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Association of phthalates exposure and sex steroid hormones with late-onset preeclampsia: a case-control study

BMC Pregnancy and Childbirth volume 24, Article number: 577 (2024) Cite this article

Abstract

Background

This study aimed to investigate the relationship between phthalates exposure and estrogen and progesterone levels, as well as their role in late-onset preeclampsia.

Methods

A total of 60 pregnant women who met the inclusion and exclusion criteria were recruited. Based on the diagnosis of preeclampsia, participants were divided into two groups: normotensive pregnant women (n = 30) and pregnant women with late-onset preeclampsia (n = 30). The major metabolites of phthalates (MMP, MEP, MiBP, MBP, MEHP, MEOHP, MEHHP) and sex steroid hormones (estrogen and progesterone) were quantified in urine samples of the participants.

Results

No significant differences were observed in the levels of MMP, MEP, MiBP, MBP, MEHP, MEOHP, and MEHHP between women with preeclampsia and normotensive pregnant women (P > 0.05). The urinary estrogen showed a negative correlation with systolic blood pressure (rs= -0.46, P < 0.001) and diastolic blood pressure (rs= -0.47, P < 0.001). Additionally, the urinary estrogen and progesterone levels were lower in women with preeclampsia compared to those in normotensive pregnant women (P < 0.05). After adjusting for confounding factors, we observed a significant association between reduced urinary estrogen levels and an increased risk of preeclampsia (aOR = 0.09, 95%CI = 0.02–0.46). Notably, in our decision tree model, urinary estrogen emerged as the most crucial variable for identifying pregnant women at a high risk of developing preeclampsia. A positive correlation was observed between urinary progesterone and MEHP (rs = 0.36, P < 0.05) in normotensive pregnant women. A negative correlation was observed between urinary estrogen and MEP in pregnant women with preeclampsia (rs= -0.42, P < 0.05).

Conclusions

Phthalates exposure was similar in normotensive pregnant women and those with late-onset preeclampsia within the same region. Pregnant women with preeclampsia had lower levels of estrogen and progesterone in their urine, while maternal urinary estrogen was negatively correlated with the risk of preeclampsia and phthalate metabolites (MEP).

Trial registration

Registration ID in Clinical Trials: NCT04369313; registration date: 30/04/2020.

Peer Review reports

Introduction

Preeclampsia (PE) is a pregnancy-specific disorder, characterized by the new-onset hypertension and either proteinuria or multiple maternal system dysfunctions occurring after 20 weeks of gestation [1]. It represents a major contributor to maternal morbidity and mortality worldwide [2]. Therefore, it is imperative to elucidate the etiology and pathogenesis of PE, which still remains unclear at present. Previous studies have demonstrated that placental dysfunction and angiogenic response disruption may be involved in the pathogenesis of PE [3]. Environmental factors including exposure to endocrine-disrupting chemicals, like phthalates, may also play a role in the development PE [4].

Phthalates, a class of plasticizers, are widely used in our daily products [5]. Exposure to phthalates can take place through inhalation, ingestion, skin absorption and contaminated surfaces contact [5]. It has been reported that phthalates can enter amniotic fluid and fetal circulation though the fetal-placental barrier [6]. Despite their usefulness, however, phthalates can interfere with and disrupt the endocrine system, potentially leading to the elevated blood pressure and an increased risk of cardiovascular diseases [7]. Recently, researchers have found that the presence of phthalate metabolites in the urine of pregnant women is significantly associated with an increase in blood pressure, and those who are exposed to phthalates have a higher risk of developing PE [8].

Estrogen and progesterone, mainly synthesized by the placenta after 10 weeks of gestation, are essential for maintaining pregnancy. Estrogen can regulate angiogenic processes by altering the concentration of vascular endothelial growth factor (VEGF) and increasing placental blood perfusion [2]. Progesterone can reduce vascular resistance by reducing the sensitivity to angiotensin, exerting a protective effect on vascularization [9]. A recent research has found that the serum concentrations of estradiol and progesterone are significantly lower in pregnant women with PE compared to those in healthy pregnant women [10]. MEE-NA PARK et al. revealed that the expression of estrogen receptor-1 (ESR1) was reduced in the placenta of pregnant women with PE [11]. Thus, the changes in estrogen and progesterone levels may be closely associated with the development of PE.

