Elsevier

Neuroscience

Volume 342, 7 February 2017, Pages 4-20
Neuroscience

The gestational foundation of sex differences in development and vulnerability

https://doi.org/10.1016/j.neuroscience.2015.07.068Get rights and content

Highlights

  • Fetal sex confers effects on pregnancy, the intrauterine milieu and early development.

  • Prenatal and perinatal adversity affects male fetuses and neonates more negatively.

  • Fetal sex has been under-recognized as physiologically consequential for pregnant women.

  • Mechanisms by which biological sex imparts vulnerability or protection are largely unknown.

Abstract

Despite long-standing interest in the role of sex on human development, the functional consequences of fetal sex on early development are not well-understood. Here we explore the gestational origins of sex as a moderator of development. In accordance with the focus of this special issue, we examine evidence for a sex differential in vulnerability to prenatal and perinatal risks. Exposures evaluated include those present in the external environment (e.g., lead, pesticides), those introduced by maternal behaviors (e.g., alcohol, opioid use), and those resulting from an adverse intrauterine environment (e.g., preterm birth). We also provide current knowledge on the degree to which sex differences in fetal neurobehavioral development (i.e., cardiac and motor patterns) are present prior to birth. Also considered are contemporaneous and persistent sex of fetus effects on the pregnant woman. Converging evidence confirms that infant and early childhood developmental outcomes of male fetuses exposed to prenatal and perinatal adversities are more highly impaired than those of female fetuses. In certain circumstances, male fetuses are both more frequently exposed to early adversities and more affected by them when exposed than are female fetuses. The mechanisms through which biological sex imparts vulnerability or protection on the developing nervous system are largely unknown. We consider models that implicate variation in maturation, placental functioning, and the neuroendocrine milieu as potential contributors. Many studies use sex as a control variable, some analyze and report main effects for sex, but those that report interaction terms for sex are scarce. As a result, the true scope of sex differences in vulnerability is unknown.

Introduction

The morphological differentiation of sex commences early in embryogenesis and unfolds in a well-known sequence. Less well-understood are the functional consequences of sex on physiological, metabolic, and hormonal systems and, in turn, their influence on the developing nervous system before birth and ramifications for postnatal life. Here we explore the gestational origins of sex as a moderator of development. In keeping with the focus of this special issue on early adversity, we will also examine how sex modulates vulnerability to prenatal exposures and consider models that have been developed to account for these observations. Scientific interest in the role of sex in human development has waxed and waned over time in tandem with societal forces that emphasized either biological or social influences on observed differences. Currently, the role of sex as a biological variable is of rising academic significance, illustrated by a call from leaders of the National Institutes of Health for investigators to both identify and include animals and cell lines of both sexes (Clayton and Collins, 2014). This is the result of converging evidence for sexual dimorphisms that include findings as diverse as differential immunological responsiveness to vaccine challenges and variation in sensitivity of neurons to stimulation depending on sex of cell origin.

The construct of differential sex-based vulnerability to adversity has been well-identified. In 1985, a section of The Behavioral and Brain Sciences (Gualtieri and Hicks, 1985) was devoted to consideration of an immunoreactive theory to explain greater vulnerability of male offspring to obstetric, pediatric, psychiatric and developmental disorders. This theory posited that maternal immunological response to an antigenic factor found on the Y chromosome conferred long-lasting deleterious influence on multiple developing systems within the fetus, including the nervous system. In doing so, it summarized the existing empirical data supportive of greater male vulnerability, termed “selective male affliction”, available at the time. These findings have been largely confirmed and expanded in the 30 years since, along with new theories afforded by new assays and methodologies available to research.

The current literature on sex-related variation with relevance to neuroscience is too large and diverse for a single article. Instead we focus on the foundational role of the period before birth and examine the origins of sex differences in function and on prenatal exposures that differentially affect development in boys and girls. From a statistical standpoint, the former observation can be viewed as a main effect, while the latter is more traditionally detected as an interaction.

