https://orcid.org/0000-0003-4826-1683
Abstract
Objectives
Among many risk factors for preeclampsia (PE), prepregnancy body mass index (BMI) is one of few controllable factors. However, there is a lack of stratified analysis based on the prepregnancy BMI. This study aimed to determine the influencing factors for PE and assess the impact of PE on obstetric outcomes in twin pregnancies by prepregnancy BMI.
Methods
This was a retrospective cohort study between January 1, 2017, and December 31, 2022, in Southwest China. Impact factors and associations between PE and obstetric outcomes were analyzed separately for twin pregnancies with prepregnancy BMI < 24kg/m2 (non-overweight group) and BMI ≥ 24kg/m2 (overweight group).
Results
In total, 3602 twin pregnancies were included, of which, 672 women were allocated into the overweight group and 11.8% of them reported with PE; 2930 women were allocated into the non-overweight group, with a PE incidence of 5.6%. PE had a negative effect on birthweight and increased the incidence of neonatal intensive care unit admission in both the overweight and non-overweight groups (43.0% vs. 28.0%, p = .008; 45.7% vs. 29.1%, p < .001). Among overweight women, PE increased the proportion of postpartum hemorrhage (15.2% vs. 4.4%, p < .001). After adjustments, multivariate regression analysis showed that excessive gestational weight gain (aOR = 1.103, 95% CI: 1.056–1.152; aOR = 1.094, 95% CI: 1.064–1.126) and hypoproteinemia (aOR = 2.828, 95% CI: 1.501–5.330; aOR = 6.932, 95% CI: 4.819–9.971) were the shared risk factors for PE in both overweight and non-overweight groups. In overweight group, in vitro fertilization was the other risk factor (aOR = 2.713, 95% CI: 1.183–6.878), whereas dichorionic fertilization (aOR = 0.435, 95% CI: 0.193–0.976) and aspirin use during pregnancy (aOR = 0.456, 95% CI: 0.246–0.844) were protective factors. Additionally, anemia during pregnancy (aOR = 1.542, 95% CI: 1.090–2.180) and growth discordance in twins (aOR = 2.451, 95% CI: 1.215–4.205) were connected with an increased risk of PE only in non-overweight twin pregnancies.
Conclusions
Both discrepancy and similarity of impact factors on developing PE were found between overweight and non-overweight twin pregnancies in this study. However, the dosage and initiation time of aspirin, as well as twin chorionicity on the occurrence of PE in two subgroups, are still debated.
Introduction
Hypertensive disorders of pregnancy (HDP), a group of diseases coexisting with pregnancy and elevated blood pressure, includes gestational hypertension, preeclampsia (PE), eclampsia, chronic hypertension with superimposed preeclampsia and pregnancy with chronic hypertension. PE, in particular, has the highest mortality among the HDP [Citation1]. According to statistics, PE affects approximately 10 million pregnant women and is responsible for 76 thousand maternal deaths per year worldwide [Citation2]. In China, its prevalence is 2% to 8% among all pregnant women annually, and it is a major contributor to perinatal and long-term morbidity of the mother and offspring [Citation3]. The pathogenesis of PE is not completely understood; however, its risk factors, including advanced maternal age, primiparity, obesity, basic medical diseases and pathological conditions such as autoimmune disease and abnormal cardiac function, have been extensively studied [Citation4, Citation5].
With the extensive popularization and application of assisted reproductive technology, mainly in vitro fertilization (IVF), in recent years, the incidence of twin pregnancies has increased by up to 70% [Citation6]. But it is well known that twin pregnancies pose a high risk of PE, with the rate being two- to fivefold higher than that of singleton pregnancy; furthermore, the progression and severity of PE are, respectively, earlier and greater in twin pregnancies [Citation7]. In the population of twin pregnancies, on the other hand, the rates of adverse pregnancy outcomes, maternal death, prematurity, low birthweight newborns and various neonatal complications such as neonatal asphyxia, neonatal pneumonia and septicemia, increase significantly under the influence of PE [Citation8]. Some features for twin pregnancies such as monochorionicity, IVF, and growth discordance between twins, may be reminders for the high-risk of increasing blood pressure during pregnancy, while their relevance with PE is elusive, still needing to be clarified by larger samples of studies [Citation9]. In conclusion, there are no clear guidelines or consensus to systematically summarize the impact factors for PE in twin pregnancies.
