Fetal gender has a significant impact on the outcome of pregnancies and this may have a great impact management decisions during pregnancy. There are significant differences in neonatal outcomes between male and female infants but their impact on specific organ systems are not clearly outlined. It is suspected that these differences may have both genetic, epigenetic and hormonal basis but the evidence for this has not been comprehensively reviewed. The series of reviews on this topic are focused on a current and comprehensive review of the available information on gender differences and an  evaluation of currently known mechanisms and processes involved.

University of Connecticut Health Center

School of Medicine, University of Connecticut

Frontiers in Pediatrics

Neonatology

Sex Differences in Fetal and Neonatal Outcomes

Differences in the development of the male and female brain are an evolving area of investigation. We are beginning to understand the underpinnings of male and female advantages due to differences in brain development as well as the consequences following hypoxic-ischemic brain injury in the newborn. The two main factors that appear to affect outcomes are gestation age at the time of injury and sex of the subject. This review starts with a summary of differences in the anatomy and physiology of the developing male and female brain. This is followed by a review of the major factors responsible for the observed differences in the face of normal development and hypoxic injury. The last section reviews the response of male and female subjects to various neuroprotective strategies that are currently being used and where there is a need for additional information for more precise therapy based on the sex of the infant.

Differences in the development of the male and female brain are an evolving area of investigation. We are beginning to understand the underpinnings of male and female advantages due to differences in brain development as well as the consequences following hypoxic-ischemic brain injury in the newborn. The two main factors that appear to affect outcomes are gestation age at the time of injury and sex of the subject. This review starts with a summary of differences in the anatomy and physiology of the developing male and female brain. This is followed by a review of the major factors responsible for the observed differences in the face of normal development and hypoxic injury. The last section reviews the response of male and female subjects to various neuroprotective strategies that are currently being used and where there is a need for additional information for more precise therapy based on the sex of the infant.

Sex Differences in Brain Injury and Repair in Newborn Infants: Clinical Evidence and Biological Mechanisms

Biological differences between the sexes are apparent even from the early part of the pregnancy. The crown-rump length is larger in male fetuses compared to females in the first trimester. Placentae of male and female fetuses have different protein and gene expressions, especially in adverse conditions. Even within the intrauterine milieu, the same extracellular micro RNA may show upregulation in females and downregulation in male fetuses. There appears to be a natural survival advantage for females. Maternal glucocorticoids (GC) play an important role in fetal growth and organ maturation. However, excess glucocorticoids can not only affect growth but the response may be sex-specific and probably mediated through glucocorticoid receptors (GR) in the placenta. Mild pre-eclampsia and asthma are associated with normal growth pattern in males, but in female fetuses, they are associated with a slowing of growth rate without causing IUGR probably as an adaptive response for future adverse events. Thus, female fetuses survive while male fetuses exhibit IUGR, preterm delivery and even death in the face of another adverse event. It is thought that the maternal diet may not influence growth but may influence the programming for adult disease. There is growing evidence that maternal pre-pregnancy overweight or obesity status is directly associated with a higher risk of obesity in a male child, but not in a female child, at 1 year of age. It is observed that exposure to gestational diabetes is a risk factor for childhood overweight in boys but not in girls. It is fascinating that male and female fetuses respond differently to the same intrauterine environment, and this suggests a fundamental biological variation most likely at the cellular and molecular level.

Biological differences between the sexes are apparent even from the early part of the pregnancy. The crown-rump length is larger in male fetuses compared to females in the first trimester. Placentae of male and female fetuses have different protein and gene expressions, especially in adverse conditions. Even within the intrauterine milieu, the same extracellular micro RNA may show upregulation in females and downregulation in male fetuses. There appears to be a natural survival advantage for females. Maternal glucocorticoids (GC) play an important role in fetal growth and organ maturation. However, excess glucocorticoids can not only affect growth but the response may be sex-specific and probably mediated through glucocorticoid receptors (GR) in the placenta. Mild pre-eclampsia and asthma are associated with normal growth pattern in males, but in female fetuses, they are associated with a slowing of growth rate without causing IUGR probably as an adaptive response for future adverse events. Thus, female fetuses survive while male fetuses exhibit IUGR, preterm delivery and even death in the face of another adverse event. It is thought that the maternal diet may not influence growth but may influence the programming for adult disease. There is growing evidence that maternal pre-pregnancy overweight or obesity status is directly associated with a higher risk of obesity in a male child, but not in a female child, at 1 year of age. It is observed that exposure to gestational diabetes is a risk factor for childhood overweight in boys but not in girls. It is fascinating that male and female fetuses respond differently to the same intrauterine environment, and this suggests a fundamental biological variation most likely at the cellular and molecular level.

Sex Differences in Nutrition, Growth, and Metabolism in Preterm Infants

Fetal sex is associated with striking differences during in utero development, fetal-to-neonatal transition, and postnatal morbidity and mortality. Male sex fetuses are apparently protected while in utero resulting in a higher secondary sex rate for males than for females. However, during fetal-to-neonatal transition and thereafter in the newborn period, female exhibits a greater degree of maturation that translates into a better capacity to stabilize, less incidence of prematurity and prematurity-associated morbidities, and better long-term outcomes. The present review addresses the influence of sex during gestation and postnatal adaptation that includes the establishment of an adult-type circulation, the initiation of breathing, endurance when confronted with perinatal hypoxia ischemia, and a gender-related different response to drugs. The intrinsic mechanisms explaining these differences in the perinatal period remain elusive and further experimental and clinical research are therefore stringently needed if an individual oriented therapy is to be developed.

