https://orcid.org/0000-0003-1797-0591
Figures
Abstract
Background
It is hypothesized that male fetuses prioritize growth, resulting in increased mortality, whereas females reduce growth in the presence of adversity. Preeclampsia reflects a chronic condition, in which fetuses have the opportunity to adjust growth. If females reduce their growth in response to preeclampsia, but males attempt to maintain growth at the cost of survival, we predict that differences in birthweight between preeclamptic and non-preeclamptic pregnancies will be greater among females, whereas differences in mortality will be greater among males.
Methods
We analysed data from the Centers for Disease Control and Prevention. We compared pregnancies with pregnancy-associated hypertension (PAH) and controls.
Results
The difference in birthweight between pregnancies affected by PAH and controls varied by fetal sex and gestational age. Among pregnancies of White individuals, at 34–35 weeks, the difference between PAH and controls was higher among females, as predicted. However, this pattern was reversed earlier in pregnancy and around term. Such variation was not significant in Black pregnancies. In both Black and White pregnancies, early in gestation, males had lower odds of death in PAH pregnancies, but higher odds of death in control pregnancies, counter to our prediction. Later, males had higher odds of death in PAH and controls, although the increased odds of death in males was not higher in PAH pregnancies than in controls. Overall, the difference in birthweight between surviving and non-surviving infants was greater in males than in females, opposite to our prediction.
Conclusions
The impact of PAH on birthweight and survival varies widely throughout gestation. Differences in birthweight and survival between male and female PAH and controls are generally not consistent with the hypothesis that males prioritize fetal growth more than females, and that this is a cause of increased mortality in males.
Citation: Hercus JC, Metcalfe KX, Christians JK (2024) Sex differences in growth and mortality in pregnancy-associated hypertension. PLoS ONE 19(1): e0296853. https://doi.org/10.1371/journal.pone.0296853
Editor: Nur Aizati Athirah Daud, Universiti Sains Malaysia, MALAYSIA
Received: February 24, 2023; Accepted: December 20, 2023; Published: January 11, 2024
Copyright: © 2024 Hercus et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The datasets generated in this study are available in the National Center for Health Statistics Vital Statistics Online Data Portal, https://www.cdc.gov/nchs/data_access/vitalstatsonline.htm.
Funding: This study was funded by a Natural Sciences and Engineering Research Council of Canada Discovery Grant (JKC; grant number RGPIN-2021-02853). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Male infants are, on average, heavier at birth than female infants [1], but also have higher risks of perinatal mortality and other early adverse events [2,3]. Males are more likely to be born prematurely, particularly at earlier gestational ages [4]. Male infants are at higher risk of distress and asphyxia during labour, and have lower 5-minute Apgar scores [5]. Furthermore, males experience higher risks of various forms of pulmonary morbidity including respiratory distress syndrome, and increased need for oxygen and ventilator support [2]. Many authors have suggested that these differences may be due to males prioritizing growth at the expense of placental development, causing a higher risk of undernutrition if the pregnant person experiences adverse conditions, and that females are more adaptable to early-life challenges than males [6–8].
Sex differences in physiological traits in healthy fetuses suggest potential differences in prenatal growth strategy. Males and females have significantly different cardiovascular function as early as 30 weeks gestation [9]. Changes in brain connectivity during gestation also differ between the sexes, with females showing more development of long-range connections and males having more growth in local connectivity [10]. Males and females show differential expression of genes involved in several different functions in the placenta, providing a potential mechanism by which differential growth strategies could be achieved [11–19]. These could, in turn, contribute to sex differences in fetal oxygen extraction and maternal glucose metabolism [20,21].
The growth of males and females may respond differently to prenatal environment, although responses vary widely depending on the factor and timing of exposure. Higher maternal body mass index (BMI) is associated with higher birthweight in both sexes, but premature males are more affected than premature females, whereas at term the reverse is true [22]. Females born to asthmatic individuals who do not use glucocorticoids are significantly smaller compared to control females and females born to individuals using glucocorticoids, whereas males do not show any significant difference between groups [23]. Daily vigorous exercise significantly increases the chances of having a small for gestational age infant, but the risk is nearly twice as high for male infants compared to females [24].
Preeclampsia provides another model to examine whether the sexes respond differently to prenatal conditions. Preeclampsia is a major form of pregnancy-associated hypertension, affecting 2–8% of pregnancies globally [25–27]. Preeclampsia is defined by hypertension arising after 20 weeks gestation, in combination with other maternal symptoms, or with observed intrauterine growth restriction (IUGR) [28]. While preeclampsia is a heterogeneous syndrome, it is believed that most cases are caused by impaired placentation very early in pregnancy [29,30], leading to altered blood flow to the placenta throughout pregnancy and reduced nutrient and oxygen availability for the fetus. Due to this etiology, preeclampsia is a known factor in IUGR, often leading to small-for-gestational age (SGA) infants [26,31–33]. As preeclampsia is a chronic adverse condition in utero, we may expect to observe different growth strategies between sexes in response to this challenge [34] in addition to differing mortality rates.
