Introduction
The placenta is an organ for material exchange between the fetus and the mother. To support the health of the pregnant mother and better growth of the fetus during pregnancy, many physiological alterations occur in the mother; these alterations are induced by activated factors, some of which are produced by the fetoplacental unit.1
Previous studies have verified that some activated factors produced by the placenta, including cytokines, and hormones, can obviously affect the maternal physiology and health as well as fetal growth.
Pre-eclampsia (PE) is a serious complication of pregnancy, the incidence of which is estimated to be 3%–5% of pregnancies globally.2 It still remains as a major obstetric problem due to the high prevalence of maternal and fetal mortality/morbidity. Fetal growth restriction (FGR) is another complication of pregnancy, with an incidence rate of 5%–10% in pregnant women. It is the second most frequent cause of fetal mortality. Ischemic placental disease encompasses early-onset PE, late-onset PE, and FGR, which develop due to placental dysfunction.3 Several risk factors for PE, including multiple pregnancy, obesity, short maternal stature, underlying cardiovascular disease, and a history of gestational hypertension or PE, have been identified.4 However, the etiology of PE and FGR remains elusive.
More recently, the effect of the fetal gender on the development of pregnancy-related complications has gained increasing attention. Based on some research on fetal sex and disorders, scholars have found that different patterns of gene and protein expression in the human placenta occur with male vs. female fetuses.5,6 Additional evidence also indicates that changes of maternal physiology in pregnancy are deeply affected by the sex of the fetus to a certain extent.
Furthermore, a number of clinical studies have suggested that the fetal gender significantly exerts an effect on the processes of pregnancy-related disorders. Male fetuses are closely associated with preterm birth, fetal loss, and infant mortality. However, observations concerning the association between PE and fetal gender are still contradictory.7,8 Although many studies have focused on the impact of singleton pregnancies on fetal sex-related maternal disorders, few studies have focused on the association in twin pregnancies. To determine whether the fetal gender affects PE and FGR in China, we retrospectively surveyed the data including singleton and twin pregnancies retrieved from the Guangzhou Medical Center for Critical Pregnant Women, Guangzhou, China, from January 2009 to January 2019.
Materials and methods
General information
This was a 10-year retrospective cohort study conducted at the Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical Center for Critical Pregnant Women, Guangzhou, China, from January 2009 to January 2019. All data were anonymously analyzed with individual patient consent and the study protocol was approved by the Research Ethics Board of the Third Affiliated Hospital of Guangzhou Medical University with ethical number Medical Research 2016 (0406) before the study began. All participants gave written informed consent. The eligibility criteria for recruitment were women who delivered in our hospital, including singleton and twin pregnancies with ages between 18–55 years old, data without fetal sex were excluded.
Data collection
Detailed data of 60,828 pregnancies were recorded, including maternal age, height, body mass index (BMI) before pregnancy, gestational week, number of abortions, history of vaginal delivery and/or cesarean section, mode of conception, level of education, smoking, and drinking. The outcomes of the components of placenta-derived disease, including PE and FGR, were recorded.
Diagnosis
PE was defined as a pregnancy with de-novo hypertension (either systolic blood pressure above 140 mmHg or diastolic blood pressure above 90 mmHg, or both) after 20 weeks of gestation accompanied with proteinuria (protein >300 mg/day) and other organ dysfunction (renal insufficiency, liver damage, uteroplacental dysfunction, hematological or neurological complications, or FGR).9
The onset time of PE was usually not accurate; however, the termination of pregnancy was clear. Therefore, in this study, early-onset PE referred to onset of hypertension and proteinuria beyond 20 weeks of gestation in mothers who needed to deliver before 34 weeks of gestation either for maternal or fetal indications. Late-onset PE did not require delivery before 34 weeks of gestation.3 FGR was defined as a baby whose birthweight was below the 10th percentile of the corresponding gestational week weight.10
Statistical analysis
All data were statistically analyzed by using SPSS Statistics 24 for Windows (IBM, Somers, NY, USA). Categorical variable data were expressed as percentages and were analyzed with the Chi-squared test. The nonparametric Mann–Whitney U-test was applied to analyze continuous variable data. Multivariate analysis was performed to determine the role of fetal gender in PE and FGR. Crude odds ratio (OR) and adjusted odds ratio (aOR), along with the 95% confidence interval (CI), were calculated. The adjustment factors included maternal height, BMI, gestational week of delivery, prior numbers of vaginal deliveries and cesarean sections, mode of conception, and level of education in singleton pregnancies. While in twin pregnancies, the adjustment factors included maternal height, BMI, gestational week of delivery, maternal age, prior numbers of abortions, vaginal deliveries and cesarean sections, and mode of conception. A P < 0.05 was considered as statistically significant.
