Early Pregnancy Blood Fat Problems Linked to Poor Outcomes in Women with Mild Thyroid Issues

The cohort study enrolled pregnant women who established archives at the Beijing Obstetrics and Gynecology Hospital, Capital Medical University, from February 2018 to December 2020 and who had taken part in the China Birth Cohort Study (CBCS) [15]. All participants were asked to complete questionnaires, underwent clinical laboratory measurements, and were followed up with to assess pregnancy outcomes. To establish reference ranges for lipids in the first trimester, pregnant women who satisfied the following criteria were excluded: (1) dropped out after enrolment; (2) pregnancies with non-singletons; (3) were outside the range of 18 to 50 years old; (4) had incomplete lipid data in the first trimester; (5) had preexisting conditions before pregnancy (e.g., severe cardiac, hepatic, or renal disorders; hypertension; diabetes; thyroid disorders; malignant tumours or postoperative tumours; infectious diseases; or hyperlipidaemia); (6) had used of lipid-affecting medications prior to pregnancy; (7) had pregnancies achieved through assisted reproductive technologies; and (8) were lost to follow-up regarding pregnancy outcomes. Furthermore, during the screening process for pregnant women with SCH, who matched at least one of these conditions were excluded: had used medications affecting thyroid function before pregnancy (e.g., levothyroxine (L-T4), prednisone, budesonide, dexamethasone, propylthiouracil, labetalol, methylprednisolone); had TSH levels in the normal ranges of reference; had TSH levels lower than normal reference ranges; or had FT4 concentrations outside of the normal range. This study received approval from the Ethics Committee of Beijing Obstetrics and Gynecology Hospital, Capital Medical University on February 2nd, 2018 (reference number: 2018-KY-003-02). All participants provided informed consent.

Baseline data were collected using the questionnaires from the CBCS and the medical records at the hospital. Age was calculated using the birthdate and enrolment date. Prepregnancy body mass index (pre-BMI) was obtained by dividing prepregnancy weight in kilograms by height in meters squared. Smoking status and alcohol consumption during pregnancy were categorized as “yes”. Education levels were classified into three groups: high school and below, undergraduate, and graduate. Additionally, prepregnancy health conditions and medication usage were verified through a combination of questionnaires and medical records. The use of L-T4 before and during pregnancy was confirmed through questionnaires, hospital records, and phone follow-ups.

During the first trimester (≤ 13^{+ 6} weeks gestation), serum samples were collected from those enrolled in the CBCS study and archived at Beijing Obstetrics and Gynecology Hospital, Capital Medical University. The samples were maintained at 4 °C for less than 24 h, and the test was completed on the day of sample collection. Then, if samples need extended storage, they were kept at -20 °C for 48 h or -80 °C for more than three months. TSH and FT4 serum levels were collected via electrochemiluminescence immunoassays (Siemens Healthcare Diagnostics, ADVIA Centaur XP, Tarrytown, NY/USA). A fully automated Integrated System Chemistry/Immunology Analyser (ARCHITECT ci16200, Abbott Park, IL, USA) was used to quantify lipid levels, comprising LDL-C, HDL-C, TG, and total cholesterol (TC) using the appropriate assay kits (reagent cat. No. H05119R02 for TC, G07893R02 for TG, G05251R03 for HDL-C, and G69452R13 for LDL-C, Abbott Park, IL, USA). Initial blood lipid and thyroid function test results in early pregnancy were utilized as key indicators in this investigation.

During early pregnancy, SCH was diagnosed by normal concentrations of FT4 and TSH concentrations above 4.0 mIU/L, which is in accordance with the 2017 American Thyroid Association Guidelines [16]. As per our hospital’s standards, the normal reference range for FT4 was established to be 11.8–18.4 pmol/L.

Reference ranges for LDL-C, TG, HDL-C, and TC in early pregnancy were established in this study. Dyslipidaemia was identified by elevated TC, elevated TG, elevated LDL, and reduced HDL according to the reference range in this study. Adverse pregnancy outcomes included abortion (a pregnancy terminated before 28 weeks and with foetal weight less than 1000 g, including artificial abortion and spontaneous abortion), gestational hypertension (diastolic blood pressure ≥ 90 mmHg and/or systolic blood pressure ≥ 140 mmHg that appears after the 20th week of pregnancy and becomes normal within 12 weeks of postpartum, and accompanied by a negative urine protein test), gestational diabetes mellitus (GDM, diagnosed if any following ranges is exceeded: 2-hour post glucose load ≤ 8.5 mmol/L, 1-hour post glucose load ≤ 10.0 mmol/L, fasting blood glucose ≤ 5.1 mmol/L), preeclampsia/eclampsia (meeting criteria for gestational hypertension coupled with significant proteinuria or convulsions arising from preeclampsia without other explanatory causes), premature rupture of foetal membranes (PROM, identified as preterm membrane rupture before 37 weeks of gestation), foetal growth restriction (FGR, characterized by foetuses whose estimated foetal weight falls below the 10th gestational age percentile) [17], low birth weight (regardless of gestational age, birth weight below 2,500 g), macrosomia (neonatal birthweight is equal to or more than 4,000 g, irrespective of gestational age), preterm birth (described as a premature birth before 37 weeks of pregnancy), and birth defects (inclusive of structural deformities and functional abnormalities). The analyses also included modes of delivery, comprising vaginal delivery (encompassing both natural childbirth and operative vaginal birth) and caesarean section.