The growth strategy hypothesis posits that males prioritize growth, resulting in increased mortality, whereas females are more adaptable, reducing growth in the presence of adversity, and thereby reducing mortality [35]. However, this hypothesis has rarely been tested directly, and has not been examined using birthweight data in the context of preeclampsia, which is the goal of the present study. The premise of this work is that pregnancy-associated hypertension (PAH) will generally indicate a chronic condition, whereby fetuses will have had opportunity to adjust their growth in response to altered nutrient supply and in utero environment. In contrast, pregnancies without PAH or other potentially chronic complications will be more likely to reflect a fetus on a normal growth trajectory, even if born premature. Given this premise and the hypothesis that males prioritize growth whereas females reduce growth in the presence of adversity, we predict:
- among surviving fetuses, differences in birthweight between PAH and non-PAH pregnancies will be greater among females than among males; females with PAH will have reduced growth whereas males will have attempted to maintain growth;
- among all fetuses, differences in birthweight between fetuses that survive and those that die prenatally or shortly after birth will be greater among females than among males [36]; females facing serious prenatal insults will have reduced growth more than males;
- the difference in mortality between the sexes will be higher among pregnancies affected by PAH; males will have attempted to maintain growth despite chronic adversity, resulting in reduced survival.
In addition, we also examined the effects of PAH on the odds of being born in males and females. We tested these predictions using data from the National Center for Health Statistics of the Centers for Disease Control and Prevention.
Materials and methods
We used the public-use Birth Cohort Linked Birth–Infant Death Data Files from the National Center for Health Statistics of the Centers for Disease Control and Prevention [37]. We used data from years 1989–1991, and 1995–2003. Prior to 1989 and after 2005, data on some pregnancy complications are not available. Changes to the coding of race after 2003 had a substantial effect on sample sizes in some states. Linked data files are not available for 1992–1994.
To obtain a relatively homogeneous sample and avoid some potential confounds, we restricted analyses to singleton pregnancies with no record of a previous live birth and where offspring sex was assigned male or female, and to Non-Hispanic White or Black individuals between the ages of 18 and 34, inclusive; White or Black individuals were analysed separately. We placed restrictions on maternal age to avoid confounding effects of increased complications at young and advanced ages, e.g., increased rates of stillbirth, fetal growth restriction, small-for-gestational age, preterm birth at advanced maternal age [38]. We excluded pregnancies where the gestational age was below 24 weeks or over 42 weeks; gestational age was primarily based on the last menstrual period, but a clinical estimate was used if the date of the last menstrual period was not available or the gestational age was not consistent with birthweight. Imputed data were considered to be missing.
A pregnancy was coded as having pregnancy-associated hypertension (PAH) if there was a record of PAH or eclampsia, regardless of the presence of other complications. PAH was defined by an increase in blood pressure of at least 30 mm Hg systolic or 15 mm Hg diastolic on two measurements taken 6 hours apart after the 20th week of gestation. Eclampsia was defined as the occurrence of convulsions and/or coma unrelated to other cerebral conditions in women with signs and symptoms of pre-eclampsia. No information regarding severity of hypertension, or the presence of proteinuria was available in this dataset. A pregnancy was coded as a control if there was no report of chronic hypertension, premature rupture of membranes, abruption or incompetent cervix. Pregnancies with one of these other complications, but not PAH or eclampsia, were excluded. We excluded data from states where more than 5% of observations had missing values for pregnancy complications (Connecticut, Hawaii, Kentucky, Maryland, Minnesota, Nevada, North Dakota, Oklahoma, Pennsylvania, Rhode Island, Texas, Vermont, Virginia and Washington), and from states where the sample sizes were less than 100 (Kentucky, Nevada, North Dakota, and Wyoming).
We excluded observations with implausible birthweights for gestational age by excluding those below the 0.5th percentile or above the 99.5th percentile by gestational age and sex according to Aris et al 2019 [39]. We used SAS (Version 9.4) for all analyses. Models are described in further detail below. Fig 1 provides a flow chart showing inclusions and exclusions and samples used in each analysis; the number of exclusions based on birthweight by gestational age are provided in S1 Table. Table 1 provides descriptive data for PAH and control pregnancies by sex, including covariates used in analyses.
Percentages refer to percent of total for a given subgroup (e.g., for White PAH males).
