Combined Effect of Fetal Sex and Advanced Maternal Age on Pregnancy Outcomes

Background

Fetal sex and maternal age are each known affect outcomes of pregnancies. Women carrying male fetuses were reported to be at increased risk of preterm deliveries, preeclampsia, fetal distress, labor dystocia, operative deliveries, and perinatal mortality [1–8]. Hyperemesis gravidarum and hypertension-related growth retardation were significantly more common in pregnancies with female fetuses [9–12]. In recent decades more women delay family planning or continue childbirth after the age of 40. Increased maternal age was reported to be associated with diabetes mellitus, preeclampsia, preterm delivery, low birth weight, stillbirth, increased rates of cesarean section, and post-partum hemorrhage [13–20]. The combined impact of both maternal age and fetal sex on the outcomes of pregnancy has not been evaluated yet.

With the increase in maternal age during recent decades [14–16] and the increased interest in the influence of fetal sex on pregnancy outcomes [1,5], our objective was to investigate the influence of the combination of advanced maternal age (≥40) and fetal sex on the pregnancy outcomes in term and post-term singleton pregnancies in a large tertiary center, in order to improve the prenatal follow-up and counseling, especially in the group of pregnant patients over age 40 years.

Material and Methods

STATISTICAL ANALYSIS:

Differences in the study parameters between male and female neonates were tested using the chi-square test for categorical variables. Student’s t-test was used for comparison of continuous parameters between neonatal sex and between the 2 categories of maternal age: <40 and ≥40. The combination of sex and maternal age category was defined (<40, male; <40, female; ≥40, male; ≥40, female). Logistic regression models were used to assess the effect of sex and maternal age on maternal and neonatal complications, controlling for gestational age, birth weight, diabetes mellitus, and mode of delivery. Multivariate logistic regression was performed to explore factors associated with mode of delivery (cesarean section versus normal vaginal delivery, and vacuum or forceps delivery versus normal vaginal delivery). Odds ratios (OR) and corresponding 95% confidence interval were derived, and considered significant if excluding unity. In the case of outcomes in which the outcome rates are <5%, the OR approximate the rate ratios. A p-value of 0.05 or less was considered statistically significant.

Results

During the study period 37,327 singleton neonates were delivered at or after 37 weeks’ gestation at the Chaim Sheba Medical Center; 51.1% were boys and 48.9% were girls.

The characteristics of the study population are presented in Table 1. The average birth weight of male fetuses was significantly higher than female neonates. Women who delivered male neonates underwent significantly more operative deliveries and their hospitalization was longer. Significantly more pregnancies carrying female fetuses delivered post-date.

There were 1490 deliveries (4%) among women aged 40 years and more. The ratio between male and female fetuses was close to 1 both in mothers aged ≥40 and <40. The comparison of pregnancy outcomes in male and female fetuses according to maternal age is presented in Table 2. For both male and female pregnancies, as maternal age increased more women had diabetes, both gestational and pre-gestational, with no difference according to fetal sex (from <2% among women aged <25 to more than 11% among women ≥40). The risk of hypertensive disorders increased in mothers aged ≥40 both carrying male and female fetuses, but with statistical significance only in male fetuses, and borderline significance in female fetuses. The rate of shoulder dystocia and respiratory problems was higher in males than in females, with statistical significance in patients aged <40.

There were statistically more cesarean sections in women aged ≥40 and in women carrying male fetuses. In mothers aged ≥40, statistically more patients were hospitalized for more than 5 days, both with male and female neonates.

Table 3 presents the combined effect of sex and maternal age on adverse pregnancy outcomes. Arbitrarily, fetal female sex and maternal age <40 were chosen to have an odds ratio (OR) of 1. The odds ratio of other combinations of maternal age and fetal sex were calculated.

In multivariable logistic regression analysis, we found that maternal age and fetal sex were significant risk factors for neonatal hypoglycemia and respiratory problems controlling for gestational age, birth weight, maternal diabetes, and mode of delivery. Diabetes was significantly associated with neonatal hypoglycemia (OR=3.53 95%CI=2.87–4.34).

Neither maternal age nor fetal sex was found to be associated with hypertensive disorders of pregnancy, while birth weight, gestational age, diabetes, and mode of delivery were predictors of these complications.

