Male newborn as a determinant of severe preeclampsia: a case-control study

Abstract

The association between newborn sex and preeclampsia has not yet been fully investigated. The current study was conducted to assess the association between newborn sex and severe preeclampsia among women in eastern Sudan. A prospective case-control study (300 cases and 600 controls) was conducted at Gadarif Maternity Hospital in eastern Sudan. The cases were women with severe preeclampsia, while the controls were healthy women. Questionnaires were used to collect sociodemographic, clinical, and obstetric data by face-to-face interview, and multivariate binary regression was performed. Parity was significantly lower, whereas the body mass index (BMI) was significantly higher in the cases compared to the controls. Significantly more cases than controls gave birth to a male newborn (209 [69.7%] vs. 327 [54.5%], p ˂ 0.001). The multivariate logistic regression showed that women who gave birth to a male newborn had higher odds of developing severe preeclampsia (adjusted odds ratio [AOR] = 1.65, 95% confidence interval [CI] = 1.14 − 2.39). Other factors that were associated with the development of severe preeclampsia were primiparous (AOR = 2.43, 95% CI = 1.54 − 3.83), increasing BMI (AOR = 1.12, 95% CI = 1.07 − 1.17), lower level of education (AOR = 31.9, 95% CI = 18.50 − 55.15), and housewives (AOR = 3.82, 95% CI = 1.74 − 8.41). The study revealed that women who gave birth to a male newborn were at higher risk of having severe preeclampsia than those who gave birth to a female newborn.

Introduction

Fetal sex determination helps identify fetuses at risk of X-linked recessive disorders and can help predict pregnancy outcomes¹. Several studies have shown that the sex of the fetus or newborn is associated with different obstetric and perinatal outcomes^2–4. For example, a large study conducted between 2010 and 2018 reported that there was a higher risk of stillbirth and early neonatal death among male infants compared to female infants². Associations between sex and gestational diabetes, placental malaria^5,6, vitamin D metabolism in the placenta, preterm labor, failure of progression during labor, true umbilical cord knots, nuchal cord, cord prolapse, and rate of cesarean deliveries³ have also been reported.

Preeclampsia involves the occurrence of hypertension and dysfunction of one or more end organs⁷. It affects 2–8% of pregnant women and is responsible for 10–15% of direct maternal deaths, and the majority of the deaths occur in low-income countries⁴. Despite the extensive knowledge available on the clinical presentation, diagnostic criteria, and management of preeclampsia, the etiology is still not fully understood⁸. Moreover, there is no optimum screening model for identifying all patients who will develop preeclampsia. Nevertheless, the American College of Obstetrics and Gynecology (ACOG) has determined a set of risk factors for preeclampsia, including diabetes mellitus, renal disease, chronic hypertension, multifetal gestation, prior preeclampsia, and autoimmune disease⁹. In addition, different risk factors have been found in diverse populations^10–14. Identifying women who are exposed to these risk factors and thus vulnerable to developing preeclampsia can result in them receiving optimum prenatal care or even the use of preventive measures.

There are differing reports of the level of association between fetal sex and preeclampsia. While some studies have shown that carrying a male fetus increases the risk of preeclampsia^1,15, others have shown that carrying a female fetus increases the risk of preeclampsia^16,17. A further set of studies has shown no association between the sex of the newborn and preeclampsia^18–20. Notably, none of these studies was conducted in Sub-Saharan Africa, including Sudan, the third largest country in Africa.

In Sudan, preeclampsia is a leading health problem, and different determinants have been identified, such as genetic¹⁰ and nutritional¹¹ factors, as well as associations with bacterial, parasitic, and viral infections^12,13. Preeclampsia and eclampsia are responsible for one-fifth of maternal deaths among Sudanese women²¹. In 2023, the sex ratio at birth (male births per female births) in Sudan was 1.041²². Hence, this study aimed to assess the association between newborn sex and severe preeclampsia in women in eastern Sudan.

Methods

Study area

Gadarif Maternity Hospital is located in the city of Gadarif and is the largest government-run maternity hospital in eastern Sudan. It provides services to all women in the state of Gadarif. The hospital’s antenatal and postnatal clinics offer free services.

Subjects and study design

A case-control study involved women who attended the delivery room in Gadarif Maternity Hospital between May 2021 and August 2023. The guidelines of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative²³ were strictly followed in this study.