Results
Prediction 1: Among surviving fetuses, differences in birthweight between PAH and controls will be greater among females than among males
We restricted this analysis to infants who were alive at 29 days after birth, to exclude neonatal deaths. We analysed birthweight with a general linear model (proc GLM) testing effects of gestational age as a categorical variable (to allow a non-linear relationship with birthweight), sex, group (PAH or control), tobacco use (yes or no), year and all possible pairwise and three-way interactions between gestational age, sex and group (S2 Table). Overall, there was a significant effect of both sex and group on birthweight, with males heavier than females and controls heavier than PAH (S1 Fig). With regards to our prediction that differences in birthweight between PAH and controls would be greater among females, there was no significant interaction between sex and group in White or Black individuals (S2 Table). However, among White individuals, there was a three-way interaction between gestational age, sex and group (S2 Table), indicating that the strength of the sex by group interaction varied with gestational age. At 34–35 weeks, the difference between PAH and controls was higher among females, as predicted (Fig 2). However, this pattern was reversed at 29–30 weeks and around term (Fig 2). There was also a significant interaction between group and gestational age (S2 Table), such that the difference between groups was greatly reduced around term (Figs 2 and S1). The three-way interaction between gestational age, sex and group was not significant among Black individuals (S2 Table), although patterns were similar (Fig 2).
Differences in birthweight between PAH pregnancies and controls among surviving fetuses in White pregnancies (left) and Black pregnancies (right). Differences ± standard errors were calculated using the ESTIMATE statement of proc GLM and were from a model including gestational age as a categorical variable, sex, group (PAH or control), tobacco use (yes or no), year and all possible pairwise and three-way interactions between gestational age, sex and group.
Prediction 2: Among all fetuses, differences in birthweight between fetuses that survive and those that die prenatally or shortly after birth will be greater among females than among males
In this analysis, we included fetal deaths and infants who died within 28 days of birth as non-survivors. We repeated the analysis above, replacing group (PAH or control) with survival (yes or no) in interaction terms, but retaining the main effect of group, i.e., we analysed birthweight testing effects of gestational age, sex, survival, group, tobacco use, year and all possible pairwise and three-way interactions between gestational age, sex and survival (S3 Table). There was a significant effect of survival on birthweight, with surviving infants being heavier (S2 Fig). There was a significant interaction between sex and survival (S3 Table) whereby the difference in birthweight between surviving and non-surviving infants was greater in males than in females, opposite to our prediction (Fig 3). While the interaction was statistically significant, the magnitude of the difference in birthweight between surviving and non-surviving infants was similar in males and females in both White (males: 206 ± 4 g; females: 183 ± 5 g) and Black (males: 207 ± 7 g; females: 161 ± 8 g) pregnancies. The magnitude of these differences fluctuated with gestational age (Fig 3), but the three-way interaction between sex, survival and gestational age was not significant (S3 Table), indicating that the interaction between sex and survival did not vary with gestational age.
Differences in birthweight between infants that died prenatally or within 28 days and surviving infants in White pregnancies (left) and Black pregnancies (right). Differences ± standard errors were calculated using the ESTIMATE statement of proc GLM and were from a model including gestational age as a categorical variable, sex, survival, group, tobacco use (yes or no), year and all possible pairwise and three-way interactions between gestational age, sex and survival.
Prediction 3: The difference in mortality between the sexes will be higher among pregnancies affected by PAH
We first examined mortality using a fetus-at-risk approach [40,41], testing survival time using a proportional hazards model (proc PHREG), including effects of sex, group (PAH or control) and the interaction between sex and group. In this analysis, we calculated time of death from the beginning of gestation (e.g., an infant born at 24 weeks that died 5 weeks after birth would be considered to have died at 29 weeks), and censored surviving infants at 46 weeks. However, we found the proportional hazards assumption to be violated (ZPH option; P < 0.001 for all terms in the model); the effects of sex, group and the interaction between sex and group all varied with time since the beginning of gestation (Fig 4).
Effects of sex and PAH on mortality using a fetus-at-risk approach in White pregnancies (left) and Black pregnancies (right). Symbols denote deaths at a single week, whereas lines are calculated using a sliding window that averages the deaths at a focal week and in the following two weeks.
We therefore performed a logistic regression (proc LOGISTIC) analysis to examine the effects of sex, group and the interaction between sex and group on the odds of dying at specific time points. This analysis used a sliding window where, at each week, we analysed the odds of death at that week or in the following two weeks, including fetal deaths and deaths within the first 28 days after birth. This analysis included all fetuses at risk, i.e., all those still in utero or less than 28 days old. Among White pregnancies, the interaction between sex and group was significant early in gestation (weeks 24–26) with males having lower odds of death in PAH pregnancies, but higher odds of death in control pregnancies, counter to our prediction (Fig 5; S4 Table); in Black pregnancies, this interaction was significant in week 24, but marginally non-significant in weeks 25 and 26 (P = 0.08 and P = 0.06, respectively; S5 Table). From weeks 27 to 38, males in White pregnancies had higher odds of death in both groups, although for most of this time, increased risk did not differ between groups (the sex by group interaction was not significant) (Fig 5; S4 Table). In week 38, the interaction between sex and group was significant (P = 0.045), with the increased odds of death in males being higher in PAH pregnancies, as predicted (Fig 5; S4 Table). In Black pregnancies, the odds of death differed between males and females only in weeks 31 and 32 (S5 Table). Around term, there was no difference in the odds of death between males and females. From 24–37 weeks, there was significantly higher mortality in PAH pregnancies than in controls in both White and Black pregnancies (P < 0.02 in all weeks; Fig 4; S4 and S5 Tables).