Results
Distribution of pregnancies
Of the 57,215 singleton and 3738 twin pregnancies, 86 and 39 cases, respectively, were excluded because the fetal gender was not recorded. Thus, the final recruitment size was 57,129 singleton pregnancies and 3699 twin pregnancies.
General characteristics of the singleton pregnancies
Among the singletons, there were 30,336 males and 26,793 females. The average gestational weeks was statistically longer for females (37.86 ± 3.36) weeks than for males (37.64 ± 3.47) weeks (P < 0.05). The BMI of women who delivered females was smaller than delivered males (22.26 ± 3.15) vs. (22.39 ± 3.19), P < 0.05. More women who delivered males had a history of vaginal delivery and cesarean section (P < 0.05). Women who delivered males fetus were more often to accept assisted reproduction technology than those who labored with female fetus (6.7% (2020/30,336) vs. 5.9% (1593/26,793), P < 0.05). The education level in the two groups differed significantly (P < 0.05). The number of abortions, maternal height as well as the history of smoking and drinking did not differ between the two groups.
The effect of fetal sex on the incidence of PE and FGR in singletons
PE was diagnosed in 3516 women (6.2% (3516/57,129)), of whom 1242 (35.3%) had early-onset PE (before 34 weeks of gestation) and 2274 (64.7%) had late-onset PE. The incidence rate of PE was higher in the women who delivered females (6.4% (1713/26,793) vs. 5.9% (1803/30,336), P < 0.05). More pregnant women with a female fetus developed late-onset PE, compared to those with a male fetus (4.2% (1116/26,793) vs. 3.8% (1158/30,336), P < 0.05). FGR was diagnosed in 932 women who delivered a female and in 745 women who delivered a male (3.5% (932/26,793) vs. 2.4% (745/30,336), P < 0.05) (Table 1). There were 626 pregnancies complicated with both PE and FGR.
Table 1 -
Maternal characteristics by fetal gender in singleton pregnancies.
| Variables |
Male (n = 30,336) |
Female (n = 26,793) |
P
|
| Gestational age (weeks) |
37.64 ± 3.47 |
37.86 ± 3.36 |
<0.05 |
| Maternal age |
0.06 |
| <35 years |
24,919 (82.1) |
22,171 (82.7) |
|
| ≥35 years |
5417 (17.9) |
4622 (17.3) |
|
| Maternal height (cm) |
159.34 ± 4.80 |
159.34 ± 4.76 |
0.93 |
| BMI (kg/cm2) |
22.39 ± 3.19 |
22.26 ± 3.15 |
<0.05 |
| Prior abortions |
0.11 |
| 0 |
21,119 (69.6) |
18,882 (70.5) |
|
| 1 |
6185 (20.4) |
5306 (19.8) |
|
| ≥2 |
2980 (9.8) |
2570 (9.6) |
|
| Unknown |
52 (0.2) |
35 (0.1) |
|
| Prior vaginal deliveries |
<0.05 |
| 0 |
23,499 (77.5) |
21,208 (79.2) |
|
| 1 |
5972 (19.7) |
4997 (18.7) |
|
| ≥2 |
865 (2.9) |
588 (2.2) |
|
| Prior cesarean sections |
<0.05 |
| 0 |
25,361 (83.6) |
22,863 (85.3) |
|
| 1 |
4410 (14.5) |
3612 (13.5) |
|
| ≥2 |
565 (1.9) |
318 (1.2) |
|
| Mode of conception |
<0.05 |
| Nature |
28,316 (93.3) |
25,200 (94.1) |
|
| ART |
2020 (6.7) |
1593 (5.9) |
|
| Alcohol |
10 (0) |
7 (0) |
0.63 |
| Smoking |
8 (0) |
7 (0) |
0.87 |
| Level of education |
<0.05 |
| College |
17,719 (58.4) |
15,945 (59.5) |
|
| High school |
4441 (14.6) |
3918 (14.6) |
|
| High school or below |
7718 (25.4) |
6540 (24.4) |
|
| Unknown |
458 (1.5) |
390 (1.5) |
|
| PE |
1803 (5.9) |
1713 (6.4) |
<0.05 |
| Early-onset PE |
645 (2.1) |
597 (2.2) |
0.40 |
| Late-onset PE |
1158 (3.8) |
1116 (4.2) |
<0.05 |
| FGR |
745 (2.4) |
932 (3.5) |
<0.05 |
Data are presented as mean ± SD or n (%).ART: Assisted reproductive technology; BMI: Body mass index; FGR: Fetal growth restriction; PE: Pre-eclampsia; SD: Standard deviation.