It has been revealed that maternal phthalate metabolites disrupt the balance of these steroid hormones [12]. For example, the increased levels of phthalates in maternal cord blood were associated with a significant reduction in estriol and estradiol levels [13]. Phthalate metabolites in the human body could interfere with estrogen and progesterone activities, like mono-phthalate monobutyl (MBP) and mono-phthalate monomethyl (MMP) [5]. Therefore, we hypothesize that alterations in estrogen and progesterone levels resulting from exposure to phthalates may underlie the development of PE.

The objectives of our study are to investigate the association between exposure to phthalates and alterations in estrogen and progesterone levels, as well as to explore the role of this relationship in late-onset PE.

Materials and methods

Study design and population

This was an observational study conducted in the Second Affiliated Hospital of Wenzhou Medical University from March 1, 2021 to March 1, 2022 (Registration ID in Clinical Trials: NCT04369313; registration date: 30/04/2020). The study was supported by the Research Ethics Committee of our hospital (NO. LCKY2019-288). Pregnant women with PE were recruited as the study group. Normotensive pregnant women during the same period were included as the control group, matched with those in the study group based on baseline characteristics, including maternal age, body mass index (BMI) at delivery, gravidity, parity, and gestational age. The ratio of women in the study group to the control group was 1:1, and the majority of women with PE enrolled in our study were at or near full term without severe complications. All the participants provided written consent.

Eligibility criteria for participants included singleton pregnancies, 18–40 years old, and intention to give birth at our hospital. The exclusion criteria were as follows: (1) women with chronic hypertension before pregnancy, gestational hypertension, eclampsia, or chronic hypertension with superimposed PE during pregnancy; (2) women took medicine before or during pregnancy, such as hormones or antidiabetic drugs; (3) women with pregnancy complications including placenta previa, diabetes or gestational diabetes, cardiac or renal disease, intrahepatic cholestasis of pregnancy and others; (4) women with early-onset PE (< 34 weeks); (5) women who declined to participate in this study.

Data collection

Participants completed questionnaires and provided urine samples before delivery. A face-to-face interview based on structured questions was performed to collect information including maternal age, gravidity, parity, occupation, regular exercise, supplementation of folate, and medication history. We obtained data on gestational age and blood pressure at delivery, BMI at delivery, neonatal birth weight and sex of infants from computerized medical records.

BMI (in kg/m2 ) was calculated as weight (in kg) divided by the square of height (in m). PE was defined as a systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, along with the presence of proteinuria after 20 weeks of gestation or multiple maternal system dysfunctions (including thrombocytopenia, defined as platelet count < 100,000/mm3; renal insufficiency, defined as serum creatinine concentration > 1.1 mg/dl or doubling of serum creatinine concentration without other renal diseases; impaired liver function, defined as elevated liver transaminases to 2×normal or severe persistent right upper quadrant/epigastric pain unresponsive to medication; pulmonary edema, diagnosed by physical examination/chest x-ray; neurological signs, defined as new-onset headache unresponsive to medication/not accounted for by alternative diagnoses/visual symptoms; fetal growth restriction, defined as estimated fetal weight<10th percentile) in the absence of proteinuria [1].

Urine collection and analysis

Urine samples were collected from pregnant women in the morning on an empty stomach, centrifuged for 10 min at a force of approximately 3000r, and then the supernatant liquid was stored at -80 degrees Celsius.

Estrogen and progesterone levels were detected using an available enzyme-linked immunosorbent assay (ELISA) kits (ExCell Biotech, China) according to the manufacturer’s protocols. Briefly, 50uL of standards and thawed urine samples were added to the ELISA plate, followed by conjugate reagent. The plate was then incubated at 37 degrees Celsius for one hour. After incubation, each well was washed with scrubbing solution for 30 s, repeated five times. Subsequently, chromogenic agent and stop solution were sequentially added to each well, and the absorbance at 450 nm was measured within 15 min.

The other urine samples were sent to a professional company (Metabo-Profile Biotechnology (Shanghai) Co., LTD ) to measure the metabolites of phthalates by high performance liquid chromatography (HPLC). Firstly, 40µL of β-glucuronidase solution was added to 1.0 mL of thawed urine sample and shaken well, then the mixture was placed in a water bath at 37 ℃ for enzymatic hydrolysis hermetically for 120 min, after then 1.0 mL phosphate buffer was added to mix and purify. Phthalate was dissolved in acetonitrile and diluted into a series of concentration samples (0.5 to 100 µg/mL) to obtain the standard curve. The purified urine samples were detected by liquid chromatography (Shimadzu LC-20AD) combined with triple tandem quadrupole mass spectrometry; finally, the concentrations of seven major phthalates metabolitesthe concentrations (in ng/mL) of seven major phthalates metabolites were obtained: matrix metalloproteinase (MMP), monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), monobutyl phthalate (MBP), mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxy-hexyl phthalate (MEOHP) and mono-2-ethyl-5-hydroxy-hexyl phthalate (MEEHP).