The odds of death for males relative to females in PAH pregnancies and controls in White pregnancies (left) and Black pregnancies (right). An OR > 1 indicates that males are at greater risk of death than females within a group. A sliding window was used to analyse the odds of death at that week or in the following two weeks, including fetal deaths and deaths within the first 28 days after birth, and including all fetuses at risk. Odds ratios for the effect of sex were calculated using the ODDSRATIO statement of proc LOGISTIC and were from a model including effects of sex, group and the interaction between sex and group. Error bars denote 95% confidence limits.
Sex differences in the odds of birth in preeclampsia and controls
It is known that males are more likely to be born premature [4,42–44]. However, we examined whether this increased risk of preterm birth in males differed between PAH pregnancies and controls. We performed a logistic regression (proc LOGISTIC) analysis to examine the effects of sex, group and the interaction between sex and group on the odds of being born at specific gestational ages. As above, this analysis used a sliding window where, at each week, we analysed the odds of birth at a given week or in the following two weeks. Only live births were considered, although the fetuses at risk included fetal deaths that occurred later in gestation.
Early in gestation, control males had higher odds of being born than control females, whereas PAH females had higher odds of being born than PAH males (Figs 6 and 7). In White pregnancies, in weeks 34–38, males had higher odds of being born than females in both groups, but this sex difference was greater in controls (Fig 7). The interaction between sex and group was significant in weeks 24–37 in Black pregnancies and weeks 24–38 in White pregnancies. Throughout gestation, the odds of being born were higher in PAH pregnancies than in controls (Fig 6).
Effects of sex and PAH on births using a fetus-at-risk approach in White pregnancies (left) and Black pregnancies (right). Because we excluded pregnancies where the gestational age was over 42 weeks, all remaining “fetuses-at-risk” were born at 42 weeks, i.e., 10000 births per 10000 fetuses.
The odds of birth for males relative to females in PAH pregnancies and controls in White pregnancies (left) and Black pregnancies (right). An OR > 1 indicates that odds of birth are greater for males than females within a group. A sliding window was used to analyse the odds of birth at that week or in the following two weeks, including all fetuses at risk. Odds ratios for the effect of sex were calculated using the ODDSRATIO statement of proc LOGISTIC and were from a model including effects of sex, group and the interaction between sex and group. Error bars denote 95% confidence limits.
Discussion
Prediction 1: Among surviving fetuses, differences in birthweight between PAH and controls will be greater among females than among males
Birthweights were lower in PAH pregnancies than in controls, likely reflecting the increased prevalence of a chronic condition in the PAH group. However, this difference was not consistently greater in one sex than the other. Overall, the interaction between sex and group was not significant, i.e., the difference in birthweight between PAH and controls did not differ between sexes. However, among White pregnancies, this interaction did vary significantly across gestational ages, with males showing a larger difference between PAH and controls compared to females around 29–30 weeks, and again around 40–41 weeks, but with females showing the reverse pattern around 34–35 weeks. Black pregnancies showed similar patterns, although not statistically significant, perhaps due to a lower sample size. A previous study found that preterm males reduced their growth more in response to preeclampsia, which agrees with our results [34]. While not consistent with our prediction, this result might indicate that pregnancies with male fetuses are associated with more severe forms of PAH/ preeclampsia, although we did not have information regarding the severity of the condition. We found that the difference in birthweight between PAH and control pregnancies was reduced around term, which is consistent with late-onset preeclampsia being a less severe condition than early-onset preeclampsia [45].
Prediction 2: Among all fetuses, differences in birthweight between fetuses that survive and those that die prenatally or shortly after birth will be greater among females than among males
Based on the growth strategy hypothesis, we would expect females to reduce their growth in response to prenatal insults, whereas males should sustain their growth [35]. This should lead to a larger difference in birthweight between females who survived and those who died due to prenatal insults. However, we found the opposite: throughout gestation, males had a significantly greater difference between the birthweight of surviving and non-surviving fetuses compared to females. This contrasts with our previous work in a different cohort, where we found that prior to 33 weeks, the difference in birthweight between surviving and non-surviving fetuses was greater in females [36]. However, in this previous work, we had not restricted observations based on maternal race or age, or the presence of specific pregnancy complications. The additional restrictions in the present study may have reduced confounding effects (e.g., differences in the prevalence of complications) and provided more accurate patterns. Alternatively, births in the previous cohort [36] occurred from 1959 to 1966 whereas those in the present study occurred from 1989 to 2003, and so changes in clinical management may have led to real changes in patterns of birthweight and survival.