Inclusion and exclusion criteria

All Sudanese women who gave birth to a singleton baby after 20 weeks of gestation in Gadarif Maternity Hospital during the study period and who agreed to participate were enrolled in the study. The cases were women with severe preeclampsia, which refers to preeclampsia with one of the following features: severe headache, altered cerebral or visual disturbance, hepatic abnormality, renal abnormality, severe hypertension (≥ 160/110 mmHg), thrombocytopenia (< 100 × 10⁹ platelets/L)⁷.

Two consecutive women were the controls, healthy women who gave birth in the same hospital. Women with systemic disease, with multiple gestations in the current pregnancy (could have born male and female newborns at the same time), and whose fetus had a major congenital malformation were excluded from both the cases and controls. Also, women who refused to participate or could not communicate were excluded.

Sample size

The sizes of the case (n = 300) and control (n = 600) groups were calculated using the case-control study formula²⁴, and a control-to-case ratio of 2:1 was achieved. The findings of a previous meta-analysis showed that the probability of giving birth to a male newborn is higher (51.2%) in women with preeclampsia²⁵, were also taken into account. Therefore, we assumed that 50.0% of women carrying male fetuses would have preeclampsia and that 30.0% would not have preeclampsia. The sample size (300 cases and 600 controls) was used to achieve 80% power and 5% precision; it was assumed that 10% of the women would not respond or would have incomplete data.

Data collection

After the participants signed an informed consent form, they were interviewed by two female medical officers face-to-face. A questionnaire was utilized during the interviews (during the delivery) to collect data on various sociodemographic characteristics, including age, parity, residence, occupation (housewife, employed), educational level (≥ secondary was 8-year and < secondary level), and the newborn’s sex. Each participant’s weight was measured using the standard methods (Seca, Deutschland, Germany), and height was measured using a Seca stadiometer (Shorr Board, Olney, MD, USA). Body mass index (BMI) was computed by dividing the weight in kilograms by the height in meters squared (BMI = kg/m²).

Data analysis

Version 22.0 of the Statistical Package for the Social Sciences^® (SPSS^®) for Windows (SPSS Inc., New York, United States) was used to analyze the data. Categorized data are expressed as frequencies (%) and were compared between the two groups using a chi-square test. The normality of continuous data was assessed using the Shapiro–Wilk test; the data were not normally distributed and were expressed as medians (interquartile ranges [IQRs]) and were compared between the cases and the controls using the Mann-Whitney U test. Univariate analysis was conducted with preeclampsia as the dependent variable. The independent variables were age, parity, BMI, educational level, residence, occupation, and sex of the newborn. Variables with a P-value < 0.05 were used to build a multivariate model to rule out confounders. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated as they were applied. A two-sided P-value of < 0.05 was considered statistically significant.

Results

The participants of this study consisted of 300 women in the case group and 600 women in the control group. There was no significant difference in age between the two groups (P = 0.994). Compared with the controls, the median (IQR) of the BMI was significantly higher in the cases [25.91(24.03 − 29.36) kg/m² versus 25.39 (23.14 − 27.66) kg/m², p = 0.002]. There was a significantly higher proportion of primiparous in the case group than in the control group [72/300 (24.0%) vs. 60/600 (10.0%), p < 0.001]. Moreover, a significantly higher proportion of cases had lower education levels and lived in rural areas. There was a significantly higher proportion of males born to the women in the case group than to those in the control group [209/300 (69.7%) vs. 327/600(54.5%), p ˂ 0.001], Table 1.

Table 1.

Comparing the factors associated with severe preeclampsia in women in Eastern sudan, 2021–2022, using the chi-squared test.

Variable		Women with preeclampsia N = 300	Controls N = 600	P value
		Frequency (proportion)
Parity	Primiparous	72(24.0)	60(10.0)	< 0.001
	Multiparous	228(76.0)	540(90.0)
Maternal education level	≥ secondary	31 (10.3)	405 (67.5)	< 0.001
	< secondary	269 (89.7)	195 (32.5)
Residence	Urban	96 (32.0)	312 (52.0)	<0.001
	Rural	204 (68.0)	288 (48.0)
Maternal employment status	Employed	15 (5.0)	57 (9.5)	0.019
	Housewife	285 (95.0)	543 (90.5)
Sex of newborn	Male	209 (69.7)	327 (54.5)	< 0.001
	Female	91 (30.3)	273 (45.5)

As shown in Table 2, the univariate analysis results indicated that primiparous (OR = 2.84, 95% CI = 1.95 − 4.13), increasing BMI (OR = 1.05, 95% CI = 1.02 − 1.09), lower education level (OR = 18.02, 95% CI = 11.97 − 27.13), being a housewife (OR = 1.99, 95% CI = 1.10 − 3.58), living in a rural area (OR = 2.30, 95% CI = 1.72 − 3.07), and having a male newborn (OR = 1.92, 95% CI = 1.43 − 2.57) were associated with severe preeclampsia.

