Multiple gestation: more research challenges to come

Nearly 1500 papers were published in the past 5 years with the subject heading of “twin” or “multiple pregnancies”. This figure undoubtedly represents the ever increasing interest in this group of high-risk pregnancies. It is very impossible to encompass the myriad issues that caught the attention of clinicians when dealing with difficult clinical cases related to twins and triplets which prompted research. This issue of the Journal of Perinatal Medicine includes 10 papers on various aspects of multiple pregnancy and birth. Three papers deal with the quarter-century-old issue of discordant birth weight [1]. In the first, Biron-Shental and her colleagues [2] evaluated the possible association between intermediate birth weight discordance (>20% difference) and infertility treatment. As in all likelihood the two embryos were conceived by the same method of infertility treatment [intracytoplasmic sperm injection (ICSI) vs. in vitro fertilization (IVF), ovulation induction vs. IVF, fresh vs. thawed embryos, etc.], the authors unsurprisingly found similar discordant levels as well as similar outcomes. As the authors did not detail the incidence of nulliparas (but the average parity) one is unable to appreciate the influence of this important confounding variable. The second paper reviews available data on outcomes related to estimated fetal weight (EFW) and crown-rump length (CRL) discordance [3]. Whereas the former was found to be associated with adverse outcomes, the latter was not. The authors also wonder about the best cut-off of EFW difference to describe severe discordance. As EFW is a poor predictor of discordance (because of the ± situation that exists [4, 5]), one should aim for a higher value (i.e. 25%–30% difference) to avoid over diagnosis. Moreover, it appears that discordance, per se, is not that important unless the smaller twin is small for gestational age (SGA) or exhibits clear growth restriction on repeated scans [i.e. selective intrauterine growth restriction (IUGR)] [6]. In fact, moderate levels of discordance have been shown to be an adaptive measure to increase gestational age. The authors rightly noted the differences between the mechanism and significance of selective IUGR in monochorionic (MC) and dichorionic (DC) twins.

Three papers of this batch discuss various aspects of monochorionicity. The Lisbon research group repeated their seminal study related to the prospective risk of intrauterine fetal death in MC twins [7]. Despite the publication of several studies on this subject, significant differences exist in recruitment and management of these sets. Thus, the paper of Simoes and her colleagues [6] showed that, with doubling of the sample size over time since the last report in 2006, and with implementation of intensive prenatal surveillance, a relatively low unexpected fetal death rate after 33 weeks’ gestation could be achieved. These findings evidently do not support elective preterm birth for uncomplicated MC twins proposed by several authorities. At present it appears that close surveillance is recommended rather than elective preterm birth.

A second paper of the Lisbon group analyzed outcomes of DC triplets, notorious for having the combined risks of triplets as well as the risk of MC twins [8]. The immediate reaction of many scholars to this pregnancy would be to reduce the set of MC twins, leaving a singleton. In fact, relatively few studies evaluated these triplets and there is no evidence to support this intuitive, albeit logical, approach. The data, however, indicate that DC triplets are not significantly disadvantaged compared to TC triplets. These data might be reassuring for those who are physically suitable to carry triplets [9] and consider continuing their DC triplet pregnancy.

The third study relates to the risk of MC twins conceived by IVF. This study was aimed to double-check the findings of Simoes et al. [10] who found that MC twins after assisted reproductive techniques (ART) are at increased risk of adverse perinatal outcomes compared with spontaneous MC twins and with DC twins conceived by ART. However, the population-based study performed by Trojner Bregar and her colleagues [11] disagreed with the hospital-based results of Simoes et al. [10] and suggested that MC twins following ART have similar perinatal outcomes compared to spontaneous MC twins as well as to DC twins conceived by ART.

Two other papers discuss the issue of “near term” (or the newer nomenclature “late preterm”) births in twins, which bear a direct relationship to the clinical, albeit controversial, question of the appropriate timing of twin birth [12]. Simchen and her co-workers [13] observed that a significant proportion of late preterm (34 0/7–35 6/7 weeks) births is iatrogenic. Importantly, they observed optimistic results whereby twins were at lower risk of medical intervention in the immediate neonatal period as compared with singletons. The latter conclusion, however, did not agree with that of Sung et al. [14] who concluded that late-preterm birth in twins was associated with a higher risk of adverse neonatal outcome regardless of chorionicity and indication for delivery. This difference between the results of the two studies might be due to the large difference in sample size (114 vs. 679 twins in the Israeli and Korean groups, respectively). Other studies [12] seem to support the pessimistic view.

The last paper in this batch discusses glucose metabolism during multiple pregnancy. Weissman et al. [15] found that glucose intolerance is aggravated in multifetal pregnancies. Furthermore, the likelihood of an abnormal glucose challenge tests and gestational diabetes mellitus (GDM) was higher in twins and triplets compared to singletons. This observation is of particular importance because controversy exists as to whether GDM is increased among multiple pregnancies [16]. Regrettably, and probably because of the nature of data collection, these authors could control for maternal age but not for maternal pre-gravid BMI – a most significant confounder of the incidence of GDM in twins (as well as in singletons) [17]. For example, very recently it was found that twining appears to ameliorate the adverse outcomes of the combination of diabetes and obesity (“diabesity”) that has been repeatedly shown in singletons [18].

This ensemble of fine studies represents laborious research to elucidate, each in its own way, a specific aspect of multiple gestation. Together, they are evidence of the unequivocal worldwide interest in multiples which further calls for more research challenges. In particular, studies focusing on the interface between production (i.e. generation of twins), maintenance (i.e. pregnancy care), and performance (perinatal outcomes) are welcomed.