Fetal sex is associated with striking differences during in utero development, fetal-to-neonatal transition, and postnatal morbidity and mortality. Male sex fetuses are apparently protected while in utero resulting in a higher secondary sex rate for males than for females. However, during fetal-to-neonatal transition and thereafter in the newborn period, female exhibits a greater degree of maturation that translates into a better capacity to stabilize, less incidence of prematurity and prematurity-associated morbidities, and better long-term outcomes. The present review addresses the influence of sex during gestation and postnatal adaptation that includes the establishment of an adult-type circulation, the initiation of breathing, endurance when confronted with perinatal hypoxia ischemia, and a gender-related different response to drugs. The intrinsic mechanisms explaining these differences in the perinatal period remain elusive and further experimental and clinical research are therefore stringently needed if an individual oriented therapy is to be developed.

Influence of Sex on Gestational Complications, Fetal-to-Neonatal Transition, and Postnatal Adaptation

Fetal sex plays an important role in modifying the course and complications related to pregnancy and may also have an impact on maternal health and well-being both during and after pregnancy. The goal of this article is to review and summarize the findings from published research on physiologic and pathologic changes that may be affected by fetal sex and the effect of these changes on the maternal and obstetrical outcomes. This will help create awareness that fetal sex is not just a random chance event but an interactive process between the mother, the placenta, and the fetus. The reported effects of male sex on the course of pregnancy and delivery include higher incidence of preterm labor in singletons and twins, failure of progression in labor, true umbilical cord knots, cord prolapse, nuchal cord, higher cesarean section rate, higher heart rate variability with increased frequency, and duration of decelerations without acidemia and increased risk of gestational diabetes mellitus through the poor beta cells function. Similarly, female fetal sex has been reported to modify pregnancy and delivery outcomes including altered fetal cardiac hemodynamics, increased hypertensive diseases of pregnancy, higher vulnerability of developing type 2 DM after pregnancy possibly because of influences on increased maternal insulin resistance. Placental function is also influenced by fetal sex. Vitamin D metabolism in the placenta varies by fetal sex; and the placenta of a female fetus is more responsive to the relaxing action of magnesium sulfate. Male and female feto-placental units also vary in their responses to environmental toxin exposure. The association of fetal sex with stillbirths is controversial with many studies reporting higher risk of stillbirth in male fetuses; although some smaller and limited studies have reported more stillbirths with female fetus pregnancies. Maternal status such as BMI may in turn also affect the fetus and the placenta in a sex-specific manner. There is probably a sex-specific maternal–placental–fetal interaction that has significant biological implications of which the mechanisms may be genetic, epigenetic, or hormonal. Determination of fetal sex may therefore be an important consideration in management of pregnancy and childbirth.

Fetal sex plays an important role in modifying the course and complications related to pregnancy and may also have an impact on maternal health and well-being both during and after pregnancy. The goal of this article is to review and summarize the findings from published research on physiologic and pathologic changes that may be affected by fetal sex and the effect of these changes on the maternal and obstetrical outcomes. This will help create awareness that fetal sex is not just a random chance event but an interactive process between the mother, the placenta, and the fetus. The reported effects of male sex on the course of pregnancy and delivery include higher incidence of preterm labor in singletons and twins, failure of progression in labor, true umbilical cord knots, cord prolapse, nuchal cord, higher cesarean section rate, higher heart rate variability with increased frequency, and duration of decelerations without acidemia and increased risk of gestational diabetes mellitus through the poor beta cells function. Similarly, female fetal sex has been reported to modify pregnancy and delivery outcomes including altered fetal cardiac hemodynamics, increased hypertensive diseases of pregnancy, higher vulnerability of developing type 2 DM after pregnancy possibly because of influences on increased maternal insulin resistance. Placental function is also influenced by fetal sex. Vitamin D metabolism in the placenta varies by fetal sex; and the placenta of a female fetus is more responsive to the relaxing action of magnesium sulfate. Male and female feto-placental units also vary in their responses to environmental toxin exposure. The association of fetal sex with stillbirths is controversial with many studies reporting higher risk of stillbirth in male fetuses; although some smaller and limited studies have reported more stillbirths with female fetus pregnancies. Maternal status such as BMI may in turn also affect the fetus and the placenta in a sex-specific manner. There is probably a sex-specific maternal&#x2013;placental&#x2013;fetal interaction that has significant biological implications of which the mechanisms may be genetic, epigenetic, or hormonal. Determination of fetal sex may therefore be an important consideration in management of pregnancy and childbirth.

Effect of Fetal Sex on Maternal and Obstetric Outcomes

For the past century, researchers have underscored the “disadvantage” observed in respiratory morbidity and mortality of male newborns. In this contemporary review, we examine gender differences in preterm infant respiratory morbidity and mortality specifically appraising differences in the very low birth weight (VLBW) population as well as the late preterm (LPT) population. In the era of postnatal surfactant and antenatal corticosteroids, the gender gap in neonatal outcomes has not narrowed. Structural, physiologic, and hormonal sex differences may be at the root of this disparity. Further exploration into the origin of gender differences in respiratory morbidity and neonatal mortality will shape future therapies. These therapies may need to be gender specific to close the gender gap.

For the past century, researchers have underscored the &#x201c;disadvantage&#x201d; observed in respiratory morbidity and mortality of male newborns. In this contemporary review, we examine gender differences in preterm infant respiratory morbidity and mortality specifically appraising differences in the very low birth weight (VLBW) population as well as the late preterm (LPT) population. In the era of postnatal surfactant and antenatal corticosteroids, the gender gap in neonatal outcomes has not narrowed. Structural, physiologic, and hormonal sex differences may be at the root of this disparity. Further exploration into the origin of gender differences in respiratory morbidity and neonatal mortality will shape future therapies. These therapies may need to be gender specific to close the gender gap.