Prediction 3: The difference in mortality between the sexes will be higher among pregnancies affected by PAH
At 24–37 weeks of gestation, PAH pregnancies had significantly higher mortality compared to control pregnancies. This is consistent with other studies that have found infants exposed to PAH have higher risks of stillbirth and neonatal mortality [46,47]. Early in gestation, males had a higher risk of death in control pregnancies than females, but a lower risk in PAH pregnancies, inconsistent with our prediction. This reversal of sex differences in PAH pregnancies may indicate that females are exposed to more severe PAH at very early gestational ages (weeks 24–26). From weeks 27–38, males were more likely to die than females in both PAH and control groups in White pregnancies, which is consistent with other studies finding higher stillbirth risks for males [3,48]. However, sex did not moderate the effect of PAH on mortality risk, i.e., males exposed to PAH were not disproportionately more likely to die.
Sex differences in the odds of birth in preeclampsia and controls
Early in gestation, control males had higher odds of being born than control females, whereas the opposite was true among PAH pregnancies. Later in pregnancy, males had a higher odds of being born than females in both groups in White pregnancies, but this sex difference was greater in controls. These results are consistent with previous findings that overall males are at greater risk of premature birth [4,42–44], although we found this male bias to be reduced among Black pregnancies. While our analysis did not examine the rates of PAH in males and females (i.e., proportion of PAH pregnancies among all pregnancies), the female bias in births early in gestation among PAH pregnancies may reflect females being exposed to a more severe condition, and/ or being exposed earlier in gestation; female pregnancies are at increased risk of preterm preeclampsia [49,50].
Limitations
Our study only included non-Hispanic White and Black primiparous individuals from 18–34 years of age, leading to more homogenous samples. However, our results may not be generalizable to other groups. We were not able to distinguish between preterm and term preeclampsia, and we could not determine the severity of preeclampsia, which could be confounding if one sex is more likely to experience a more severe form of the disorder. Indeed, female pregnancies are at increased risk of preterm preeclampsia, whereas male pregnancies are at increased risk of term preeclampsia [49,50]. However, a greater incidence of early, severe preeclampsia among females would be expected to cause a greater difference in birthweight between PAH and controls among females than among males, which was not observed prior to 34 weeks. The prevalence of various causes of preterm birth among controls may have also differed between the sexes. The lack of clinical information also precluded identification of potential mechanisms underlying reduced fetal growth. For example, during healthy pregnancy, there is an increase in maternal cardiac output and blood volume, along with reduced systemic vascular resistance and blood pressure [51]. Failure to undergo these normal changes is associated with pre-eclampsia (PE) and fetal growth restriction [52–55], perhaps because of impairment of placental development and growth [55]. Inconsistent data collection could have introduced bias into the sample, although it is not clear how such biases would have affected one sex more than the other. While we did exclude states if more than 5% of observations had missing values, there may be undetected bias if, for example, rural or underserved areas were more likely to have incorrectly recorded values.
Conclusions
Overall, results regarding sex differences were similar among White and Black pregnancies, despite the rates of hypertensive disorders of pregnancy, SGA and preterm birth differing between these groups [56–58]. Among surviving infants, the impact of PAH on birthweight varies throughout gestation; early in gestation, males reduce their birthweight more, while this reverses around late pre-term so that females are more affected, with males again being more affected at term. This result is not consistent with the hypothesis that males and females have different growth strategies; if the sexes were employing different strategies in response to PAH, we would expect this to be consistent throughout gestation. Furthermore, non-surviving males show greater reductions in birthweight than non-surviving females, opposite to predictions based on the growth strategy hypothesis. Finally, males are not disproportionately more likely to die due to PAH exposure. While these results may reflect sex differences in the prevalence and severity of pregnancy complications, rather than growth strategies, they do not provide any support for the growth strategy hypothesis, indicating that other explanations for the excess mortality and morbidity experienced by male infants should be considered.
Supporting information
S1 Table.
Number of exclusions based on birthweight by gestational age in (A) White live births, (B) Black live births, (C) White fetal deaths, and (D) Black fetal deaths.
https://doi.org/10.1371/journal.pone.0296853.s001
(XLSX)
S2 Table. Effects on birthweight among infants who were still alive at 29 days after birth among White (N = 5122926) and Black (N = 1089012) individuals.
https://doi.org/10.1371/journal.pone.0296853.s002
(DOCX)
S3 Table. Effects on birthweight, including fetal deaths and infants who died within 28 days of birth among White (N = 5143779) and Black (N = 1097178) individuals.
https://doi.org/10.1371/journal.pone.0296853.s003
(DOCX)
S4 Table. The odds of death for males relative to females in PAH pregnancies and controls in White pregnancies.
https://doi.org/10.1371/journal.pone.0296853.s004
(DOCX)
S5 Table. The odds of death for males relative to females in PAH pregnancies and controls in Black pregnancies.
https://doi.org/10.1371/journal.pone.0296853.s005
(DOCX)
S1 Fig.
