Female neonates from male–female pregnancies were at increased risk of respiratory distress syndrome (RDS) (NNH=35), intraventricular hemorrhage (IVH) (NNH=42), and convulsions (NNH=77) compared with female neonates from female–female twin pregnancies (Table 4). The rate of RDS and IVH in female neonates from male–female pairs was similar to the overall rate of RDS and IVH observed in male neonates (P=.2 and P=.7, respectively, Table 4). Of the 24 cases of convulsions in this group (female neonates from male–female pairs, Table 4), 13 were attributed to IVH (of them, six cases were of third to fourth degree). Female neonates from female–female pregnancies had a lower overall rate of IVH, but the rate of third to fourth degree IVH was similar to that of female neonates from male–female pregnancies. None of the cases of IVH in this group (female neonatess from female–female pairs) was associated with neonatal convulsions.
Male neonates from male–male pregnancies had a similar rate of neonatal complications compared with male neonates from unlike-sex twin pregnancies except for a higher rate of convulsions (NNH=47) (Table 4). Of the 24 cases of convulsions in male neonates from the male–male group (Table 4), 12 were attributed to IVH (of them, eight cases were of third to fourth degree). For comparison, of the 18 cases of convulsions in male neonates from unlike-sex pregnancies, nine were attributed to IVH (of them, two cases were of third to fourth degree). Thus, although the rate of IVH (overall and third to fourth degree) was similar in male neonates from male–male and male–female twin pairs (Table 4), IVH was more likely to be associated with convulsion in male neonates from male–male compared with male–female pregnancies.
In the current study, we estimated the effect of male and female fetuses on their opposite-sex co-twin in dichorionic twin pregnancies. Our main findings were 1) male–male twin pregnancies, and to a lesser extent male–female pregnancies, were at increased risk of prematurity compared with female–female pregnancies, 2) for male neonates, the presence of a female rather than a male co-twin was associated with a higher birth weight due to both longer duration of pregnancy and a higher in utero growth rate, and 3) for female neonates, the presence of a male rather than a female co-twin was associated with not only an increased risk for prematurity, but also with an increased risk for prematurity-related morbidity.
In singleton pregnancies, the risk of prematurity has been reported to be higher in the presence of a male compared with a female fetus.24 We have recently corroborated these findings in a retrospective study which included over 66,000 singleton pregnancies (Melamed N, Yogev Y, Glezerman M. Fetal gender and pregnancy outcome. J Matern Fetal Neonatal Med. In press). In the current study, we have found this to be true also for twin pregnancies: the risk of prematurity was highest in male–male pregnancies and lowest in female–female pregnancies. Most previous studies in twin pregnancies also found that male–male pregnancies have the highest rate of preterm delivery.18,20–22,25,26 Loos et al18 found that the mean duration of gestation of male–female pairs (36.8±2.7 weeks) was similar to that of female–female pairs (36.9±2.6 weeks), but both study groups had a significantly longer gestation than male–male pairs (36.4±2.8 weeks). They concluded that it is the female who governs the length of gestation. Since the mean gestational age for the three groups in our study followed a similar pattern, this interpretation concerning a female-protective factor that prolongs gestation may also be applied to our results. However, the finding that the risk of preterm delivery at 31 and 28 weeks of gestation in male–female pairs was higher than in female–female pairs and lower than in male–male pairs can also be explained by a potential “dose-dependent” male-offending factor that increases the risk of prematurity. The higher testosterone level in male pregnancies, which has been implicated in the onset of preterm labor,27 may be an example for such a male-related factor.28,29
We have found that, for a male twin, the presence of a female rather than a male co-twin was associated with a higher birth weight. This finding is in agreement with previous reports and had been attributed, as in our study, to both a longer gestation18,21,22 and a higher growth rate18,21 in the presence of a female co-twin. The reason for this observation is unclear. It has been speculated that due to the inherently slower growth of female compared with male fetuses, the male fetuses may be more successful in their competition for nutrients in the presence of a female rather than a male co-twin.30
Preterm male neonates in singleton pregnancies have been shown to be at increased risk of respiratory and neurologic morbidity when compared with female neonates of comparable gestational age.11 Considering the possible inhibitory effect of androgens on lung development,14,15 it has been suggested that this male disadvantage may be related in part to the higher level of androgens in male pregnancies.23 Based on this assumption, we aimed to determine whether female neonates having a male compared with a female co-twin are at increased risk of neonatal morbidity. We have found that for female neonates, the presence of a male rather than a female co-twin is associated with an increased risk of respiratory and neurologic morbidity to a level similar to that observed in male neonates.
We have found a higher rate of short-term neurologic morbidity among male and female neonates having a male co-twin. Interestingly, the rate of IVH for female neonates from male–female pregnancies was very similar to the rate of IVH in male neonates and significantly higher than that observed for female neonates from female–female pregnancies, which supports a male-related offending factor that is associated with an increased risk for IVH. The reason for these observations is not clear. In singleton pregnancies, the higher rate of IVH (overall and third and fourth degree) in male neonates34 has been attributed to the higher susceptibility of male neonates to brain injury due to differences in the steroid hormone environment35,36 and a higher cerebral blood flow.37 Furthermore, the recent findings that the beneficial effects of indomethacin in prevention of IVH and related morbidity is limited to male (versus female) preterm neonates38 provide additional support to a male-related factor in the pathogenesis of IVH and its subsequent brain injury in male neonates. It remains to be investigated whether such a male-related factor may increase the rate of IVH in a female co-twin to reach a magnitude similar to that observed in male neonates.
The main limitation of the current study is its retrospective design. Data, such as maternal body mass index, which may affect birth weight, were not available. Similarly, a large number of pregnancies were excluded from the study because of lack of data regarding chorionicity. Although the main strength of this study is the large group of pregnant women who have been treated at the same institution and according to the same clinical guidelines, this also limits the generalizability of the findings of the current study.
In summary, our results indicate that male and female fetuses affect their opposite-sex co-twins, and its essence is that it is better for a twin (male or female) to share the womb with a female rather than with a male co-twin. Although with regard to prematurity, it is not clear whether the differences are the result of a male- or a female-related factor, the analysis of neonatal outcome for preterm twin neonates supports a male-offending rather than a female-protective factor. In addition to its short-term obstetric and neonatal implications, such an in utero effect of fetuses on their opposite-sex co-twins has also been suggested to carry long-term physical,39,40 cognitive,22 and behavioral41–43 consequences, as well to increase the risk of cancer in adult life.21,44–47
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