Characteristics of Serum Lipid Metabolism among Women Complicated with Hypertensive Disorders in Pregnancy: A Retrospective Cohort Study in Mainland China

Background Altered maternal serum lipid metabolism is associated with hypertensive disorders in pregnancy (HDP). However, its range in pregnancy and characteristic among different subgroups of HDPs are unclear. Methods Pregnant women with HDP who underwent antenatal care and delivered in Obstetrics and Gynecology Hospital of Fudan University during January 2018 to August 2022 were enrolled. The levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), apolipoprotein (Apo)-A, B, and E, free fatty acids (FFA), and small and dense low-density lipoprotein cholesterol (sdLDL) were measured during 4–16 weeks and 28–42 weeks of pregnancy. Results A total of 2648 pregnant women were diagnosed with HDP, 1,880 of whom were enrolled for final analysis, including 983 (52.3%) preeclampsia (PE), 676 (36.0%) gestational hypertension (GH), and 221 (11.7%) chronic hypertension (CH). For all HDPs, serum TC, TG, LDLC, HDLC, Apo-A, Apo-B, Apo-E, and sdLDL increased significantly during pregnancy, while FFA decreased significantly. Notably, the levels of TC, LDLC, Apo-B, and sdLDL in PE group were equal to or lower than those in CH group at 4–16 weeks of pregnancy, but increased greatly during pregnancy (P < 0.05). Conclusions Maternal serum lipid levels changed through pregnancy among women with HDPs. Women complicated with PE seem to have undergone a more significant serum lipid change compared to those with GH or CH.


Introduction
Hypertensive disorders in pregnancy (HDP) are a pregnancy-specifc syndrome, with a 2-8% incidence [1,2].Tere were evidences suggesting that hyperlipidemia and related metabolic disorders be associated with higher risk of HDP [3][4][5].A meta-analysis of 74 studies [6] showed that total cholesterol and triglyceride levels were elevated in women with preeclampsia during the third trimester of pregnancy.Lipid metabolism during pregnancy is the adaptive increases in serum total cholesterol and triglyceride levels with the increasing level of estrogen, progesterone, and lactogen during pregnancy, providing a fatty acid energy bank for fetal growth and placental tissue steroid synthesis in late pregnancy [7].Till now, the changing ranges of lipid metabolism among women complicated with HDP spanning the whole pregnancy are lacked.
Moreover, the pathogenesis of diferent subgroups of HDP, such as preeclampsia (PE), gestational hypertension (GH), and chronic hypertension (CH), is considered varied in oxidative stress and endothelial dysfunction [8], which is closely related with metabolism of lipoproteins [9,10].An important gap is the characteristics of maternal lipid metabolism among these HDPs.Tus, we hypothesize that maternal lipid metabolism may difer among subgroups of HDPs.
Herein, this retrospective cohort study aimed to describe the changes in serum lipid metabolism among women complicated with PE, GH, and CH at 4-16 weeks and 28-42 weeks of pregnancy.

Study Design and Participants.
A retrospective cohort study was conducted in Obstetrics and Gynecology Hospital of Fudan University.Pregnant women with HDP who underwent antenatal care and delivered from January 2018 to August 2022 were included.Tose women with multiple pregnancies, maternal complications including cardiovascular disease, diabetes, cancer, kidney, and liver disease, and incomplete or missing medical records were excluded.

Data Collection.
Maternal baseline and clinical information were extracted from medical records.Baseline information included maternal age, weight, height, educational level, ABO and Rh blood types, histories of preeclampsia, alcohol consumption, and smoking.Prepregnancy weight, alcohol consumption, and smoking information was self-reported at the frst antenatal visit.Educational levels were classifed as low (high school or below) and high (bachelor or above).
Related clinical information was picked from the participants delivery record, including systolic and diastolic blood pressure (BP) at admission(Te same arm of the pregnant woman should be measured at least twice, and the interval between the two measurements should be ≥4 h), proteinuria (protein excretion in a 24 h urine collection), antiphospholipid syndrome (APS) [11], gestational diabetes mellitus (GDM)(any one of fasting blood glucose ≥5.1 mmol/L, 1 h blood glucose ≥10.0 mmol/L, or 2 h blood glucose ≥8.5 mmol/L at 24 to 28 weeks of gestation by the 75 g oral glucose tolerance test (OGTT)) [12], postpartum hemorrhage [13], placental abruption [14], gestational age of delivery, mode of delivery (divided into vaginal delivery and cesarean section), placental weight, neonatal birthweight, sex, and distress.Apgar score [15] includes appearance, pulse, grimace, activity, and respiration.Low Apgar score is defned as ≤7.