Effects of sex and PAH on birthweight in White pregnancies (left) and Black pregnancies (right).
https://doi.org/10.1371/journal.pone.0296853.s006
(DOCX)
S2 Fig.
Effects of sex and survival on birthweight in White pregnancies (left) and Black pregnancies (right).
https://doi.org/10.1371/journal.pone.0296853.s007
(DOCX)
Acknowledgments
We thank Bernard Crespi, K.S. Joseph, and Pablo Nepomnaschy for helpful feedback and discussion, and two anonymous reviewers for constructive comments.
References
- 1. Catalano PM, Drago NM, Amini SB. Factors affecting fetal growth and body composition. Am J Obstet Gynecol. 1995;172: 1459–1463. pmid:7755054
- 2. Stevenson DK, Verter J, Fanaroff AA, Oh W, Ehrenkranz RA, Shankaran S, et al. Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage. Arch Dis Child Fetal Neonatal Ed. 2000;83: F182–5. pmid:11040165
- 3. Voskamp BJ, Peelen MJCS, Ravelli ACJ, van der Lee R, Mol BWJ, Pajkrt E, et al. Association between fetal sex, birthweight percentile and adverse pregnancy outcome. Acta Obstet Gynecol Scand. 2020;99: 48–58. pmid:31424085
- 4. Challis J, Newnham J, Petraglia F, Yeganegi M, Bocking A. Fetal sex and preterm birth. Placenta. 2013;34: 95–99. pmid:23261268
- 5. Bekedam DJ, Engelsbel S, Mol BWJ, Buitendijk SE, Van der Pal-de Bruin KM. Male predominance in fetal distress during labor. Am J Obstet Gynecol. 2002;187: 1605–1607. pmid:12501071
- 6. Eriksson JG, Kajantie E, Osmond C, Thornburg K, Barker DJP. Boys live dangerously in the womb. Am J Hum Biol. 2010;22: 330–335. pmid:19844898
- 7. DiPietro JA, Voegtline KM. The gestational foundation of sex differences in development and vulnerability. Neuroscience. 2017;342: 4–20. pmid:26232714
- 8. Sandman CA, Glynn LM, Davis EP. Is there a viability-vulnerability tradeoff? Sex differences in fetal programming. J Psychosom Res. 2013;75: 327–335. pmid:24119938
- 9. Schalekamp-Timmermans S, Cornette J, Hofman A, Helbing WA, Jaddoe VWV, Steegers EAP, et al. In utero origin of sex-related differences in future cardiovascular disease. Biol Sex Differ. 2016;7: 1–7. pmid:27757222
- 10. Wheelock MD, Hect JL, Hernandez-Andrade E, Hassan SS, Romero R, Eggebrecht AT, et al. Sex differences in functional connectivity during fetal brain development. Dev Cogn Neurosci. 2019;36. pmid:30901622
- 11. Saif Z, Hodyl NA, Stark MJ, Fuller PJ, Cole T, Lu N, et al. Expression of eight glucocorticoid receptor isoforms in the human preterm placenta vary with fetal sex and birthweight. Placenta. 2015;36: 723–730. pmid:25990415
- 12. Sood R, Zehnder JL, Druzin ML, Brown PO. Gene expression patterns in human placenta. Proc Natl Acad Sci U S A. 2006;103: 5478–5483. pmid:16567644
- 13. Gabory A, Roseboom TJ, Moore T, Moore LG, Junien C. Placental contribution to the origins of sexual dimorphism in health and diseases: Sex chromosomes and epigenetics. Biol Sex Differ. 2013;4: 5. pmid:23514128
- 14. Kalisch-Smith JI, Simmons DG, Dickinson H, Moritz KM. Review: Sexual dimorphism in the formation, function and adaptation of the placenta. Placenta. 2017;54: 10–16. pmid:27979377
- 15. Rosenfeld CS. Sex-specific placental responses in fetal development. Endocrinology. 2015;156: 3422–3434. pmid:26241064
- 16. Dearden L, Bouret SG, Ozanne SE. Sex and gender differences in developmental programming of metabolism. Mol Metab. 2018;15: 8–19. pmid:29773464
- 17. Tarrade A, Panchenko P, Junien C, Gabory A. Placental contribution to nutritional programming of health and diseases: epigenetics and sexual dimorphism. J Exp Biol. 2015;218: 50–58. pmid:25568451