Sample size estimation

Firstly, we recruited a total of 10 normotensive pregnant women and 10 women with PE based on inclusion and exclusion criteria in an initial experiment. They were matched to ensure a balanced baseline in terms of maternal age, gestational age, parity, gravidity, and BMI at delivery. In this preliminary experiment, measurements of estrogen and progesterone concentrations, as well as phthalate metabolite concentrations, were obtained. Subsequently, the mean and standard deviation of these measurements were calculated for both groups − 10 normotensive pregnant women and 10 women with PE. The PASS software (Power Analysis and Sample Size) was used to estimate the sample size required for this study. After setting the “Alpha error” at 0.05 and “power (1-beta)” at 0.9, we determined that a sample size of n = 28 was needed for each group based on the results obtained from the preliminary experiment: pregnant women with PE group (n = 28) and normotensive pregnant women group (n = 28).

Statistical analysis

We conducted a descriptive analysis using SPSS 26.0 software to examine the overall situation and characteristics of the data. Additionally, we utilized SPSS 26.0 software to perform 1:1 Case Control Matching through Propensity Score Matching. After assessing normality assumptions by Kolmogorov-Smirnov test, continuous variables with normal distributions were reported as mean ± standard deviation, while those with non-normal distributions were reported as median (interquartile range). Student t-test was employed for analyzing normally distributed continuous variables, whereas Mann-Whitney U test was used for non-normally distributed continuous variables. Correlation analysis was performed to explore the relationship between sex steroid hormones and the metabolites of phthalates, as well as between sex steroid hormones and blood pressure in pregnant women. Logistic regression analysis was applied to investigate the impact of sex steroid hormones on PE after adjusting for confounding factors. Odds ratio (OR) and 95% confidence interval (CI) were utilized to present logistic regression results. In the decision tree model, the dependent variable was grade data representing the presence of PE in pregnant women (0 = normotensive pregnant women, 1 = pregnant women with PE). The independent variables included confounding factors that may affect PE: maternal age, gestational weeks, gravidity, parity, BMI at delivery, phthalate metabolites, and steroid hormones. A p-value < 0.05 was considered statistically significant.

Results

In this study, a total of 305 pregnant women with PE and 3147 women with normal pregnancies were enrolled in our institution from March 1, 2021 to March 1, 2022. After applying exclusion criteria and Propensity Score Matching, a total of 60 pregnant women were included in the final analysis (as detailed in Fig. 1). They were divided into two groups: the control group consisted of normotensive pregnant women (n = 30), and the study group comprised pregnant women with late-onset PE (n = 30), among whom 28 presented mild PE, while 2 presented severe PE (characterized by blood pressure ≥ 160/110 mmHg without any severity features).

Fig. 1
figure 1

Flowchart of the study (ELISA: enzyme-linked immunosorbent assay; HPLC: high performance liquid chromatography; MMP: matrix metalloproteinase; MEP: monoethyl phthalate; MiBP: monoisobutyl phthalate; MBP: monobutyl phthalate; MEHP: mono-2-ethylhexyl phthalate; MEOHP: mono-2-ethyl-5-oxy-hexyl phthalate; MEEHP: mono-2-ethyl-5-hydroxy-hexyl phthalate)

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The demographic and clinical characteristics of the enrolled women were summarized in Table 1. There were no significant differences in maternal age, gestational age, gravidity, parity, maternal weight and BMI at delivery, and newborn infant sex ratio between the two groups (P > 0.05). However, the neonatal weights of normotensive pregnant women were higher than those of women with PE (P < 0.05). The systolic and diastolic blood pressure of women with PE was significantly higher than that of normotensive pregnant women (P < 0.001). And the median urinary protein of women with PE was 0.95 g/24 h.

Table 1 Comparisons of clinical characteristics between normotensive pregnant women and pregnant women with preeclampsia
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As shown in Table 2, there were no significant differences in the concentrations of phthalate metabolites (MMP, MEP, MiBP, MBP, MEHP, MEOHP and MEEHP) in urine between pregnant women with PE and normotensive women (P > 0.05).