Epidemiological studies have revealed that overweight and obesity can result in pregnancy complications and adverse perinatal outcomes, especially leading to increased blood pressure, further enhancing the risk of PE [Citation10]. Notably, for twin pregnancies, overweight and obesity may increase the PE risk by 1.37 times [Citation11]. A possible explanation is that PE is associated with higher and/or lower mean levels of many of the same metabolites as obesity, which include five lipoprotein subclasses, total triglycerides and triglycerides in monounsaturated fatty acids, very low density lipoprotein, leucine and isoleucine, and the associations remain significant after full adjustment [Citation12]. Body mass index (BMI), a statistical index, is utilized to estimate body fat in people of any age and is calculated by taking weight (kilograms) divided by height (meters) squared, and BMI = weight (kg)/height2 (m2). The WHO classification criteria are as follows: (1) overweight—BMI greater than or equal to 25 to 29.9 kg/m2 and (2) obesity—BMI greater than or equal to 30 kg/m2 [Citation2, Citation13]. Based on the population characteristics, however, a different grading standard of BMI in China has been made: (1) overweight—BMI greater than or equal to 24 to 27.9 kg/m2 and (2) obesity—BMI greater than or equal to 28 kg/m2 [Citation2, Citation14].
Among those influencing factors for PE mentioned above, prepregnancy BMI is a controllable and changeable factor. Identifying its effect on PE can help obstetrical medical staff provide personalized preconception care and strengthen nutrition and weight management, so as to reduce the risk of PE and ensure the health and well-being of the mothers. But there is a lack of stratified analysis based on the prepregnancy BMI of Chinese women expecting twins. In view of the BMI classification standards in China differing from that in other developed countries, a scientific analysis of the impact factors and obstetric outcomes of PE in twin pregnancies on the basis of prepregnancy BMI in accordance with Chinese grading standards would provide more specific information.
Based on whether the prepregnancy BMI was greater than or equal to 24 kg/m2 (overweight and non-overweight groups), we performed a 6-year retrospective cohort of pregnant women with twins to determine valuable influencing factors of PE and compare the impact of PE on obstetric outcomes in twin pregnancies.
Methods
Participants and study design
In this retrospective cohort study, women with twin pregnancies who were monitored prenatally and delivered in Chongqing Health Center for Women and Children, an institute of genetics and reproduction with approximately 17,000 ∼ 18,600 deliveries per year in Southwest China, were recruited from January 1, 2017, to December 31, 2022. The inclusion criterion was Chinese pregnant women with twins who were at least 18 years old. The exclusion criteria were (1) one fetus with intrauterine death or multifetal pregnancy reduction; (2) abortion; (3) hypertension diagnosed before pregnancy; and (4) singleton pregnancy or multiple pregnancy. Participants were divided into an overweight group and a non-overweight group based on their prepregnancy BMI, and they were further allocated into a PE group and a non-PE group.
This study was approved by the medical ethics committee of Chongqing Health Center for Women and Children (approval number: 2022-011). We informed all participants that their data could be used to conduct medical practices and that all information that could identify participants would not be disclosed.
Data collection
Using the electronic medical record system, three well-trained researchers collected the data of participants who met the inclusion and exclusion criteria and reviewed the data for accuracy. It included mainly maternal characteristics, pregnancy complications and neonatal outcomes. The maternal characteristics included maternal age, gravidity, prepregnancy BMI, gestational weight gain, mode of conception, chorionicity, gestational age at delivery and information of taking aspirin during pregnancy. The pregnancy complications included anemia during pregnancy, hypoproteinemia, gestational hypothyroidism, postpartum hemorrhage (PPH), gestational diabetes mellitus (GDM), intrahepatic cholestasis during pregnancy (ICP), and placental-related diseases, including placenta previa and placental implantation. Neonatal outcomes included birthweight, growth discordance in twins, and admission to the neonatal intensive care unit (NICU).