Next, we performed multivariate analysis for PE and FGR in singleton pregnancies. The results indicated that a female fetus was an independent risk factor for PE (aOR: 1.169, 95% CI: 1.036–1.319) and FGR (aOR: 1.563, 95% CI: 1.349–1.810) (Table 2).
Table 2 -
Multivariate analysis for PE and FGR in singleton pregnancies.
| Variables |
OR
|
95% CI
|
aOR
∗
|
95% CI
|
| PE |
1.081 |
1.010–1.157 |
1.169 |
1.036–1.319 |
| Early-onset PE |
1.049 |
0.937–1.174 |
1.141 |
1.010–1.292 |
| Late-onset PE |
1.095 |
1.007–1.191 |
1.152 |
1.013–1.310 |
| FGR |
1.431 |
1.298–1.578 |
1.563 |
1.349–1.810 |
aOR: Adjusted odds ratio; BMI: Body mass index; CI: Confidence interval; FGR: Fetal growth restriction; OR: Odds ratio; PE: Pre-eclampsia.
∗Adjusted for BMI, maternal height, gestational weeks, prior numbers of vaginal deliveries/cesarean sections, mode of conception, and level of education.
After adjustment for BMI, maternal height, gestational week, prior numbers of vaginal delivery and cesarean section, mode of conception, and level of education, a female fetus was found to be an independent risk factor for both early-onset (aOR: 1.141, 95% CI: 1.010–1.292) and late-onset PE (aOR: 1.152, 95% CI: 1.013–1.310) (Table 2).
General characteristics of the twin pregnancies
Among the twin pregnancies, 1391 women delivered one male and one female, 1305 women delivered two males, and 1003 women delivered two females. The average time of delivery was (34.34 ± 3.93) weeks, (33.71 ± 4.07) weeks, and (33.91 ± 3.93) weeks for male-female, male-male, and female-female twins, respectively (P < 0.05).
Women with a male-female twin pregnancy were more likely to be ≥35 years old at the time of delivery and to have received assisted reproductive technology than those who delivered two males or two females (23.4% (326/1391) vs. 19.1% (249/1305) vs. 17.5% (176/1003); 75.1% (1045/1391) vs. 50.6% (660/1305) vs. 49.9% (500/1003), P < 0.05, respectively). Numbers of abortions, prior vaginal delivery and cesarean sections in the three groups differed significantly (P < 0.05); however, maternal height, BMI, the history of drinking, smoking, and level of education were not statistically different between groups (P = 0.48, P = 0.72, P = 0.38, P = 0.45, and P = 0.33, respectively) (Table 3).