Section snippets

Male vulnerability and the continuum of reproductive casualty

That adversities experienced during the prenatal and perinatal period have consequences that persist through life, independent of fetal sex, was promulgated in the 1960’s as the “continuum of reproductive casualty” (Pasamanick and Knobloch, 1964). Until very recently, it has been scientific dogma that there is an excess of male conceptions but greater loss in male pregnancies throughout gestation. However, based on a comprehensive study of multiple sources of data, it appears that the ratio of

Fetal sex as a moderator of prenatal exposures

So far, we have illustrated instances of perinatal risk in which there is both heightened male exposure as well as potentiated consequences. However, when male infants exhibit poorer developmental outcomes following perinatal risks, such as preterm birth, it is not possible to disambiguate cause from effect. That is, it is unclear whether the greater incidence of shortened gestation should be viewed simply as a main effect or as a differential response to undetected intrauterine adversity which

Sex differences before birth

The antepartum constitutes the most rapid developmental period, a time where structural development occurs in tandem with functional gains (DiPietro et al., 2010). In this section, we describe current knowledge regarding the development of sex differences in indicators of nervous system maturation prior to birth.

On the origins of male vulnerability

So far we have presented evidence the there is both greater exposure and greater vulnerability to many prenatal and perinatal adversities for male fetuses than for female fetuses. In contrast, there are relatively few well-documented sex differences expressive of neurological development before birth. When significant differences are detected, as illustrated in Fig. 2, Fig. 3, they are accompanied by highly overlapping distributions. This finding echoes the long-standing conclusion of others

Conclusion

The review consolidated empirical information regarding prenatal sex differentials in vulnerability from a variety of diverse sources and literatures. We found converging evidence that developmental outcomes of male fetuses and infants exposed to prenatal and perinatal adversities are more highly impaired than those of female fetuses and infants. Although sex differences in vulnerability are most often found for male offspring, there are reports of female vulnerability, particularly with

Acknowledgments

This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) award 5R01 HD27592 to the first author.

References (188)

  • E.P. Davis et al.

    Sexually dimorphic responses to early adversity: implications for affective problems and autism spectrum disorder

    Psychoneuroendocrinology

    (2014)
  • N. Dawes et al.

    Fetal heart rate patterns in labor vary with sex, gestational age, epidural analgesia, and fetal weight

    Am J Obstet Gynecol

    (1999)
  • A.T. de Bruijn et al.

    Sex differences in the relation between prenatal maternal emotional complaints and child outcome

    Early Hum Dev

    (2009)
  • J.I.P. de Vries et al.

    The emergence of fetal behaviour. III. Individual differences and consistencies

    Early Hum Dev

    (1988)
  • G.C. Di Renzo et al.

    Does fetal sex affect pregnancy outcome?

    Gend Med

    (2007)
  • J.A. DiPietro

    Maternal stress in pregnancy: considerations for fetal development

    J Adolesc Health

    (2012)
  • J.A. DiPietro et al.

    Cross-correlation of fetal cardiac and somatic activity as an indicator of antenatal neural development

    Am J Obstet Gynecol

    (2001)
  • J.A. DiPietro et al.

    Fetal response to induced maternal stress

    Early Hum Dev

    (2003)
  • J.A. DiPietro et al.

    Maternal salivary cortisol differs by fetal sex during the second half of gestation

    Psychoneuroendocrinology

    (2011)
  • S.F. Evans et al.

    Prenatal bisphenol A exposure and maternally reported behavior in boys and girls

    Neurotoxicology

    (2014)
  • A. Fausto-Sterling et al.

    Sexing the baby: Part 1–what do we really know about sex differentiation in the first three years of life?

    Soc Sci Med

    (2012)
  • A. Fausto-Sterling et al.

    Sexing the baby: Part 2–applying dynamic systems theory to the emergences of sex-related differences in infants and toddlers

    Soc Sci Med

    (2012)
  • T.E. Froehlich et al.

    Interactive effects of a DRD4 polymorphism, lead, and sex on executive functions in children

    Biol Psychiatry

    (2007)
  • A. Gabory et al.

    Sexual dimorphism in environmental epigenetic programming

    Mol Cell Endocrinol

    (2009)
  • G.F. Giesbrecht et al.