Statistical Analyses.
Descriptive data were presented as mean ± SD (standard deviation) for continuous variables or number (%) for categorical variables.Te range and percentiles of the maternal serum lipid concentration at 4-16 weeks and 28-42 weeks of pregnancy were described from 2.5% to 97.5%.
Te means between 4-16 weeks and 28-42 weeks of pregnancy were compared by the paired Student's t-test.Analysis of variance (ANOVA) with Bonferroni test was used to determine statistical diferences in the distribution of maternal serum lipid concentration and comparisons among PE, GH, and CH groups.SPSS (Statistical Package for the Social Sciences, Chicago, IL, USA) version 26.0 was used for statistical analysis.A P value < 0.05 was considered statistically signifcant.

Enrollment of Participants.
A total of 51,896 pregnant women registered at Obstetrics and Gynecology Hospital of Fudan University during January 2018 to August 2022, among whom 25,929 women were excluded due to nondelivery in our hospital, 1,032 women had twin or multiple pregnancies, and 22,287 women did not have HDP.Among 2,648 women complicated with HDPs, missing data of serum lipid at 4-16 weeks and 28-42 weeks of pregnancy (n � 630), serum lipid sampled beyond 4-16 gestational weeks and 28-42 gestational weeks (n � 138), were excluded.A total of 1,880 HDP women were enrolled for fnal analysis, including 983 (52.3%)PE, 676 (36.0%)GH, and 221 (11.7%)CH (Figure 1).

Maternal Serum Lipid Concentration in among Women
with PE, GH, and CH.Te characteristics and validity number of serum lipid concentrations among three subgroups of HDPs was shown in Figure 2 and Table 3. Except for FAA of CH group (P � 0.077), other lipid indicators have signifcant changes during pregnancy (P < 0.001).Notably, serum lipid levels among women with PE were signifcantly altered during the whole pregnancy, compared to those with GH and CH shown in Figure 2 and Table 3.
Higher levels of TC, LDLC, Apo-B, and sdLDL and lower levels of HDLC and Apo-A levels (P < 0.05) were found among women with PE than those with GH (P > 0.05), both at 4-16 weeks and 28-42 weeks of pregnancy.Notably, the increase in TC, LDLC, Apo-B, and sdLDL were greater in PE than in GH, and the decrease in HDLC and Apo-A were also greater in PE than in GH.Also, compared to women with CH, women with PE had lower level of TC, LDLC, HDLC, Apo-E, sdLDL (P > 0.05), TG, Apo-A, Apo-B, and FFA (P < 0.05) at 4-16 weeks of pregnancy; moreover, the increase in TC, LDLC, Apo-B, and sdLDL from 4-16 weeks to 28-42 weeks of pregnancy were signifcantly higher (P < 0.05) as shown in Figure 2 and Table 3.
Blood lipid diferences between severe and mild preeclampsia in the PE group were analyzed as shown in Table S3.Our data showed that there was no statistical diference of blood lipid levels between mild and severe preeclampsia, except for Apo-A (P < 0.05).

Main Finding.
Altered lipid metabolism is associated with hypertensive disorders during pregnancy, but the characteristics during whole pregnancy among diferent subgroups of HDPs are unclear.Herein, we have demonstrated signifcant fuctuations of serum lipid levels among women complicated with HDPs, from 4-16 weeks to 28-42 weeks of pregnancy, characterized with signifcant diference among PE, GH, and CH.