Continuous variables with a normal distribution were displayed in both average and standard deviations; nonnormally distributed values were then in the form of medians and interquartile ranges. For categorical variables, standard deviation and median were used. Subsequently, reference ranges were then established for the first trimester of pregnancy using the 5th to 95th percentiles of lipid measurements. Differences between groups were investigated using Mann-Whitney U and chi-square tests. The relationships between dyslipidaemia and pregnancy consequences were investigated by logistic regression analysis. The adjusted model included age, pre-BMI, smoking status, alcohol use, and L-T4 use during pregnancy as sequential adjustment factors. Receiver operating characteristic (ROC) curve determined the threshold levels for TSH, FT4, lipid levels, age, and pre-BMI for predicting adverse outcomes in pregnant women with SCH. Prediction accuracy was analysed by area under the curve (AUC). Youden index was adopted to find the optimal trade-off between sensitivity and specificity. Analysis of data was carried out with SPSS 26.0 (SPSS, Inc., Chicago, IL, USA). P < 0.05 was seen as an indicator of statistical significance.

Among the enrolled pregnant women, 26,776 were included in the analysis to establish reference values. Table 1 displays the average TC, HDL-C, TG, and LDL-C concentrations in the first trimester, and also the respective percentiles. As it is customary to use the 95th percentiles to define the normal reference range [18], the first-trimester reference ranges for serum LDL-C, TG, HDL-C, and TC were set between the 5th and 95th percentiles. Therefore, the following reference values for the first trimester: TC: 3.20 ~ 5.39 mmol/L; TG: 0.56 ~ 1.92 mmol/L; HDL-C: 1.06 ~ 2.01 mmol/L; and LDL-C: 1.37 ~ 3.24 mmol/L.

In total, 952 pregnant women were identified with SCH. The flowchart is depicted in Fig. 1. Among these pregnant women with SCH, 770 (80.88%) presented without dyslipidaemia, while 182 (19.12%) presented with dyslipidaemia. Pregnant women with dyslipidaemia were characterized by advanced maternal age (32.00 years vs. 30.00 years) and had a greater pre-BMI (23.03 kg/m² vs. 20.76 kg/m²) than did those without dyslipidaemia. Additionally, a greater proportion of women in the dyslipidaemia group were classified as older (age ≥ 35 years) or obese (pre-BMI ≥ 28 kg/m²). In the first trimester of pregnancy, among those with SCH, those with dyslipidaemia exhibited a greater incidence of gestational hypertension (6.59% vs. 3.25%), preeclampsia/eclampsia (7.14% vs. 3.12%), GDM (22.53% vs. 13.77%), and low birth weight (4.95% vs. 2.08%). No significant disparities in other pregnancy outcomes were evident between the dyslipidaemia and the nondyslipidaemia group (Table 2).

Compared to women with SCH who did not have dyslipidaemia, those with dyslipidaemia exhibited an increased risk of developing gestational hypertension (odds ratio [OR]: 2.104, 95% confidence interval [CI] [1.036 ~ 4.271], P = 0.040), preeclampsia/eclampsia (OR: 2.391, 95% CI: 1.193 ~ 4.792, P = 0.014), GDM (OR: 1.821, 95% CI: 1.216 ~ 2.727, P = 0.004), and low birth weight (OR: 2.452, 95% CI: 1.066 ~ 5.640, P = 0.035) in the crude model. However, after accounting for confounding factors, the association lacked statistical significance (Table 3).

As shown in Table 4, after adjusting for L-T4 use and age, dyslipidaemia still raised the risk of the above four undesirable pregnancy outcomes. After including smoking status and alcohol use as adjustment variables, dyslipidaemia in the first trimester was only linked to an enhanced risk of gestational hypertension (OR: 2.810, 95% CI: 1.321 ~ 5.975, P = 0.007) and GDM (OR: 1.702, 95% CI: 1.101 ~ 2.632, P = 0.017) in women with SCH. Moreover, after adjusting for pre-BMI, the correlation did not reach statistical significance.

