Liver disease in pregnancy is an important medical disorder seen more often in developing countries than in developed ones. Abnormal liver test results are obtained in 3% to 5% of pregnancies because of many potential causes and the clinical outcomes ranges from self-limiting to rapidly fatal.¹ The main causes for abnormal liver tests in pregnant patients are:

1. Pregnancy-related liver disease. These are the common reasons for abnormal liver function tests in pregnancy. Five liver diseases unique to pregnancy includes the following -

(i) Hyperemesis gravidarum (HG)

(ii) Intrahepatic cholestasis of pregnancy (ICP)

(iii) Pre-eclampsia

(iv) Hemolysis elevated liver enzymes, and low platelets (HELLP)

(v) Acute fatty liver of pregnancy (AFLP).

2. Newly acquired liver diseases like acute viral hepatitis, drug induced liver injury or gallstones
3. Pre-existing chronic liver disease such as cholestatic liver disease, autoimmune hepatitis, Wilson disease, and chronic viral hepatitis.
4. Physiologic changes in pregnancy - Abnormal liver function test due to physiological changes in pregnancy without liver dysfunction have a unique pattern.²

Maternal liver disease can impact the fetoplacental unit, resulting in adverse fetal outcomes. Studies have shown that fetuses of mothers with hepatic disorders are at an increased risk of stillbirth, premature delivery, low birth weight, intrauterine growth restriction (IUGR), and admission to the Neonatal Intensive Care Unit (NICU).^3,4 The mechanisms underlying these adverse outcomes are multifactorial, involving both direct effects of liver disease on fetal development and indirect effects related to systemic complications. However, the complications associated with hepatic disorders during pregnancy extend beyond the immediate fetal implications. Maternal health can be compromised, with systemic manifestations such as hepatic encephalopathy, postpartum hemorrhage (PPH), and infections posing significant risks.^5,6 Understanding the clinical profile and outcomes of pregnant women with hepatic disorders is crucial for improving management strategies and reducing maternal and fetal morbidity. Hence the present observational study aims to assess fetal and maternal outcomes in patients with hepatic disorders during pregnancy.

After obtaining Institutional Ethical Committee approval and write informed consent from all the patients and her relatives, this prospective observational study was conducted in the Department of Obstetrics and Gynecology at tertiary care hospital during a period of 2 years from January 2020 - August 2021.  A total of 52 pregnant women diagnosed with hepatic disorders or deranged liver function tests (as per raised values of serum bilirubin/ PT INR / liver enzymes like ALP / AST / alkaline phosphatase) during pregnancy, (Irrespective of cause for deranged liver function tests and gestational age) were included in the study. Patients with hemolytic anemia and who not willing to participate in the study were excluded from the study.

Demographic data including age, residence, education, socio-economic status by modified Kuppuswamy classification was noted. Detailed history was taken. Thorough general examination was done in all patients. Anemia, jaundice, edema, bleeding gums, hepatic tremor were looked for Temperature, Pulse Rate, Blood Pressure, Cardiovascular system and Respiratory system findings were recorded. Abdominal examination was done to make out any liver and spleen enlargement and free fluid. Obstetric examination was done to note the size of uterus, lie, presentation and attitude of fetus, fetal heart rate, liquor volume and rough estimation of fetal weight. Patients who were either in labour or seriously ill were admitted in labour ward for intensive care. Patients with either good general condition or not in labour were admitted in antenatal ward for further evaluation.

Complete hemogram and reticulocyte count were done. Liver function tests like S. Bilirubin total, direct and indirect, total proteins, albumin and globulin, ALT, AST, S. Alkaline phosphatase, clotting time, bleeding time and USG were done. Coagulation profile was done for all, and values were noted. Viral markers study including HBs Ag, Anti HAV IgM, Anti HCV Ab, Anti HEV IgM by enzyme immunoassay (ELISA) technique was done. VDRL and HIV examination was done in all patients. Blood grouping and typing was done. After cross matching fresh blood and FFP was kept ready as alternation in coagulation profile was expected in jaundice complicating pregnancy. Medical gastroenterologist opinion was obtained in nearly all cases.

Diagnosis done according to clinical and laboratory findings by following standard guidelines.

(The above table was taken from William’s textbook of obstetrics 25th edition page no.1059).

All the patients admitted are managed according to the standard protocol. Mode of delivery was recorded. Jaundice per se was not an indication for caesarean section. Vaginal delivery with close monitoring was preferred and caesarean section was done only for obstetric indication. During vaginal delivery, labour was monitored by using partogram.