Clinical Implications.
HDP is a heterogeneous disease, with diferent types having diferent mechanisms and different efects on lipid metabolism [20,21].Our results showed that there were diferences in lipid levels among PE, GH, and CH groups.TG, LDLC, Apo-B, and Apo-E levels in PE group increased greater than those in GH group, while HDLC and Apo-A levels decreased signifcantly from 4-16 weeks to 28-42 weeks of pregnancy, suggesting that abnormal lipid metabolism was more common in PE.Te comparative data of PE group and CH group showed that the levels of TC, LDLC, Apo-B, and sdLDL were lower in PE group than those in CH group at 4-16 weeks of pregnancy, but increased more signifcantly during pregnancy, suggesting that the degree of these "bad" lipids increase during the course of pregnancy might play a more important role in the pathogenesis of PE.
Previous literature focused on the association of blood lipid comparison with pregnancy outcome between HDP and PE with normal pregnancy [3,22,23].Tus, there was a lack of research on comparing serum lipids among different subtypes of HDP, and no consistent view on the change of serum lipids levels.Some studies [6,10,24] had shown that serum concentrations of TC, TG, LDLC, apolipoprotein, and FFA were higher in women with preeclampsia compared to controls with normal blood pressure, while other studies [25,26] had shown that they were unchanged.A large prospective longitudinal cohort study [3] evaluated lipid elevation throughout pregnancy, showing that greater increase in TG levels from 4-16 weeks to 28-42 weeks of pregnancy were associated with an increased risk of HDP.A case-control study [27] included 1366 preeclampsia cases which also reported that elevated TG and Apo-E levels increased the risk of preeclampsia.In a review of 22 studies, Ray et al. [4] found that women with elevated TG had a 4 times greater risk of preeclampsia than women with normal TG.A meta-review of 74 studies [6] reported that preeclamptic women had elevated total cholesterol and triglyceride and lower HDLC levels than those of normotensive pregnant women at 28-42 weeks of pregnancy.Consistent with these fndings, our results showed that serum lipids of HDP pregnant women were increased during pregnancy generally, except that FFA was decreased.
In addition, in terms of mechanism, it has been reported that GH was commonly seen in women with unfavorable metabolic profle, while PE was partly caused by genetic factors [28,29].At odds with them, our data of 1,880 HDP women showed that PE had the largest range of lipid metabolism fuctuation among GH, CH, and PE.Although all serum lipids of CH group were the highest at 4-16 weeks of pregnancy, the TC, sdLDL, LDLC, and Apo-B of PE group were the highest at 28-42 weeks of pregnancy and increased the most during pregnancy.Our results indicate that the increase, instead of the primary level, of "bad" lipids may play a more important role in the development of PE.Obstetrics and Gynecology International

Obstetrics and Gynecology International
In addition, a higher rate of postpartum hemorrhage and placental abruption was noted in PE group.Along with the abundant evidence of endothelial progenitor cells [30] and sFlt-1 (soluble fms-like tyrosine kinase 1) and PlGF (placental growth factor) [31] in the placental dysfunction, our fnding suggested potentially synergetic pathology of lipid alternation in postpartum hemorrhage and placental abruption among preeclamptic women.Detailed molecular mechanism is required to be further elucidated.

Strengths and Limitations
. Tis was a large retrospective cohort study.As far as we know, we are the frst to describe the range of HDP maternal serum lipids during pregnancy in the Chinese population and the efects of diferent types on lipids.
Tis study also had some limitations.First, since this was a single-center study which could not well represent the characteristics of the entire Chinese or Asian population, the multicenter and prospective study with a larger sample size would be more representative.Second, the confounding variables was not adjusted and recall bias could not be ruled out.For example, BMI and diet before pregnancy were important factors afecting dyslipidemia during pregnancy.Tird, previous studies showed that serum lipids generally increase in pregnancy in both normotensive or hypertensive pregnancies [32,33].Te relationship between increased 'bad' lipids and preeclampsia needs to be further analyzed along with normotensive pregnancies.

Conclusions
In conclusion, maternal serum lipid metabolism is altered from 4-16 weeks to 28-42 weeks of pregnancy among women with HDPs.Women complicated with PE seem to undergo a more signifcant serum lipid change compared to those with GH and CH.

Data Availability
Te datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Figure 2 :
Figure 2: Comparison of maternal serum lipid concentrations among women with PE, GH, and CH.

Table 1 :
Baseline and clinical characteristics of enrolled women with HDPs.

Table 3 :
Comparison of maternal serum lipid concentrations among women with PE, GH, and CH.