Relative definitions
PE is characterized by new-onset hypertension after 20 gestational weeks with proteinuria, organ injury or uteroplacental dysfunction and diagnosed by an experienced obstetrician according to the Chinese Guidelines for the Diagnosis and Treatment of Hypertensive Diseases during Pregnancy [Citation15]. Based on the International Association of Diabetes in Pregnancy Study Groups criteria, GDM refers to any degree of glucose intolerance with new-onset recognition during pregnancy [Citation16]. The diagnosis of ICP is considered in pregnant women who have itching in skin of normal appearance and raised peak random total bile acid concentration of 19 micromol/L or more according to the Royal College of Obstetricians and Gynecologists guidelines for intrahepatic cholestasis of pregnancy [Citation17]. Growth discordance in twins, a unique complication of multiple pregnancies, is defined as a twin birth weight difference ≥20% (larger fetal birth weight—small fetal birth weight/larger fetal birth weight × 100%) [Citation18].
Statistical analysis
Statistical analysis was conducted by SPSS version 25.0 (IBM, Armonk, NY, USA). The Shapiro–Wilk test was used to assess the normality of the data, and data were expressed as the mean and standard deviation (SD) if continuous variables conformed to a normal distribution; for comparisons between groups, an independent t test was used. If the data did not conform to a normal distribution, they were represented by the median and interquartile interval (M (Q1, Q3)), and the Wilcoxon rank-sum test was used for intergroup comparisons. Categorical variables were expressed as numbers and percentages (%), and the chi-square test was used for comparisons between groups. The adjusted odds ratio (aOR) and 95% confidence interval (95% CI) were calculated for risk factors for PE. A two-tailed p < .05 was considered statistically significant.
Results
Maternal characteristics of study participants
Our study involved 3845 twin pregnancies in total. We excluded 243 cases, including 111 with preexisting hypertension, 55 with abortion, 67 in which there was one fetus with intrauterine death, and 10 with missing data. Finally, a total of 3602 participants were enrolled in this study ().
Figure 1. Study flow-chart.
The maternal characteristics are presented in . In total, 672 women were overweight before this gestation (prepregnancy BMI≥ 24 kg/m2), in this group, of whom 79 (11.8%) reported with PE. On the other side, the number of women in the non-overweight group (prepregnancy BMI< 24 kg/m2) was 2930, of whom 164 (5.6%) reported with PE. Obviously, the rate of PE in the overweight group was higher than that in the non-overweight group (11.8% vs. 5.6%). First of all, in the overweight group, women who were not diagnosed as PE had a lower prepregnancy BMI (M (Q1, Q3) (25.24 (24.46, 26.67) vs. (25.80 (24.64, 27.38)), p = .029) and less gestational weight gain (mean (SD)15.06 (5.89) vs. 18.11 (5.01), p < .001) than women diagnosed with PE. Similar findings were observed in the non-overweight group: (M (Q1, Q3) (20.58 (19.20, 22.03) vs. (21.30 (19.88, 22.43)), p = .001), (mean (SD) 16.91 (5.28) vs. 19.37 (5.39), p < .001). Second, with respect to the non-overweight group, gestational age at delivery was lower in the PE group than in the non-PE group (mean (SD) 35.57 (1.42) vs. 35.83 (2.15), p = .030). Moreover, it was worth noting that there was obviously significant difference in aspirin use during pregnancy in overweight group (p = .002), however, it was not found in the non-overweight group (p = .377). Finally, there was no significant difference in maternal age, gravidity, percentage of primipara, height, conception mode and chorionicity in two groups (p > .05).
Table 1. Maternal characteristics of study participants.
Pregnancy complications and neonatal outcomes of study participants
The pregnancy complications and neonatal outcomes were analyzed in . In the overweight group, twin-pregnant women who were not diagnosed with PE had a lower likelihood of hypoproteinemia and PPH than women with PE (9.6%, vs. 24.1%, p < .001; 4.4% vs. 15.2%, p < .001). On the other hand, among non-overweight women, the rates of hypoproteinemia, anemia during pregnancy and ICP in women reported with PE were significantly higher than those among women in the non-PE subgroup (42.7% vs. 9.6%, p < .001; 40.9% vs. 25.8%, p < .001; 23.2% vs. 16.6%, p = .029). Furthermore, it was found that regardless of overweight status, twin offsprings delivered from PE pregnancies had a lower birthweight and a higher incidence of NICU admission than those born from non-PE pregnancies. No significant difference was found between the PE and non-PE subgroups in either overweight or non-overweight participants regarding the rate of placenta previa, placental implantation, GDM, gestational hypothyroidism or growth discordance in twins (p > .05).