Fetal outcome- Soon after delivery all babies were assessed by pediatrician. Alive or dead, sex of the body, gestational age at birth, weight, Apgar score and presence or absence of any congenital anomalies were looked for and noted. Need of resuscitation, need of intubation, need of ICU admission assessed. As per pediatrician opinion, sick babies were admitted in preterm unit for intensive care. Babies were followed by, and cause of death was noted. Neonate was investigated for jaundice by the pediatrician. All these data were noted.

Maternal outcome- The outcome like- need of massive blood transfusion, PPH, APH, ICU admission, hospital stay duration. Cause of death is noted in cases of maternal mortality.

Data Analysis

The data was collected systematically and entered in Microsoft excel and analysed and expressed in terms of percentage, mean and standard deviation.

Among the studied population, most patients, i.e., 34 (65.38%), belonged to the age group of 21-25 years. The majority of them (44.23%) were from the lower middle class, 48.08% were primigravida, while 51.92% were multigravida. 46 patients presented in the third trimester, and 3 patients each presented in the first and second trimesters. A total of 49 (94.23%) patients delivered, while 3 (5.77%) remained undelivered. Most patients, i.e., 24, underwent LSCS (48.97%), while 22 (44.89%) delivered vaginally, (Table 1).

Table 1: Demographic and obstetrics characteristics of patients

The most common cause for hepatic disorders in pregnancy from our study group was viral hepatitis (28.85%) followed by preeclampsia (15.38%) as shown in figure 1. Hepatitis E virus (HEV) was the most commonly observed viral marker (7 patients). Hepatitis B virus (HBV) was found in 4 patients, while Hepatitis A virus (HAV) and Hepatitis C virus (HCV) were each observed in 2 patients.

Figure 1: Distribution according to diagnosis

The most common complication in the study group was Gestational hypertension reported in 19 cases as depicted in figure 2.

Figure 2: Distribution of Associated medical disorders in the study population

The mean systolic and diastolic blood pressure were 130 mmHg and 83.46 mmHg, respectively. Mean heart rate was 92.08 bpm, and mean temperature was 37.1°C. Icterus was present in 33 patients, pallor in 15, edema in 14, and clubbing in 8 patients. Hemoglobin levels were <5 g/dL in 3.85% and 5-7 g/dL in 15.38% of patients. Thirty-two patients had platelet counts <150,000, and 15 had elevated serum creatinine. Mean bilirubin levels increased from 4.81 mg/dL to 5.01 mg/dL before dropping to 4.34 mg/dL, (Table 2). Ultrasound showed hepatitis in 28.85% of patients, with 34 having hepatomegaly, 15 splenomegaly, and 15 ascites.

Table 2: Clinical examination and laboratory investigations

In the study, there were 37 live births, 10 stillbirths, and 2 abortions. Of 49 patients, 20 had preterm deliveries, and 27 had term deliveries. Six babies had a birthweight of less than 1500 grams, 9 weighed between 1500 and 2000 grams, 11 weighed between 2000 and 2500 grams, and 3 weighed over 3 kg. Out of the 37 live births, 31 (83.78%) neonates required NICU admission, and 7 neonates died despite NICU care, (Table 3).

Table 3: Distribution according to fetal outcome

The most common maternal complication was HELLP; 10 cases, followed by Disseminated intravascular coagulation with 7 cases. Among 52 patients, 21 (40.38%) patients required blood transfusion. 42 patients (80.77%) were discharged in good condition, 9 were expired, and 1 patient went discharged against medical advice, (Table 4).

Table 4: Distribution according to maternal complications and maternal outcome

Among 47 patients with bilirubin levels less than 10 mg/dL, 40 were discharged, and 6 died. Among 5 patients with bilirubin levels over 10 mg/dL, 2 were discharged, and 3 died. There was a significant association between total bilirubin levels and maternal outcomes (p = 0.029). Maternal death rate was 12.76% for bilirubin levels less than 10 mg/dL and increased to 60% for levels over 10 mg/dL.

Out of 49 patients, 5 had bilirubin levels over 10 mg/dL, 2 of which resulted in stillbirths. Among 44 patients with bilirubin levels less than 10 mg/dL, there were 34 live births, 8 stillbirths, and 2 abortions. Among the 5 patients with bilirubin levels over 10 mg/dL, 3 had live births, and 2 had stillbirths. There was a significant association between total bilirubin levels and fetal outcomes (p = 0.038). Fetal death rate was 34% for bilirubin levels less than 10 mg/dL and increased to 40% for levels over 10 mg/dL.