Table 3 -
Maternal characteristics by fetal gender in twin pregnancies.
| Variables |
Male-female (n = 1391) |
Two males (n = 1305) |
Two females (n = 1003) |
P
|
| Gestational age (weeks) |
34.34 ± 3.93 |
33.71 ± 4.07 |
33.91 ± 3.93 |
<0.05 |
| Maternal age |
<0.05 |
| <35 years |
1065 (76.6) |
1056 (80.9) |
827 (82.5) |
|
| ≥35 years |
326 (23.4) |
249 (19.1) |
176 (17.5) |
|
| Maternal height (cm) |
159.15 ± 4.67 |
159.40 ± 4.66 |
159.39 ± 4.73 |
0.48 |
| BMI (kg/cm2) |
23.24 ± 3.06 |
23.21 ± 3.58 |
23.28 ± 3.34 |
0.72 |
| Prior abortions |
<0.05 |
| 0 |
1115 (80.2) |
970 (74.3) |
765 (76.3) |
|
| 1 |
198 (14.2) |
222 (17.0) |
174 (17.3) |
|
| ≥2 |
78 (5.6) |
113 (8.7) |
64 (6.4) |
|
| Prior vaginal deliveries |
<0.05 |
| 0 |
1220 (87.7) |
1059 (81.1) |
1220 (87.7) |
|
| 1 |
147 (10.6) |
210 (16.1) |
147 (10.6) |
|
| ≥2 |
24 (1.7) |
36 (2.8) |
24 (1.7) |
|
| Prior cesarean sections |
<0.05 |
| 0 |
1306 (93.9) |
1153 (88.4) |
909 (90.6) |
|
| 1 |
78 (5.6) |
142 (10.9) |
91 (9.1) |
|
| 2 |
7 (0.5) |
10 (0.8) |
3 (0.3) |
|
| Mode of conception |
<0.05 |
| Natural |
346 (24.9) |
645 (49.4) |
503 (50.1) |
|
| ART |
1045 (75.1) |
660 (50.6) |
500 (49.9) |
|
| Alcohol |
1 (0.1) |
0 (0) |
0 (0) |
0.38 |
| Smoking |
1 (0.1) |
0 (0) |
0 (0) |
0.45 |
| Level of education |
0.33 |
| College |
762 (54.8) |
655 (50.2) |
532 (53.0) |
|
| High school |
216 (15.5) |
224 (17.2) |
163 (16.3) |
|
| High school or below |
394 (28.3) |
409 (31.4) |
289 (28.8) |
|
| Unknown |
19 (1.4) |
17 (1.3) |
19 (1.9) |
|
| Pre-eclampsia |
175 (12.6) |
164 (12.6) |
157 (15.7) |
0.05 |
| Early-onset PE |
33 (2.4) |
54 (4.1) |
46 (4.6) |
<0.05 |
| Late-onset PE |
142 (10.2) |
110 (8.4) |
111 (10.2) |
0.09 |
| FGR |
117 (8.4) |
102 (7.8) |
96 (9.6) |
0.32 |
Data are presented as mean ± SD or n (%).ART: Assisted reproductive technology; BMI: Body mass index; FGR: Fetal growth restriction; PE: Pre-eclampsia; SD: Standard deviation.
The effect of fetal sex on the incidence of PE and FGR in twins
The incidence of PE was higher in the female-female twin pregnancies than in male-male or male-female pregnancies, respectively; however, the difference was not statistically significant among the three groups (15.7% (157/1003) vs. 12.6% (164/1305) vs. 12.6% (175/1391), P = 0.05). The women who delivered twins of the same gender were more likely to develop early-onset PE (4.6% (46/1003) vs. 4.1% (54/1305) vs. 2.4% (33/1391), P < 0.05). Meanwhile, the incidence rate of late-onset PE was lower in the women who delivered two males compared with those who delivered one female and one male or two females, although there was no statistical difference among the three groups (8.4% (110/1305) vs. 10.2% (142/1391) vs. 10.2% (111/1003), P = 0.09) (Table 3).
Unlike singleton pregnancies, the incidence rate of FGR was comparable in the three groups of twins (P = 0.32) (Table 3). Multivariate analysis indicated that female-female twins was an independent risk factor for PE (aOR: 1.367, 95% CI: 1.011–1.849), especially for early-onset PE (aOR: 2.241, 95% CI: 1.041–4.825) (Table 4).