Table 2. Pregnancy complications and neonatal outcomes of study participants.
Impact factors for PE in twin pregnancies
After adjusting for maternal age, prepregnancy BMI, gravidity and parity, multivariate regression analysis was performed (). First, for the overweight group, our results demonstrated that gestational weight gain (aOR = 1.103, 95% CI: 1.056–1.152, p < .001), hypoproteinemia (aOR = 2.828, 95% CI: 1.501–5.330, p = .001) and IVF (aOR = 2.713, 95% CI: 1.183–6.878, p = .022) were risk factors for PE, whereas dichorionicity (aOR = 0.435, 95% CI: 0.193–0.976, p = .044) and aspirin use during pregnancy (aOR = 0.456, 95% CI: 0.246–0.844, p = .012) were protective factors. Second, in the non-overweight group, risk factors for PE included gestational weight gain (aOR = 1.094, 95% CI: 1.064–1.126, p < .001), hypoproteinemia (aOR = 6.932, 95% CI: 4.819–9.971, p < .001), anemia during pregnancy (aOR = 1.542, 95% CI: 1.090–2.180, p = .014) and growth discordance in twins (aOR = 2.451, 95% CI: 1.215–4.205, p = .028).
Table 3. Impact factors for PE in twin pregnancies of overweight and non-overweight groups.
Discussion
Evidence demonstrated that both prepregnancy BMI and much weight gain during pregnancy were closely connected with PE and maternal - infant outcomes [Citation19]. Clinically, weight management for twin pregnant women is a substantial part of prenatal care. As a result, clarifying the influencing factors of PE in twin-pregnant women who are overweight before this gestation and those who are not is beneficial for taking targeted intervention measures, thus contributing to decreasing the probability of PE.
Researchers proposed that overweight and obesity may lead to larger placenta area in twin pregnancies. In addition, an increase in angiogenic factors caused by enlarged placenta area was mainly related to subsequent events of systemic endothelial dysfunction and excessive inflammatory response, causing vasoconstriction and increased blood pressure, thus inducing PE [Citation20]. Our study indicated that excessive weight gain during gestation was associated with elevated PE risk regardless of whether women were overweight before this conception. As a result, we speculated that excessive gestational weight gain associated with PE risk may be due to higher release of angiogenic factors such as serum soluble fms-like tyrosine kinase-1 (sFlt-1) and serum endoglin (sEng), which are biomarkers for PE [Citation21]. Fortunately, with respect to various risk factors for PE in twin pregnancies, gestational weight gain is a controllable and changeable factor. Obstetricians should comprehensively evaluate the nutritional status of pregnant women and develop personalized pregnancy weight management programs through multidisciplinary team cooperation, particularly for prepregnancy overweight or obese populations.
Serum albumin, the most abundant protein in plasma, is a multifunctional transport protein that is generally considered the major circulating antioxidant in plasma. Studies have found that the lower levels of serum albumin connected with augmenting oxidative stress in pregnant women [Citation22]. Hypoalbuminemia results from serum albumin leaking from the maternal body through urine. The pathogenesis of PE remains unclear, but it is widely thought that the morbidity is related to maternal endothelial dysfunction and the systemic increase in oxygen-derived free radicals, leading to oxidative stress [Citation23]. A previous study reported that serum albumin can inhibit nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in vascular smooth muscle to decrease oxidative stress, and serum albumin in pregnant women has been confirmed to be positively related to endothelial function and inversely related to oxidative stress [Citation24]. Our study revealed that hypoalbuminemia was a shared risk factor for PE both in overweight and non-overweight groups, and one potential explanation was that reduced serum albumin levels will aggravate oxygen-derived free radical production, resulting in maternal vascular endothelial function, thereby increasing the risk of PE. Consequently, pregnant women with hypoalbuminemia are worth attaching importance to obstetric medical staff, and it is necessary to clarify the etiology of hypoproteinemia and take intervention measures as early as possible.