Both sex and maternal age were associated with mode of delivery. Women aged ≥40 carrying male fetuses were at an almost 3-fold risk to give birth by cesarean section compared with younger women for both fetal sexes.

Discussion

During the last 2 decades, several studies have reported an association between fetal sex and pregnancy outcome, and between increased maternal age and complications of pregnancies. The present study examined the combined effect of both maternal age and fetal sex on pregnancy outcomes in term singleton pregnancies. We presented the odds ratio for different outcomes of pregnancy according to fetal sex and to maternal age. We arbitrarily chose fetal female sex and maternal age <40 to have the odds ratio of 1 and calculated the OR of the other combinations accordingly.

More women with advanced age at pregnancy have pre-pregnancy chronic medical conditions that may have an impact on pregnancy outcomes [21–24]. The increased risk of diabetes as maternal age increased was reported before [16,24,25], as well as the elevated risk for diabetes in pregnancies carrying male fetuses [3,5]. The present study demonstrates that, in younger women, significantly more pregnancies carrying male fetuses have diabetes. Furthermore, the risk of diabetes increases as maternal age advanced in both male- and female-carrying pregnancies. Diabetes may account for excessive fetal weight, leading to increased risk for difficult deliveries, operative vaginal deliveries, cesarean sections, and neonatal complications such as shoulder dystocia and neonatal hypoglycemia [8], all found in our study to be increased in pregnancies carrying male fetuses.

Maternal age did not have any statistical impact on neonatal shoulder dystocia and respiratory problems, but male sex did. The risk of neonatal hypoglycemia in our study increased in males for all maternal ages.

Another pre-pregnancy chronic condition that may be more frequent as maternal age advances is hypertension [26]. Indeed, our study demonstrated an increased risk of hypertensive disorders in mothers aged ≥40 of both male and female fetuses, but with statistical significance only in male fetuses. The effect of sex on hypertensive disorders of pregnancies has been evaluated previously. Studies that did find differences between male and female fetuses attributed these differences to hormonal influences on infiltration by extravillous trophoblasts into the placental bed [10,11] and differences in maternal blood plasma volume expansion [27]. Contrary to these studies, we did not find a significant association between fetal sex and hypertensive disorders of pregnancy.

Previous studies reported an increased risk of cesarean section in women ≥40 [21,22], and in pregnancies carrying male fetuses [3]. There were statistically more cesarean sections in pregnancies carrying male fetuses and when maternal age was ≥40. The combined effect of maternal age and fetal sex on the mode of delivery has not been reported yet. Sheiner et al. [3] attributed the increased risk of cesarean section in pregnancies with male fetuses to the higher birth weight of males, leading to prolonged and more complicated deliveries. Indeed, and similar to previous studies [1,3,5], the birth weight of male neonates was significantly higher than in females. Since fetal macrosomia is an important risk factor for prolonged and operative deliveries [4,28], our study too found an increased rate of both operative vaginal deliveries and cesarean sections in pregnancies carrying male fetuses. Although we did not differentiate between the causes of the cesarean sections, these results are in agreement with Liberman et al. [29] who hypothesized that while the increased rate of cesarean section due to dystocia in pregnancies carrying male fetuses was related to the larger size of males, the increased risk of cesarean section for fetal distress might be the result of intrinsic sex-related differences in the fetal response to hypoxia.

One of the outcomes of increased rates of diabetes, hypertensive disorders, and operative deliveries is longer hospitalization. We found that in mothers aged ≥40, statistically more patients were hospitalized for more than 5 days, both with male and female neonates. In women <40, the duration of hospitalization was longer in patients carrying male fetuses.

We acknowledge limitations of our study, especially the retrospective nature of the analysis. Nevertheless, the fact that clinical findings were entered into the database by an experienced team at delivery, as well as the large size of our study cohort, both increase the reliability of our findings.

Conclusions

In the last 3 decades the prevalence of delaying family planning significantly increased [23,30]. Since increased maternal age and male fetal sex have each elevated risks for pregnancy complications, the combination of increased maternal age and male fetal sex may augment these risks. The obstetrician needs to evaluate pre-pregnancy medical conditions of every pregnant woman and monitor the pregnancy according to the known risk factors along with the possible adverse situations of each woman. We demonstrated that knowledge of fetal sex adds value to the risk assessment of pregnancies, allowing for optimal follow-up and management of every pregnancy and delivery.