    Sexually dimorphic adaptations in basal maternal stress physiology during pregnancy and implications for fetal development

    Psychoneuroendocrinology

    (2015)
  • V. Glover et al.

    Sex differences in the programming effects of prenatal stress on psychopathology and stress responses: an evolutionary perspective

    Physiol Behav

    (2012)
  • R.L. Goldenberg et al.

    The Alabama Preterm Birth Study: intrauterine infection and placental histologic findings in preterm births of males and females less than 32 weeks

    Am J Obstet Gynecol

    (2006)
  • P. Grandjean et al.

    Cognitive performance of children prenatally exposed to “safe” levels of methylmercury

    Environ Res

    (1998)
  • L. Groome et al.

    Behavioral state affects heart rate response to low-intensity sound in human fetuses

    Early Hum Dev

    (1999)
  • K.G. Harley et al.

    Prenatal and early childhood bisphenol A concentrations and behavior in school-aged children

    Environ Res

    (2013)
  • M.K. Horton et al.

    Does the home environment and the sex of the child modify the adverse effects of prenatal exposure to chlorpyrifos on child working memory?

    Neurotoxicol Teratol

    (2012)
  • Y. Hou et al.

    Differential effects of gestational buprenorphine, naloxone, and methadone on mesolimbic mu opioid and ORL1 receptor G protein coupling

    Brain Res Dev Brain Res

    (2004)
  • I. Ingemarsson

    Gender aspects of preterm birth

    BJOG

    (2003)
  • C. Jacklin

    Methodological issues in the study of sex-related differences

    Dev Rev

    (1981)
  • L.M. Jansson et al.

    Fetal response to maternal methadone administration

    Am J Obstet Gynecol

    (2005)
  • L. Jansson et al.

    Infant autonomic functioning and neonatal abstinence syndrome

    Drug Alcohol Depend

    (2010)
  • W. Jedrychowski et al.

    Gender specific differences in neurodevelopmental effects of prenatal exposure to very low-lead levels: the prospective cohort study in three-year olds

    Early Hum Dev

    (2009)
  • H. Johnson et al.

    24-month neurobehavioral follow-up of children of methadone-maintained mothers

    Infant Behav Dev

    (1984)
  • M.J. Khoury et al.

    Factors affecting the sex differential in neonatal mortality: the role of respiratory distress syndrome

    Am J Obstet Gynecol

    (1985)
  • R. Achiron et al.

    Sex-related differences in the development of the human fetal corpus callosum: in utero ultrasonographic study

    Prenat Diagn

    (2001)
  • L. Aibar et al.

    Fetal sex and perinatal outcomes

    J Perinat Med

    (2012)
  • C.E. Aiken et al.

    Sex differences in developmental programming models

    Reproduction

    (2013)
  • M.H. Aliyu et al.

    Fetal sex and differential survival in preeclampsia and eclampsia

    Arch Gynecol Obstet

    (2012)
  • C.R. Almli et al.

    Human fetal and neonatal movement patterns: gender differences and fetal-to-neonatal continuity

    Dev Psychobiol

    (2001)
  • H. Als

    Toward a synactive theory of development: promise for the assessment and support of infant individuality

    Infant Ment Health J

    (1982)
  • C. Amiel-Tison et al.

    Neurosonography in the second half of fetal life: a neonatologist’s point of view

    J Perinat Med

    (2006)
  • M. Anastario et al.

    Impact of fetal versus perinatal hypoxia on sex differences in childhood outcomes: developmental timing matters

    Soc Psychiatry Psychiatr Epidemiol

    (2012)
  • S.J. Astley

    Profile of the first 1,400 patients receiving diagnostic evaluations for fetal alcohol spectrum disorder at the Washington State Fetal Alcohol Syndrome Diagnostic & Prevention Network

    Can J Clin Pharmacol

    (2010)
  • J. Bernardes et al.

    Sex differences in linear and complex fetal heart rate dynamics of normal and acidemic fetuses in the minutes preceding delivery

    J Perinat Med

    (2009)
  • D.W. Bianchi et al.

    Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum

    Proc Natl Acad Sci U S A

    (1996)
  • Cited by (0)

    View full text