Anemia, a common complication during pregnancy, greatly increases the risk of hypertension during pregnancy due to anemic heart disease that is caused by hypoxia in myocardial cells, and iron deficiency anemia (IDA) is the main form of anemia during pregnancy [Citation25]. Because of the sharp increase in blood volume and the sharper increase in plasma than red blood cells, blood dilution in twin pregnancy is significant; simultaneously, because nutrition must be supplied for two fetuses, the demand for iron is much higher in twin pregnancy than in singleton pregnancy [Citation26]. Lewandowska et al. noted that IDA increases the incidence of PE (experimental group 65% vs. control group 25%, p < .0001) [Citation27]. Our study showed that anemia during pregnancy was a risk factor for PE in non-overweight twin-pregnant women, while the association was null in cases of the overweight group. There are some plausible explanations for this surprising result. First, women who are overweight before this gestation are less likely to suffer from anemia during pregnancy due to the intake of more red meat. Second, Vanderlelie’s study found that taking an iron-rich multimineral supplement in early pregnancy can reduce the risk of PE (OR = 0.67, 95% CI: 0.14–0.75) for overweight women. Prepregnancy BMI < 30 can reduce the risk for PE by 55%, and prepregnancy BMI > 30 was associated with a 62% lower risk of PE; however, the OR did not reach statistical significance for lean women with BMI < 25 (OR = 0.60; 95% CI: 0.39–1.36) [Citation28]. At present, the vast majority of pregnant women start taking iron-rich multimineral supplements in the first trimester, as twins are often “precious babies,” which tends to decrease the risk for PE in the population of overweight pregnant women to a greater extent compared to non-overweight women.
It has been proven that placentas from intertwin weight discordance were more unequally shared and had a higher rate of velamentous cord insertions and a larger diameter of the arterio-arterial anastomosis [Citation29]. Previous studies have provided evidence that growth discordance in twins was strongly associated with early-onset PE [Citation30], and in dichorionic but not in monochorionic twin pregnancy [Citation31]. Moreover, velamentous cord insertions, a major indicator of growth inconsistency, have been verified as a vital risk factor for PE [Citation32]; therefore, umbilical cord abnormalities may affect the association between growth discordance and PE in twin pregnancies. On the basis of these findings, we speculate that the relationship between growth discordance in twins and PE may be caused by the coexistence of multiple factors. Our findings showed that growth inconsistency was an independent risk factor for PE in non-overweight women. However, the association was not significant in the overweight group, so this needs to be explored in further researches with larger samples.
An increasing number of studies have proposed that IVF is a significant risk factor for PE and that the incidence of PE in IVF twin pregnancies is 2.1 times higher than that in natural conception [Citation33, Citation34]. This relationship is further supported by our findings that IVF is related to an increased risk of PE in overweight women, but this association was not significant for non-overweight twin pregnancies. This may be due to the underlying mechanism by which IVF and overweight can jointly induce PE to a certain extent. Some pathophysiological hypotheses have been proposed to clarify the association between IVF and PE. The process of IVF, such as the use of various follicle-stimulating drugs before IVF and luteal support drugs after IVF, is connected with gene expression changes and epigenetic changes in maternal and fetal tissues, and changes in the maternal endometrium lead to trophoblast infiltration and placental dysfunction [Citation35]. Additionally, studies have shown that IVF may lead to ischemic placental diseases [Citation36]. On the other hand, overweight is related to an increase in the placenta area. Both placental ischemia and larger placenta can result in increased release of angiogenic factors such as sFlt-1 [Citation20]. sFlt-1 can lead to placental dysfunction via vasoconstriction and endothelial injury, thereby triggering PE further.
There is controversy over the relationship between PE and chorionicity of twin pregnancies, and published data are conflicting. Some studies indicated that PE occurs more frequently in dichorionic pregnancy than in monochorionic pregnancy because dichorionic pregnancy are more likely to be exposed to fetal antigens or membrane particles via the placenta, leading to a more significant immune response mechanism for the development of PE [Citation37–39]. But on the other, some studies also showed that there was no significant difference in the incidence of PE between dichorionic pregnancy and monochorionic pregnancy [Citation40]. Last but most importantly, it was reported that chorionicity was not a high-risk factor for PE among the Asian population [Citation41]. Our studies showed that dichorionicity was a protective factor for PE in the overweight twin pregnancies but not in the non-overweight group. Therefore, it is necessary to clarify the relationship between chorionicity and PE based on sufficient samples.
