Study population
A retrospective matched case–control study was conducted in a single tertiary medical center. The study group consisted of all pregnant women with a history of chronic liver disease who gave birth between July 2012 and August 2019. For the control group, we selected women without liver disease who gave birth during the same period and were matched 1-to-3 with the study group for age, parity, and number of fetuses. Only women with known pregnancy outcomes were eligible. Preexisting chronic liver disease in the study group was defined as hepatitis B carrier status, hepatitis C carrier status, primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, Wilson disease, or NAFLD.
Women less than age 18 years and women who were diagnosed with chronic liver disease after the index pregnancy were excluded from the study.
Outcome measures
The primary outcome measure of the study was the incidence of preeclampsia during pregnancy and postpartum, with and without severe features. Secondary outcome measures were obstetrical and neonatal complications.
Data collection
The data set was retrieved from the hospital’s comprehensive computerized healthcare database and included demographic and obstetric history, pre-gestational medical history, pregnancy complications, and pregnancy outcomes.
Sample size
Sample size calculation was made using a statistical significance of 5% and a statistical power of 80%. The method that was used is a proportional comparison between two groups by a z-test. We assumed that the average rate of preeclampsia in the general population at our center is 5% and we hypothesize that the rate of preeclampsia among women with a chronic liver disease will be at least 2–3 times higher, according to previous publications. In order to show that the risk is doubled, the study group should contain 305 women and for a triple risk the study group should contain 100 women.
Statistical analysis
Statistical analysis was generated using SAS, version 9.4. Continuous variables were presented by Mean ± Std, Categorical variables were presented by (N,%).
T-test was used to compare the value of normally distributed continuous variables between study groups, Wilcoxon was used for skewed continuous variables and Fisher's exact test was used to compare the value of categorical variables between study groups. Two sided p values less than 0.05 were considered statistically significant. Missing data were assumed to be missing at random, therefore only available data were analysed.
Confounders found to be significant on univariate analysis were evaluated using logistic regression models, and odds ratios (OR) and confidence intervals (CI) were calculated.
Ethical approval
The study was approved by the local Institutional Review Board (approval number 0339–19-RMC).
Definitions
The diagnosis of preeclampsia in a previously normotensive woman was based on the following criteria: new-onset hypertension (defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, on at least two occasions at least 4 h apart; or systolic blood pressure of 169 mmHg or more or diastolic blood pressure of 110 mmHg or more, confirmed within a short interval of minutes) and proteinuria (defined as ≥ 0.3 g in a 24-h urine collection or protein/creatinine ratio ≥ 0.3 in a random urine specimen or random dipstick > 2 +) occurring after 20 weeks of gestation [17,18,19]. In the absence of proteinuria, preeclampsia was diagnosed if the new-onset hypertension was accompanied with the new onset of any of the following severe features: renal insufficiency (serum creatinine > 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease), pulmonary edema, platelet count less than 100 X 109/L, impaired liver function (elevated blood concentrations of liver transaminases to twice normal concentration, or new onset headache unresponsive to medication and not accounted for by alternative diagnoses or visual symptoms. [19]. Severe features of preeclampsia were defined as either systolic blood pressure ≥ 160 mmHg or more, or diastolic blood pressure ≥ 110 mmHg or more, on at least two occasions at least 4 h apart; platelet count less than 100 X 109/L; renal insufficiency; pulmonary edema; new onset headache unresponsive to medication and not accounted for by alternative diagnoses, or visual disturbances; or impaired liver function that is not accounted for by alternative diagnoses and as indicated by abnormally elevated liver enzymes or by severe persistant right upper quadrant or epigastric pain unresponsive to medications.
The definition of severe features secondary to impaired liver function was changed in the updated ACOG Practice Bulletin No. 222 [19], replacing ACOG Practice Bulletin No. 202 [17], which was withdrawn.
Gestational age was calculated by the last menstrual period or by the first-trimester ultrasound if the discrepancy from the last menstrual period exceeded 7 days.
Fetal growth restriction (FGR) was defined as either estimated fetal weight below the 10th percentile for gestational age or abdominal circumference below the 10th percentile for gestational age, according to the local growth curves [20].
Gestational diabetes mellitus was diagnosed with the two-step approach. Gestational diabetes was defined as either a glucose challenge test of 200 mg/dL or higher between 24 and 28 gestational weeks or an abnormal 100-g oral glucose tolerance test with at least one pathological value, according to the criteria of Carpenter and Coustan [21].