Table 2 Comparisons of urinary phthalate metabolite concentrations between normotensive pregnant women and pregnant women with preeclampsia
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The negative correlations between urinary estrogen and systolic blood pressure, diastolic blood pressure, as well as the negative correlation between progesterone and diastolic blood pressure were presented in Table 3 (P < 0.05). In addition, Table 4 showed that the levels of maternal estrogen and progesterone in urine were significantly lower in pregnant women with PE compared to normotensive women (P < 0.05). Moreover, after adjusting for age, gestational weeks, gravidity, parity, BMI at delivery, estrogen and progesterone, we observed a significant association between reduced urinary estrogen levels and an increased risk of PE (aOR = 0.09, 95%CI = 0.02–0.46) (Table 5).

Table 3 The correlations between urinary sex hormones and blood pressure in pregnant women
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Table 4 Comparisons of urinary sex hormones between normotensive pregnant women and pregnant women with preeclampsia
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Table 5 Logistics regression analysis of the effects of estrogen and progesterone levels on preeclampsia
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The decision tree depicted in Fig. 2 illustrated the prediction of PE. It consisted of 5 nodes, including 3 terminal nodes, and had a depth of 2. Four rules were extracted from the decision tree: - Rule 1: If estrogen levels are > 4.16ng/mL, THEN classify as pregnant women with PE (24.3%). - Rule 2: If estrogen levels are ≤ 4.16ng/mL, THEN classify as pregnant women with PE (91.3%). - Rule 3: If estrogen levels are ≤ 4.16ng/mL and progesterone levels are ≤ 6.02ng/mL, THEN classify as pregnant women with PE (100%). - Rule 4: If estrogen levels are ≤ 4.16ng/mL and progesterone levels are > 6.02 ng/mL, THEN classify as pregnant women with PE (66.7%). In the decision tree model, the urinary estrogen was the most critical variable for identifying pregnant women who were at a risk of developing PE.

Fig. 2
figure 2

The decision tree model for identifying pregnant women at risk of preeclampsia

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The correlation between sex steroid hormones and phthalate metabolites in the urine of pregnant women was presented in the Tables 6 and 7. In the urine of normotensive pregnant women, there was a positive correlation between progesterone and MEHP (rs = 0.36, P = 0.047), but there were no correlations between progesterone and MMP, MEP, MiBP, MBP, MEOHP or MEHHP (P > 0.05). Besides, there were no correlations between estrogen and phthalate metabolites in the urine of normotensive pregnant women (P > 0.05) (Table 6). In the urine of pregnant women with PE, there was a negative correlation between estrogen and MEP (rs= -0.42, P = 0.02), but there were no correlations between estrogen and MMP, MiBP, MBP, MEHP, MEOHP, MEHHP (P > 0.05); and there was no correlation between progesterone and phthalate metabolites (P > 0.05) (Table 7).

Table 6 The correlations between urinary sex hormones and phthalate metabolites of normotensive pregnant women
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Table 7 The correlation between urinary sex hormones and phthalate metabolites of pregnant women with preeclampsia
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Discussion

Our study indicated that phthalate exposure was similar in normotensive pregnant women and those with late-onset PE within the same region, and both urinary estrogen and progesterone levels were lower in women with late-onset PE compared to those in normotensive pregnant women. Moreover, our study showed a negative correlation between urinary estrogen and blood pressure of pregnant women, as well as a significant association between reduced urinary estrogen levels and an increased risk of PE. Additionally, estrogen was negatively correlated with MEP in women with late-onset PE.

It has been reported that the toxicological effects are caused by the metabolites of phthalates, a class of endocrine disruptors, rather than the original parent compounds [4]. Previous studies have drawn inconsistent conclusions regarding the association between maternal phthalate exposure and PE. Cantonwide et al. conducted a study that analyzed prenatal urine samples for nine phthalate metabolites and found that these metabolites, particularly MEHP, were significantly associated with the risk of PE [7]. The similar results have been shown in some cohort studies [8, 14]. However, Philips et al. found no association between prenatal exposure to phthalates and changes in maternal blood pressure, gestational hypertensive disorders, or placental hemodynamics [15]. This result was consistent with our findings, which showed no difference in phthalate metabolite concentrations between pregnant women with normal blood pressure and those with PE. These conflicting results may be due to the differences in geographic locations, demographic profiles, and the degree of PE severity.