Table 2.

Univariate and multivariate analysis of factors associated with severe preeclampsia in women in Eastern sudan, 2021–2022.

Variable		Univariate analysis		Multivariate analysis
		Odds ratio (95% confidence interval)	P value	Adjusted odds ratio (95% confidence interval)
Maternal age, years		1.00 (0.97–1.02)	0.994
Body mass index, kg/m2		1.05 (1.02 − 1.09)	0.002	1.12(1.07 − 1.17)	< 0.001
	Frequency (proportion)
Parity	Primiparous	2.84 (1.95 − 4.13)	< 0.001	2.43 (1.54 − 3.83)	< 0.001
	Multiparous	Reference		Reference
Maternal education level	≥ secondary	Reference	< 0.001	Reference	< 0.001
	< secondary	18.02 (11.97 − 27.13)		31.9(18.50 − 55.15)
Residence	Urban	Reference	< 0.001	Reference	0.474
	Rural	2.30 (1.72 − 3.07)		1.15(0.77 − 1.72)
Maternal employment status	Employed	Reference	0.021	Reference
	Housewife	1.99 (1.10 − 3.58)		3.82(1.74 − 8.49)
Sex of newborn	Male	1.92 (1.43 − 2.57)	0.001	1.65(1.14 − 2.39)	0.008
	Female	Reference		Reference

The multivariate logistic regression analysis results, which are shown in Table 2, indicated that that primiparous (AOR = 2.43, 95% CI = 1.54 − 3.83), increasing BMI (AOR = 1.12, 95% CI = 1.07 − 1.17), lower level of education (AOR = 31.9, 95% CI = 18.50 − 55.15), housewives (AOR = 3.82, 95% CI = 1.74 − 8.41, p = 0.001), and male newborn (AOR = 1.65, 95% CI = 1.14 − 2.39, p = 0.008) were associated with preeclampsia. Residence was not associated with preeclampsia (AOR = 1.16, 95% CI = 0.78 − 1.72, p = 0.474). Thirty-five (11.7) women had early (< 34 weeks of gestation) severe preeclampsia. The women with early preeclampsia delivered a similar proportion of male newborns as the women with late preeclampsia (early: 24/35 [68.5%] vs. late: 185/265 [69.8%], P = 0.880).

Discussion

In this study, women who gave birth to a male newborn had 1.65 times higher odds of developing severe preeclampsia than those who gave birth to a female newborn. Moreover, a similar proportion of male newborns was delivered by women with early-onset preeclampsia as by women with late-onset preeclampsia. Similarly, Mirzakhani et al.¹⁵ found that Black Americans who carried male fetuses had a higher chance of developing preeclampsia; however, they failed to see such an association in White Americans. A meta-analysis of 22 studies and 3,163,735 women showed a significant association between male fetal sex and preeclampsia²⁶.

It has been suggested that the time of onset of preeclampsia may influence the association between fetal sex and preeclampsia: a predominance of female newborns has been reported in early-onset cases and of male newborns in late-onset cases^1,25,27. More specifically, Taylor et al.²⁷ found that women with preeclampsia before 34 weeks of gestation had higher odds of carrying a female fetus. In addition, an analysis of 11 studies and 219,575 pregnancies revealed a prevalence of preterm preeclampsia in women carrying female fetuses, but there was no difference in the female/male distribution among women with term preeclampsia (delivered ≥ 37 weeks)²⁵. Similarly, in a meta-analysis that included 74 studies and 12.5 million women, Brown et al.¹ concluded that the male fetal sex was associated with total preeclampsia and late-onset preeclampsia and that the female fetal sex was associated with early-onset preeclampsia.