- 18. Christians JK. The placenta’s role in sexually dimorphic fetal growth strategies. Reprod Sci. 2021. pmid:34699045
- 19. Braun AE, Mitchel OR, Gonzalez TL, Sun T, Flowers AE, Pisarska MD, et al. Sex at the interface: the origin and impact of sex differences in the developing human placenta. Biol Sex Differ. 2022;13: 1–24. pmid:36114567
- 20. Richardson BS, Rajagopaul A, de Vrijer B, Eastabrook G, Regnault TRH. Fetal sex impacts birth to placental weight ratio and umbilical cord oxygen values with implications for regulatory mechanisms. Biol Sex Differ. 2022;13: 1–8. pmid:35768846
- 21. Petry CJ, Hughes IA, Ong KK. Increased basal insulin sensitivity in late pregnancy in women carrying a male fetus: a cohort study. Biol Sex Differ. 2022;13: 1–9. pmid:35509032
- 22. Reynolds SA, Roberts JM, Bodnar LM, Haggerty CL, Youk AO, Catov JM. Fetal Sex and Race Modify the Predictors of Fetal Growth. Matern Child Health J. 2015;19: 798–810. pmid:25030701
- 23. Murphy VE, Gibson PG, Giles WB, Zakar T, Smith R, Bisits AM, et al. Maternal Asthma Is Associated with Reduced Female Fetal Growth. Am J Respir Crit Care Med. 2003;168: 1317–1323. pmid:14500261
- 24. Van Der Vlugt ER, Verburg PE, Leemaqz SY, McCowan LME, Poston L, Kenny LC, et al. Sex- And growth-specific characteristics of small for gestational age infants: A prospective cohort study. Biol Sex Differ. 2020;11: 1–10. pmid:32370773
- 25. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365: 785–789. pmid:15733721
- 26. Steegers EAP, Von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010;376: 631–644. pmid:20598363
- 27. Duley L. The Global Impact of Pre-eclampsia and Eclampsia. Semin Perinatol. 2009;33: 130–137. pmid:19464502
- 28. Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin, Number 222. Obstet Gynecol. 2020;135: e237–e260. pmid:32443079
- 29. Jung E, Romero R, Yeo L, Gomez-Lopez N, Chaemsaithong P, Jaovisidha A, et al. The etiology of preeclampsia. Am J Obstet Gynecol. 2022;226: S844–S866. pmid:35177222
- 30. Brosens I, Brosens JJ, Muter J, Puttemans P, Benagiano G. Preeclampsia: the role of persistent endothelial cells in uteroplacental arteries. Am J Obstet Gynecol. 2019;221: 219–226. pmid:30738027
- 31. Liu Y, Li N, An H, Li Z, Zhang L, Li H, et al. Impact of gestational hypertension and preeclampsia on low birthweight and small-for-gestational-age infants in China: A large prospective cohort study. J Clin Hypertens. 2021;23: 835–842. pmid:33507600
- 32. Bakker R, Steegers EAP, Hofman A, Jaddoe VWV. Blood pressure in different gestational trimesters, fetal growth, and the risk of adverse birth outcomes. Am J Epidemiol. 2011;174: 797–806. pmid:21859836
- 33. Ray JG, Burrows RF, Burrows EA, Vermeulen MJ. MOS HIP: McMaster outcome study of hypertension in pregnancy. Early Hum Dev. 2001;64: 129–143. pmid:11440825
- 34. Reynolds SA, Roberts JM, Bodnar LM, Haggerty CL, Youk AO, Catov JM. Newborns of preeclamptic women show evidence of sex-specific disparity in fetal growth. Gend Med. 2012;9: 424–435. pmid:23217566
- 35. Meakin AS, Cuffe JSM, Darby JRT, Morrison JL, Clifton VL. Let’s talk about placental sex, baby: Understanding mechanisms that drive female- and male-specific fetal growth and developmental outcomes. Int J Mol Sci. 2021;22: 6386. pmid:34203717
- 36. Christians JK, Chow NA. Are there sex differences in fetal growth strategies and in the long-term effects of pregnancy complications on cognitive functioning? J Dev Orig Health Dis. 2022;13: 766–778. pmid:35431021
- 37. National Center for Health Statistics. Vital Statistics Online Data Portal. 2022. Available: https://www.cdc.gov/nchs/data_access/vitalstatsonline.htm.