Table 4 -
Multivariate analysis for PE and FGR in twin pregnancies.
|
|
Two males |
Two females |
|
|
|
|
| Variables |
Male-female reference |
OR
|
95% CI
|
aOR
∗
|
95% CI
|
OR
|
95% CI
|
aOR
∗
|
95% CI
|
| PE |
1 |
0.999 |
0.795–1.254 |
1.095 |
0.816–1.470 |
1.290 |
1.022–1.627 |
1.367 |
1.011–1.849 |
| Early-onset PE |
1 |
1.776 |
1.144–2.758 |
1.531 |
0.719–3.260 |
1.978 |
1.255–3.117 |
2.241 |
1.041–4.825 |
| Late-onset PE |
1 |
0.810 |
0.623–1.051 |
0.996 |
0.724–1.368 |
1.095 |
0.842–1.423 |
0.837 |
0.605–1.160 |
| FGR |
1 |
0.923 |
0.700–1.218 |
0.781 |
0.563–1.083 |
1.153 |
0.868–1.530 |
1.004 |
0.720–1.401 |
aOR: Adjusted odds ratio; BMI: Body mass index; CI: Confidence interval; FGR: Fetal growth restriction; OR: Odds ratio; PE: Pre-eclampsia.
∗Adjusted for maternal height, BMI, gestational weeks, maternal age, prior numbers of abortions, vaginal deliveries, and caesareans; and mode of conception.
Discussion
Gender differences exist in many diseases, including hypertension, cardiovascular disease, metabolic diseases, cancer, psychiatric and neurological disorders, and so on. Currently, many researchers have reported associations between sexual dimorphism and several pregnancy complications. In this retrospective 10-year study, we found that in singleton pregnancies, a female fetus was an independent risk factor for PE and FGR. In twin pregnancies, the incidence of PE was the highest in the women who delivered twin females. In our study, the association of PE with the delivery of females in singleton pregnancies was consistent with the results of 219,575 singleton pregnancies analyzed by a meta-analysis including 11 studies.8 Other studies obtained similar results as well. For example, another meta-analysis reported that preterm PE was more prevalent among pregnancies with a female fetus, but no differences were found in the term pregnancies.8 In addition, Liu et al. have indicated that a female fetus is a risk factor for PE at a later gestational age as well as for FGR in northern China.11 Moreover, a nested case–control analysis has suggested that a female fetus is related to early-onset PE.12 In particular, our twin pregnancy analysis results were similar to those of Shiozaki et al., they also reported that the incidence rate of PE was significantly higher in mothers bearing twin girls than in those with twin boys, while those with boy-girl twins were in the middle.13 In contrast, a meta-analysis has shown that a male fetus increases the maternal risk of PE/eclampsia in non-Asian populations.7 For FGR, Liu et al. also found an association of female fetuses with FGR in singleton pregnancies, which is similar to our results.11 However, Stimac et al. have reported that there was no significant difference in FGR between mothers bearing males vs. females. Their data did not support any influence of gender in preterm-birth infants, who are most likely to have FGR.14
To date, the literature still remains contradictory and the mechanisms have not been elucidated. The observed differences between males and females may result from genetics, epigenetics, hormonal secretion, receptor levels, fetal health, and interactions with environmental factors, including diet, infection, stress, drugs, and so on.15
Considering the developmental origin of health and disease, PE and FGR are placenta-derived diseases. Although infections, maternal malnutrition, or chromosomal abnormalities lead to FGR in some cases, placental pathological abnormalities, including defective placentation, abnormal immune response, relative placental hypoxia–ischemia, and oxidative/nitrative stress,16 are believed to cause more cases of FGR and PE, in particular early-onset PE.17
At conception, it has been hypothesized that different hormone concentrations may affect the infiltration of extravillous trophoblasts into the placental bed, resulting in reperfusion damage caused by impaired remodeling of the spiral arteries. Additionally, some researchers have suggested that the concentrations of human chorionic gonadotropin and testosterone affect the maternal blood flow and blood volume expansion in early gestation.18
In PE, ischemia/reperfusion episodes contribute to the development of oxidative stress, which leads to apoptosis, inflammation, and the release of some antiangiogenic factors.19 Pregnancies with FGR are also associated with oxidative stress. For example, Madeleneau et al. have shown that some genes involved in mitochondrial function and oxidation as well as protein phosphorylation were decreased in human placentas with intrauterine growth restriction.20 In addition, Ghidini and Salafia have shown more aggressive immune responses against invading interstitial trophoblasts in pregnancies with male fetuses. As PE has been identified as an inflammatory state, it is possible that the placental immune system is sexually dimorphic. Similarly, Veerbeek et al. have observed some inflammatory changes in pregnancies complicated with early FGR. Their study showed that the levels of chronic chorioamnionitis were higher in pregnancies with early FGR and hypertensive disease.17 Moreover, microarray analysis has identified that in the global transcriptomic profile, more immune-regulating genes were upregulated in placentas with a female fetus.