The findings of a study on Chinese phthalate exposure revealed regional disparities in the levels of phthalate exposure, with higher exposures observed in northeastern and southern provinces compared to those in central provinces [16]. Our study population was all recruited from the Wenzhou area, so the levels of phthalate exposure in normotensive pregnant women was comparable to those in women with PE. In addition, the research design ensured a well-balanced distribution of clinical characteristics between the study group and the control group, thereby facilitating further investigation. Consequently, the pregnant women with PE in our study were primarily comprised of near or full term singleton pregnancies with mild PE. In contrast, the population of the previous study consisted of pregnant women who were at a high risk of PE, including those with severe or early onset PE. Therefore, further investigations are warranted to elucidate the association between geographical factors, the severity of PE and maternal exposure to phthalates.

Phthalates can act as endocrine disruptors, potentially inducing alterations in hormone levels within the human body [5]. Interestingly, although there was no statistically significant difference in the levels of phthalate metabolites in the urine between the two groups, pregnant women with PE had significantly lower levels of estrogen and progesterone in the urine compared to those in normotensive women. Relevant studies have also indicated an association between decreased levels of estrogen and progesterone and the occurrence of PE [10]. The rat model demonstrated that estradiol treatment effectively reduced blood pressure and alleviated symptoms of preeclampsia, such as urinary protein excretion [17].

Furthermore, administering progesterone supplements to women at higher risk for pregnancy during the gestational period from 6 to 20 weeks has been shown to effectively reduce the incidence of PE [18]. Placental insufficiency and ischemia may constitute the primary etiology of PE [3]. It has been reported that progesterone possesses the ability to reduce the resistance of the uterine spiral artery and lower vascular resistance in uteroplacental blood flow [19]. This mechanism is likely attributed to the potent immunomodulatory functions exerted by progesterone, which promote the expansion or differentiation of regulatory T cells at the maternal-fetal interface and induce pro-angiogenic neutrophils that facilitate homeostatic placental T cell function [20,21,22]. Therefore, the improvement of PE symptoms by progesterone may be associated with its enhancement of uteroplacental blood flow and immunomodulatory function. Based on these findings, the preliminary conclusion would seem to be that changes in estrogen and progesterone levels are closely involved in the development of PE.

Limited research has been conducted on the mechanism underlying the decreased levels of estrogen and progesterone in pregnant women with PE. Recent studies indicated that this mechanism may be related to endocrine disrupting chemicals, placental ischemia-reperfusion injury and increased oxidative stress response [3, 7, 23]. For hypothesizing, the phenomenon we observed may be attributed to maternal exposure to endocrine disruptors in the surrounding environment. Our study investigated the correlation between prenatal exposure to phthalates and estrogen and progesterone levels in the urine. The correlation analysis conducted in our study revealed a significant negative association between estrogen levels and phthalate metabolites (MEP), with this relationship being particularly pronounced among pregnant women diagnosed with PE. Estrogen has also been found to be inversely associated with levels of phthalates in maternal cord blood [12]. Furthermore, the levels of serum estrogen and progesterone were significantly lower in mice exposed to 0.05 mg/kg/day DEHP (a dosage relevant to human exposure) compared to those in the control group [24]. Therefore, the decreased levels of estrogen in pregnant women with PE may be closely associated with prenatal exposure to phthalates.

As is known, the enzymes 3-beta-hydroxysteroid dehydrogenase 1 (HSD3B1) and cytochrome P450 family 19 subfamily A member 1 (CYP191a1) play pivotal roles in the synthesis and secretion of estrogen and progesterone [25]. An in vitro experiment indicated that phthalates and their metabolites decreased levels of progesterone and estradiol by inhibiting the activity of HSD3B1 and CYP191a1 [26]. Placental trophoblast cells can express peroxisome proliferator-activated receptor gamma (PPARG), a ligand-dependent transcription factor that is involved in human hormone secretion [27]. Besides, the results of an in vitro experiment have confirmed that MEHP exhibited anti-estrogenic effects through direct receptor activity [28]. Thus, these findings suggested that exposure to phthalates may lead to a decrease in estrogen and progesterone levels by inhibiting the synthesis and secretion of estrogen and progesterone, as well as antagonizing estrogen activity.

Furthermore, researchers are paying more attention to placental epigenetics, including DNA methylation, histone modification, and small RNA-mediated control. It has been reported that placental epigenetics are sensitive to environmental conditions such as endocrine disruptors (e.g., phthalates) [29]. The team led by Machtinger et al. identified and quantified a total of 87 long noncoding RNAs (lncRNAs) derived from the placental tissue. Their findings revealed strong correlations between phthalates and the majority of these lncRNAs [30]. A study conducted by Grindler et al. aimed to determine the epigenome-wide DNA methylation marks and gene expression associated with phthalates exposure in placenta. The results showed that most of the genes with significantly altered methylation were negatively correlated with high levels of phthalate exposure [31].

