Letter to the Editor

I read the article by Dr De Matteo et al with interest. Considering developmental effects of autonomic nervous system (ANS), vagal activity on the cardiovascular system may provide new insights into De Matteo’s data. The authors studied cardiovascular and endocrine characteristics of dizygotic twins versus singletons in near-term fetal sheep at 123-126 and 131-137 days of gestation (dGA, term 147 dGA), and in lambs at birth, 4, and 8 weeks of life. In their model of mild naturally occurring intrauterine growth restriction (IUGR), they found that natural twinning in sheep that grow normally in utero and postpartum does not result in elevated diastolic or mean arterial blood pressure (dABP and mABP) or abnormal endocrine markers near term and in early postnatal life. This suggests that neural or endocrine branches of the sympathetic stress axis were not differently regulated in twins versus singletons at any age studied. Interestingly, systolic ABP (sABP) was decreased in twins versus singletons 8 weeks postnatally, despite some degree of postnatal catch-up growth associated with postnatal hypertension. If this difference is cardiogenic, one would expect lower heart weights in the twins. Because similar cortisol levels were found in both groups near term and postnatally, I infer that the IUGR was too mild to produce stress-induced myocardial growth (although due to absence of preterm data one cannot say if stress axis development differed between twins and singletons from preterm to near term). Lower sABP in twins at 8 weeks might result from lower cardiac output in IUGR fetuses. In a study conducted at a similar gestational age (125 + 3 dGA), we found no differences in heart weights between singletons and twins. Taken together, it appears that since fetuses studied showed only mild IUGR, decreased cardiac output is an unlikely cause of the lower sABP postnatally. The lack of dABP differences also suggests that both groups showed no significant difference in developmental increase of peripheral resistance related to stress axis maturation. I suggest the differences in sABP were due to varying ANS control of cardiac output. Specifically, increased influence of vagal activity on fetal heart rate (FHR) occurring in the context of twins’ postnatal catch-up growth might explain their lower sABP compared to singletons. This can be studied by analyzing FHR variability (fHRV). In the antenatal group, FHR decreased from 123-126 to 131-137 dGA in singletons, but not in twins. However, postnatally a comparable developmental decrease of FHR was found in both singletons and twins. The lack of FHR decrease in twins, but not singletons, in utero might reflect delayed vagal maturation. Indeed, fetal body weight correlates to vagal modulation of fHRV in near-term fetal sheep and lighter sheep fetuses showed delayed vagal maturation in the last trimester. Fetal programming in singletons links small size at birth with adult cardiovascular and metabolic diseases. The authors concluded that postnatal ABP in twins might be affected by maternal and neonatal nutrition with mild IUGR in twins surprisingly leading to early postnatal hypotension rather than hypertension. Indeed, the twin data have been controversial; De Matteo et al contribute evidence that associations ascribed to fetal programming in growth-restricted singletons may not extend to twins. These animal findings complement previous human studies that are inconsistent as to whether birth size in twins is associated with cardiovascular morbidity. In conclusion, I suggest that an in utero delay in maturation and postnatal catch-up development of the vagal branch of the ANS—a physiological mechanism involved in fetal programming of cardiovascular system —may explain the absent FHR decrease near term in twins compared to singletons and the lower sABP in twins versus singletons at 8 weeks of life. This mechanism may be a function of individual fetal body weight reflecting the current growth trajectory rather than fetal twinning per se.