that the discrepancy in cognitive scores at 24 months may be due, in part, to those effects. Parental stress may also be demonstrated by the higher incidence of maternal depression and child abuse in multiple-birth families (9).

RECOMMENDATIONS FOR FOLLOW-UP

Because preterm multiples do not appear to be at a greater risk of adverse neurodevelopmental outcomes than singletons matched for age and weight, we suggest that the criteria for follow-up should be equivalent in these populations. Therefore, the criteria for follow-up may include the very low birth weight cohort (1000 g or less birth weight or 28 weeks’ gestation or less) and defined risk categories, such as significant cranial ultrasound abnormalities or being small for gestational age (19). Specific groups, such as survivors of twin-to-twin transfusion, should also be included.

Because triplets and higher-order multiples are at a greater risk of having at least one growth-restricted infant among them, birth weight criteria (eg, less than 1000 g) may include some infants who are of a greater gestational age than the singletons. It has generally been our practice that when one infant among a group of triplets is being followed, the other triplets are also seen. The literature does not appear to support this practice, except in the case of monochorionic twins, when the larger survivor may also be at risk.

Given the resource constraints in follow-up clinics, it may not be possible to follow all at-risk infants (eg, larger twins). Information about the outcomes of multiple gestations should be disseminated so that general paediatricians can perform careful developmental assessments of these infants and provide anticipatory guidance to families. It is important that patients can be referred promptly for more detailed neuromotor and cognitive assessments, as well as appropriate intervention in their communities.

CONCLUSION

Infants born following a multiple gestation are at increased risk of an adverse neurological outcome. A careful antenatal history, including the method of conception and zygosity, may be necessary to truly estimate the risk. Parents should be counselled regarding these risks, and appropriate follow-up should be arranged.

The follow-up literature on neurological outcomes of multiples has been criticized because many studies are limited by small sample size or failure to adjust for important covariates, such as IUGR, chorionicity and zygosity, as well as sociode-mographic factors. In the future, collaborative, multicentre studies will be required to look at specific issues in multiples, such as the outcome of infants with twin-to-twin transfusion, and the impact of other antenatal and postnatal factors.