- 38. Lean SC, Derricott H, Jones RL, Heazell AEP. Advanced maternal age and adverse pregnancy outcomes: A systematic review and meta-analysis. PLoS One. 2017;12: e0186287. pmid:29040334
- 39. Aris IM, Kleinman KP, Belfort MB, Kaimal A, Oken E. A 2017 US reference for singleton birth weight percentiles using obstetric estimates of gestation. Pediatrics. 2019;144: 1–10. pmid:31201230
- 40. Platt RW, Joseph KS, Ananth C V., Grondines J, Abrahamowicz M, Kramer MS. A proportional hazards model with time-dependent covariates and time-varying effects for analysis of fetal and infant death. Am J Epidemiol. 2004;160: 199–206. pmid:15257989
- 41. Joseph KS, Kramer MS. The fetuses-at-risk approach: survival analysis from a fetal perspective. Acta Obstet Gynecol Scand. 2018;97: 454–465. pmid:28742216
- 42. Cooperstock M, Campbell J. Excess males in preterm birth: Interactions with gestational age, race, and multiple birth. Obstet Gynecol. 1996;88: 189–193. pmid:8692499
- 43. Zeitlin J, Ancel PY, Larroque B, Kaminski M. Fetal sex and indicated very preterm birth: Results of the EPIPAGE study. Am J Obstet Gynecol. 2004;190: 1322–1325. pmid:15167836
- 44. Harlow BL, Frigoletto FD, Cramer DW, Evans JK, LeFevre ML, Bain RP, et al. Determinants of preterm delivery in low-risk pregnancies. J Clin Epidemiol. 1996;49: 441–448. pmid:8621995
- 45. Wadhwani P, Saha PK, Kalra JK, Gainder S, Sundaram V. A study to compare maternal and perinatal outcome in early vs. late onset preeclampsia. Obstet Gynecol Sci. 2020;63: 270–277. pmid:32489971
- 46. Tokumasu H, Tokumasu S, Kawakami K. Impact of pre-eclampsia in extremely premature infants: Population-based study. Pediatr Int. 2016;58: 578–583. pmid:26724482
- 47. Basso O, Rasmussen S, Weinberg CR, Wilcox AJ, Irgens LM, Skjaerven R. Trends in fetal and infant survival following preeclampsia. Surv Anesthesiol. 2007;51: 185–186.
- 48. Mondal D, Galloway TS, Bailey TC, Mathews F. Elevated risk of stillbirth in males: systematic review and meta-analysis of more than 30 million births. BMC Med. 2014;12: 220. pmid:25428603
- 49. Broere-Brown ZA, Adank MC, Benschop L, Tielemans M, Muka T, Gonçalves R, et al. Fetal sex and maternal pregnancy outcomes: A systematic review and meta-analysis. Biol Sex Differ. 2020;11: 26. pmid:32393396
- 50. Verburg PE, Tucker G, Scheil W, Erwich JJHM, Dekker GA, Roberts CT. Sexual Dimorphism in Adverse Pregnancy Outcomes—A Retrospective Australian Population Study 1981–2011. PLoS One. 2016;11: e0158807. pmid:27398996
- 51. Mecacci F, Avagliano L, Lisi F, Clemenza S, Serena C, Vannuccini S, et al. Fetal Growth Restriction: Does an Integrated Maternal Hemodynamic-Placental Model Fit Better? Reprod Sci. 2021;28: 2422. pmid:33211274
- 52. Stott D, Nzelu O, Nicolaides KH, Kametas NA. Maternal hemodynamics in normal pregnancy and in pregnancy affected by pre-eclampsia. Ultrasound Obstet Gynecol. 2018;52: 359–364. pmid:28796394
- 53. Stott D, Papastefanou I, Paraschiv D, Clark K, Kametas NA. Longitudinal maternal hemodynamics in pregnancies affected by fetal growth restriction. Ultrasound Obstet Gynecol. 2017;49: 761–768. pmid:27854379
- 54. Perry H, Lehmann H, Mantovani E, Thilaganathan B, Khalil A. Are maternal hemodynamic indices markers of fetal growth restriction in pregnancies with a small-for-gestational-age fetus? Ultrasound Obstet Gynecol. 2020;55: 210–216. pmid:31381215
- 55. Perry H, Binder J, Gutierrez J, Thilaganathan B, Khalil A. Maternal haemodynamic function differs in pre-eclampsia when it is associated with a small-for-gestational-age newborn: a prospective cohort study. BJOG An Int J Obstet Gynaecol. 2021;128: 167–175. pmid:32314535
- 56. Cameron NA, Petito LC, Shah NS, Perak AM, Catov JM, Bello NA, et al. Association of Birth Year of Pregnant Individuals With Trends in Hypertensive Disorders of Pregnancy in the United States, 1995–2019. JAMA Netw open. 2022;5: e2228093. pmid:36001318
- 57. Manuck TA. Racial and ethnic differences in preterm birth: A complex, multifactorial problem. Semin Perinatol. 2017;41: 511–518. pmid:28941962
- 58. Venkatesh KK, Lynch CD, Powe CE, Costantine MM, Thung SF, Gabbe SG, et al. Risk of Adverse Pregnancy Outcomes Among Pregnant Individuals With Gestational Diabetes by Race and Ethnicity in the United States, 2014–2020. JAMA. 2022;327: 1356–1367. pmid:35412565