Thus, the sensitivity to phthalate exposure varies among pregnant women due to placental epigenetics. Individual epigenetic differences may make women with PE more susceptible to environmental phthalate exposure compared to normotensive pregnant women living in the same area. Therefore, we postulated that those pregnant women who were more sensitive to phthalate exposure may show lower levels of estrogen and progesterone, potentially leading to the development of PE, despite comparable exposure to phthalates in total pregnant women.

Strengths and limitations

This study had several notable strengths, with the most significant being its pioneering investigation into the correlation between phthalates and sex steroid hormones in PE. Secondly, urine samples were utilized for estrogen/progesterone analysis instead of blood samples to ensure consistency with the measurement of phthalate metabolites in urine, thereby mitigating potential errors arising from sample variation. One limitation is that we did not measure the levels of estrogen and progesterone in maternal serum, as well as their corresponding receptors in the placenta. This choice was made considering the ease of obtaining urine samples compared to the invasive nature of acquiring blood samples. Another limitation of this study is that its results were based on a single spot antepartum urine sample from pregnant women, rather than continuous dynamic testing. Those limitations may be addressed in a future extended study.

Conclusions

Phthalate exposure levels were comparable between normotensive pregnant women and those with PE within the same geographical region. Urinary estrogen and progesterone levels were lower in women with PE compared to those in normotensive pregnant women, and the negative correlations were observed between urinary estrogen levels and the risk of PE, as well as both systolic and diastolic blood pressure, in addition to phthalate metabolites (MEP) among pregnant women with PE.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

PE:

Preeclampsia

VEGF:

Vascular endothelial growth factor

ESR-1:

Estrogen receptor-1

MMP:

Matrix metalloproteinase

MEP:

Monoethyl phthalate

MiBP:

Monoisobutyl phthalate

MBP:

Monobutyl phthalate

MEHP:

Mono-2-ethylhexyl phthalate

MEOHP:

Mono-2-ethyl-5-oxy-hexyl phthalate

MEEHP:

Mono-2-ethyl-5-hydroxy-hexyl phthalate

ELISA:

Enzyme-linked immunosorbent assay

HPLC:

High performance liquid chromatography

HSD3B1:

3β-hydroxysteroid dehydrogenase − 1

CYP191a1:

P450 aromatase

PPARG:

Peroxisome-proliferator activated receptor gamma

lncRNAs:

Long noncoding RNAs

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Acknowledgements

The authors would like to thank the pregnant women of this study to participate in investigation and survey.

Funding

This work was supported by Wenzhou Key Laboratory of Precision General Practice and Health Management and the Obstetrics and gynecology of combine traditional Chinese and Western medicine of Zhejiang Province (2017-XK-A42).

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Author notes

  1. Xiaomin Zhao and Anjian Xu contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China

    Xiaomin Zhao, Anjian Xu, Xinyue Lu, Baoyi Chen, Ying Hua & Yanyan Ma

  2. Department of Obstetrics and Gynecology, Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China

    Xiaomin Zhao

Authors
  1. Xiaomin Zhao
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  2. Anjian Xu
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  3. Xinyue Lu
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  4. Baoyi Chen
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  5. Ying Hua
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  6. Yanyan Ma
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Contributions

ZXM and XAJ wrote the main manuscript; LXY and CBY prepared Tables 1, 2, 3, 4, 5, 6 and 7; HY and MYY prepared Fig. 1 and polished the manuscript. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Ying Hua or Yanyan Ma.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Research Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical University (NO. LCKY2019-288). Informed consent was obtained from all the participants.

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Not applicable.

Competing interests

The authors declare no competing interests.

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We ensured our manuscript reporting adhered to CONSORT guidelines.

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Zhao, X., Xu, A., Lu, X. et al. Association of phthalates exposure and sex steroid hormones with late-onset preeclampsia: a case-control study. BMC Pregnancy Childbirth 24, 577 (2024). https://doi.org/10.1186/s12884-024-06793-5

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  • DOI: https://doi.org/10.1186/s12884-024-06793-5

Keywords

BMC Pregnancy and Childbirth

ISSN: 1471-2393

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