According to the crude model, among pregnant women with SCH, elevated TC dyslipidaemia was correlated with increased preeclampsia/eclampsia risk, while elevated TG dyslipidaemia was linked to increased risks of gestational hypertension, GDM, and low birth weight. Elevated LDL-C dyslipidaemia was correlated with an elevated incidence of GDM and preeclampsia/eclampsia, and reduced HDL-C dyslipidaemia was associated with low birth weight. However, after adjusted for age, L-T4 use, smoking status, and alcohol use, there were still the significant associations between elevated TG dyslipidaemia and an increased gestational hypertension risk (OR: 4.064, 95% CI: 1.691 ~ 9.763, P = 0.002) and GDM (95% CI: 1.071 ~ 3.341, P = 0.028), as well as between elevated LDL-C dyslipidaemia and increased preeclampsia/eclampsia risk (OR: 3.870, 95% CI: 1.502 ~ 9.966, P = 0.005) and between reduced HDL-C dyslipidaemia and increased low birth weight incidence (OR: 3.581, 95% CI: 1.012 ~ 12.666, P = 0.048). Furthermore, after incorporating pre-BMI as an adjustment variable, only the associations between elevated TG dyslipidaemia and the risk of gestational hypertension (OR: 2.687, 95% CI: 1.074 ~ 6.722, P = 0.035) and between elevated LDL-C dyslipidaemia and preeclampsia/eclampsia (OR: 3.172, 95% CI: 1.204 ~ 8.355, P = 0.019) continued to be significant (Table 5).

As depicted in Table 6, among pregnant women with SCH, TSH was predictive capability for preterm birth (AUC = 0.624, 95% CI: 0.535 ~ 0.714, P = 0.017) and FGR (AUC = 0.608, 95% CI: 0.546 ~ 0.669, P = 0.001), as showed by ROC curve analysis. The established thresholds were 4.565 mIU/L and 5.575 mIU/L, respectively.

Together with pre-BMI data, the TC, TG, and LDL-C concentrations during pregnancy in women with SCH exhibited predictive value for gestational hypertension, preeclampsia/eclampsia, and GDM (TC: AUCs were 0.638, 0.610, and 0.585, respectively; TG: AUCs were 0.616, 0.629, and 0.662, respectively; LDL-C: AUCs were 0.637, 0.659, and 0.593, respectively; pre-BMI: 0.734, 0.632, and 0.625, respectively).

Furthermore, a combination of factors proved more effective in predicting certain adverse outcomes. Specifically, combining pre-BMI, TC, TG, LDL-C, TSH, and TPOAb demonstrated better predictive power for the occurrence of gestational hypertension (AUC = 0.767 95% CI: 0.661 ~ 0.873, P < 0.001, Fig. 2a). Combining pre-BMI, TC, TG, LDL-C, and TSH was suitable for predicting preeclampsia/eclampsia (AUC = 0.704 95% CI: 0. 615 ~ 0.793, P < 0.001, Fig. 2b). Additionally, combining TSH, TC, TG, LDL-C, pre-BMI, and age was found to be more suitable for predicting the occurrence of GDM (AUC = 0.706 95% CI: 0.662 ~ 0.749, P < 0.001, Fig. 2c), and combining TSH, TG, and pre-BMI was more suitable for predicting the occurrence of preterm birth (AUC = 0.672 95% CI: 0.570 ~ 0.774, P = 0.001, Fig. 2d).

As a cohort study during pregnancy, the present study had a large sample size and concentrated on how dyslipidaemia affects unfavourable pregnancy outcomes in women with SCH. Normal reference ranges for lipids in early pregnancy were established in this study and L-T4 use during pregnancy was included as an adjusting variable in the analyses. However, several limitations warrant consideration. First, the research focused on a specific geographical area, potentially introducing bias. Second, thyroid-related hormones and lipids were assessed only in the first trimester, overlooking the dynamic interplay between SCH and lipids throughout pregnancy. Third, thyroid autoimmune-related indicators, such as thyroid peroxidase antibodies and thyroglobulin antibodies, were incorporated into this study, potentially bearing relevance to the mechanistic underpinnings of dyslipidaemia in SCH during pregnancy and its associated adverse outcomes. Consequently, larger sample sizes and well-designed multicentre studies are imperative to corroborate the present findings and to gain a comprehensive understanding of the intricate interplay among dyslipidaemia, thyroid dysfunction, and unfavourable pregnancy outcomes.

The Beijing Obstetrics and Gynecology Hospital, Capital Medical University Ethics Committee gave its approval to the study protocol on February 2nd, 2018 (reference number: 2018-KY-003-02). All participants provided their informed consent to be a part of this study and approved the sharing of their data.

Not applicable.

The authors declare no competing interests.

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