To some extent, early FGR coincides with severe PE, which share similar placental changes.4 However, it is not clear whether the placental pathologies of these two conditions are associated or different. More recently, some studies have indicated different placental abnormalities between early-onset and late-onset PE and FGR.21 Further studies are needed to clarify these findings.
Currently, sexual dimorphism in placental development is gaining increasing interest. Traditionally, the placenta has been considered as an asexual organ. However, according to its extraembryonic origin, the placenta has a sex. More and more results have demonstrated differences between a male placenta and a female placenta. Barapatre et al. have reported that the number of nuclei of nonproliferative cells in the syncytial layer of villous trophoblasts is affected by the fetal sex.22 The number of nonproliferative nuclei (pCNA-negative) in villous trophoblasts of normal female placentas is greater than that of normal male placentas. In addition, Gong et al. have shown that the level of N1, N12-diacetylspermine, a spermine metabolite, is greater in the female placenta and serum of pregnant women who carry a female fetus.23 Additionally, the fetal/placental sex affects immune genes, which interfere with both inflammatory stress and metabolic processes.5 The signaling pathways of insulin/insulin-like growth factor/mitogen-activated protein kinase and transforming growth factor-β were significantly activated in female placenta compared with male placenta. More importantly, Hutter et al. have demonstrated that there is fetal gender-specific expression of tandem-repeat galectins (gal) in FGR placentas.24 They showed that gal-9 and gal-12 were elevated in the extravillous trophoblast cells and endothelial cells in intrauterine growth retardation pregnancies with female fetus, in contrast, gal-4, gal-8, and gal-9 in the intrauterine growth retardation trophoblast of male fetuses were down-regulated significantly.
One potential mechanism of sex-dependent placental differences is sex chromosomes. In males, X chromosomes are active, including in the placenta; however, in females, one of the two X chromosomes is randomly inactivated to ensure equivalent levels of X-linked gene expression between females and males. In the X chromosome, there are a number of trophoblast-specific genes, such as Esx1, which are associated with the onset of placenta hyperplasia. Differential expression of placental genes may be due to X-inactivation escape of select transcripts from the paternal or maternal X chromosome, which may in turn regulate the expression of autosomal genes. Y chromosomal disruptions are also linked with placental dysplasia.25 Further research is needed to determine whether other X-associated genes may be incompletely inactivated and whether specific genes in the Y chromosome account for sexual dimorphism in placental diseases.
Our study has some limitations. First, this is a retrospective and single-center study which potentially lacks of generalizability. Second, there are some other cofounders which may influence the incidence of PE and FGR, such as history of PE. They are not included in our study.
In conclusion, this retrospective cohort study in our center showed that female fetus was associated with PE in both singleton and twin pregnancies and was also a risk factor of FGR in singleton pregnancies. This may reveal an underlying mechanism of PE and FGR related with sexual dimorphism for further study.
Acknowledgments
The authors would like to thank Medjaden Bioscience Limited for its linguistic assistance to edit and proofread this manuscript.
Funding
This study is supported by the National Key R&D Program of China (No. 2016YFC1000405, 2017YFC1001402, 2018YFC1004104, and 2018YFC10029002) and the National Natural Science Foundation (No. 81830045, 81671533, 81571518, and 81971415). General program of Guangdong province Natural Science Foundation (No. 2020A1515010273).
Author Contributions
Lili Du and Dunjin Chen conceptualized the project and participated in research design. Shilei Bi, Lizi Zhang, and Zhijian Wang oversaw the data collection, analyzed the data, and drafted the manuscript. Jingman Tang, Sushan Xie, Jingjin Gong, Lin Lin, Luwen Ren, Lijun Huang, Shanshan Zeng, and Jingsi Chen help to collect data and data analysis.
Conflicts of Interest
None.
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