In contrast to our findings, a large study that included 29,140 delivering women in Tripoli, Libya, reported that preeclampsia was associated with preterm female newborns and that preeclampsia was more frequent among women who delivered post-term male newborns²⁸. A large population-based cohort study conducted in China showed that women with preeclampsia had a lower probability of giving birth to a male newborn²⁹, and a nationwide survey conducted in Taiwan that included 1,347,672 live births showed that more female births were associated with preeclampsia¹⁶. Furthermore, in a large study conducted in South China, it was found that preeclampsia occurred in 1.8% of 6,223 pregnancies and that it was associated with female newborns³⁰. In northern China, female fetuses have been associated with an increased risk of preeclampsia³¹, and in Japan, female fetal sex was found to be a risk factor for preeclampsia³².

Female fetuses were associated with preeclampsia in singleton and twin pregnancies in a 10-year single-center retrospective cohort study¹⁷. Furthermore, Funaki et al.³³ studied the association between fetal sex and pregnancy outcome in twin pregnancies. They revealed that women with female/female dichorionic diamniotic twins had a higher risk of preeclampsia than women with male/male dichorionic diamniotic twins and that the risk of preeclampsia was not affected by the fetal sex in monochorionic diamniotic twins. In previous studies, we found that the occurrence of preeclampsia was not related to the sex of the newborn^18–20, and these findings aligned with those of a study conducted in 39 hospitals in mainland China that included 109,722 women and showed no relationship between the sex of the newborn and preeclampsia³⁴. The sociodemographic and genetic differences in the studied populations could explain the differences in the findings of the studies.

In general, the pathogenesis of preeclampsia remains unexplained, and the cellular and molecular mechanisms underlying the condition are poorly understood. Evidence suggests that early-onset preeclampsia occurs due to the failure of the cytotrophoblast to acquire the normal invasive phenotype, which leads to a lack of the required anastomosis and a subsequent reduction in uteroplacental perfusion. In response to the resultant ischemia, the placenta releases pro-inflammatory and anti-angiogenic proteins into the maternal circulation (e.g., soluble fms-like tyrosine kinase 1 and soluble endoglin) that ultimately induce endothelial dysfunction. The anti-angiogenic proteins released by the placenta play a crucial role in developing preeclampsia^9,35,36. Late-onset preeclampsia may be caused by interactions between normal placental aging and a maternal genetic predisposition to vascular and metabolic disorders³⁷.

Maternal circulating sex steroids are essential determinants of uterine blood flow and placental vasculature during the early stages of pregnancy. Moreover, they are crucial regulators of various maternal and placental functions. For example, androgens increase the vascular resistance of the uterus, whereas progesterone and estrogens decrease uterine vessel resistance. Progesterone and estrogens also modulate the synthesis of the placenta and the release of angiogenic factors, which regulate uterine vessel remodeling and trophoblastic invasion³⁸. Toriola et al.³⁹ found that fetal gender is a determinant of sex steroid concentrations during the first half of singleton pregnancies; therefore, fetal gender may be an essential determinant of all placental pathologies, including preeclampsia.

Fetal sex determination may improve the prediction of preeclampsia. However, the exact role that the sex steroids’ hormonal milieu plays in placentation and the subsequent release of anti-angiogenic proteins and, thus, in the pathogenesis of preeclampsia remains unclear and requires further examination. In the current study, primiparous, level of education, occupation, and BMI were associated with preeclampsia. These findings align with several previous studies that showed associations between parity, education⁴⁰, and a higher BMI¹⁴ and preeclampsia.

Limitations

Women were enrolled and assessed at one point in the hospital. Perhaps some women had delivered at home, and we did not know their maternal and perinatal outcomes. This study might not reflect the actual situation in the community regarding the male-to-female ratio. A longitudinal study is needed. The hormones and cytokines were not assessed, which could have explained the associations of these biomarkers of preeclampsia and the sex ratio.

Conclusion

The current study showed that women who gave birth to a male newborn had 1.65 times higher odds of developing preeclampsia than those who gave birth to a female newborn. Also, parity, BMI, education level, and occupation were strong determinants of preeclampsia, while age and residence were not statistically significantly associated with preeclampsia in our cohort.

Author contributions

GKA: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. KN: Data curation, Conceptualization, Writing – original draft. OM: Conceptualization. IA: Conceptualization, Methodology, Writing – review & editing, Supervision.

Data availability

The data supporting the current study’s findings are available from the corresponding author upon reasonable request.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study received ethical approval from the Faculty of Medicine Research Board, University of Gadarif, Sudan (reference number 2021, #6). Written informed consent was obtained from all the enrolled women in accordance with the Human Rights Declaration of Helsinki.