Although aspirin is widely considered as the primary treatment for prevention of PE, in recent years, numerous researches have showed that there were controversial results about the low-dose aspirin efficacy on the incidence of PE. Aspirin, given to high-risk women identified in the first trimester, seems to decrease the occurrence of early-onset PE [Citation42]. On the other side, a randomized controlled study involving 11,976 nulliparity women found a decrease in the incidence of early-onset PE in the 81 mg/day aspirin group compared to the placebo group in the first trimester; however, there was no statistically significant difference in the overall incidence of PE [Citation43]. Another study included 107 high-risk pregnant women with PE who took aspirin 80 mg/day and 160 mg/day, respectively, and results suggested that there was no statistically significant difference both in the incidence of PE and early-onset PE between two groups [Citation44]. And our study found that aspirin only made protective effect on developing PE in overweight group, but not among non-overweight women. We proposed some explanations about these mixed results. First, it has been confirmed that the efficacy of aspirin is not to completely inhibit the occurrence of PE, but to delay PE developing until late pregnancy [Citation45]. Owing to twin pregnancies complicating with premature deliveries frequently, women who took aspirin may have not shown symptoms of PE before giving births, so the effect of aspirin could be underestimated. Moreover, considering the aggravated PE risk of overweight itself, overweight women would be required taking aspirin in early stage, which made larger effect of aspirin compared with non-overweight group. Finally, aspirin effect on preventing PE is dose-dependent, and aspirin dose ≥ 100 mg/day may be more effective [Citation46]. But the recommendations for aspirin prophylactic doses are not entirely consistent currently. Chinese guidelines recommend aspirin doses of 50 to 150 mg/day, whereas the dose is less than 100 mg/day in most regions [Citation47, Citation48]. Hence, as the different athophysiology among the prepregnancy BMI subgroups presenting different high-risk factors, the dosing of aspirin needs to be more personalized. Future prospective and large sample studies on twin pregnancies should be carried out to provide high-quality evidence supporting the optimum aspirin dosage for the prevention of PE.
Conclusion
Our study revealed that prepregnancy BMI had an evident modification effect on the impact factors of PE for twin pregnancies. Prepregnancy overweight and non-overweight pregnant women with twins shared some risk factors for PE, as well as some specific impact factors were also found. In addition, prophylactic aspirin use and chorionicity of twin pregnancies are matter of debate, researches into these topics still need endeavors. In general, these above impact factors are salient and relevant for early detection of PE in the clinical environment. These findings provide obstetrical staff adjunctive information for screening of high-risk of PE among twin pregnancy populations and carrying out personalized interventions in advance, so as to ensure the health and well-being of mothers and infants.
Limitations
Due to the limitations of retrospective studies, the data on some of the parameters in this study, such as the range of blood pressure and glucose and urinary protein level, were not complete. This study was a single-center research, which could bring biases. And there was a lack of data on potential long-term complications of mother and offspring. Future prospective studies will be conducted to construct a prediction model of PE risk in twin pregnancies and that internal and external validation will be conducted by multicenter studies.
Authors contributions
Jia-yi Mao designed this study, collected and analyzed data, drafted and revised the manuscript. Shuang Luo participated data analysis and manuscript revision. Lan Wang and Ya Chen supervised this study and revised the manuscript. Qing Zhou performed the initial data analysis and reviewed the manuscript. Chun-yan Yang participated data analysis and reviewed the manuscript. Xue Xiang prepared the tables and figures. Da-Ping Wang performed the initial data analysis. Hong-mei Zuo prepared the tables and collected data. Tai-hang Liu collected data, performed the data analysis and revised this manuscript. Li Wen participated data analysis and critically reviewed this paper. Si-meng Qu and Ting Hou prepared the tables and collected data.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Availability of data and materials
The datasets used and/or analyzed during this study are available from the corresponding author upon reasonable request.
Additional information
Funding
References
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