Table 5: Distribution of maternal and fetal outcome against total bilirubin level

Pregnancy associated liver diseases affect up to 3% of pregnant women and are the most frequent cause of liver dysfunction in pregnancy. When severe, they are associated with significant morbidity and mortality for both mother and infant.^5,7 In the present study, most of the patients i. e. 64.38% were in the age group of 21-25 years, which is comparable with previous study Vinayachandran S. et al⁸. This finding may be due to the fact that those women in this age group are the most reproductively active females.⁸ However, in the study by Kondareddy et al⁹, 80% of patients were aged 20-30 years. Similarly, Jyothi G et al¹⁰ found that 86.13% of patients with hepatic diseases in pregnancy were in the 20–30-year age group. The majority of patients in present study were from a lower socioeconomic class, similar to findings by Joshi et al¹¹ (65% lower class) and Jyothi et al¹⁰ (32.67% lower class). 51.92% were multigravida and 48.08% were primigravida, consistent with findings by Satia et al¹² and Vinayachandran et al⁸, but differing from Solanke et al¹³, who reported more primigravida mothers. Among 52 patients, maximum i.e., 88.6% presented in the third trimester, aligning with studies by Vinayachandran et al⁸ (98.18%) and Solanke et al¹³ (69.9%). Out of 52, 49 patients (94.23%) were delivered, and 3 (5.77%) remained undelivered, similar to findings in studies by Vinayachandran et al⁸, Jyothi et al¹⁰ and Satia et al¹². The need for delivery may be driven by the underlying cause of jaundice. Vaginal delivery occurred in 22 patients (44.89%), while 24 patients (48.97%) required a lower segment cesarean section. Among 3 instrumental deliveries, 2 patients (4.08%) needed forceps, and 1 (2.04%) required vacuum assistance. Jaundice itself is not an indication for cesarean section; it is performed based on obstetric needs.

Viral hepatitis was the most common cause of hepatic disorders in pregnancy, accounting for 28.8% of cases, followed by preeclampsia (13.5%), HELLP syndrome (13.5%), acute fatty liver of pregnancy (9.6%), cholestatic jaundice (7.7%), hyperemesis gravidarum (5.7%), and eclampsia (3.8%). This aligns with previous studies^9,12-14, which also identified viral hepatitis as a leading cause of jaundice in pregnancy. Hepatitis E (HEV) was the most prevalent type (46.7%) in our study, which is lower than the 78.8% reported by Solanke D. et al¹³ While HEV is usually self-limiting, it has a more severe course during pregnancy, with maternal mortality rates reaching up to 25%, compared to less than 0.1% in non-pregnant women. In our study, the maternal mortality rate for HEV was 14.3%. The increased severity may be due to pregnancy-induced immunosuppression, including a shift toward a TH2 immune response, reduced CD4 counts, increased CD8 counts, and elevated levels of estrogen and progesterone. These hormonal changes can impair immunity and facilitate viral replication by activating the HEV adapter protein ORF3.

In the present study, the majority of cases were associated with pre-eclampsia (36.5%), followed by chronic hypertension, gestational diabetes mellitus, severe anemia, and hypothyroidism (each 3.84%). Smaller proportions were associated with overt diabetes mellitus, hyperthyroidism, and COVID-19 (1.92% each). Similar findings were reported by Tripti et al¹⁵, who found 34.03% of cases linked to pre-eclampsia.

Presenting features included icterus in 63.44% of cases, pallor in 28.55%, and edema in 26.92%. Blood tests revealed deranged PT-INR in 37 patients, thrombocytopenia in 32, and abnormal renal function in 15. Mean total bilirubin increased from 4.81 mg/dl to 5.01 mg/dl during hospital stay before decreasing to 4.34 mg/dl. Hepatomegaly was noted in 65.38% of patients, splenomegaly in 28.85%, and ascites in 28.85%. Similar findings were reported in studies by Satia et al¹², Nath J et al¹⁴, and Tripti et al¹⁵.

The study found that 75.51% of fetuses were live born, 20.4% were stillborn, and 4.08% resulted in abortion. There were 22 female and 26 male babies. Satia et al¹² reported similar outcomes with 67% live births and 22% stillbirths. Preterm deliveries accounted for 42.5% and term deliveries 57.5% in our study, similar to findings by Kondareddy T et al⁹ (54.5% preterm) and Tripti et al (42.86% preterm).¹⁵ Low birth weight (<2.5 kg) was reported in 53% of cases, with 12.24% weighing less than 1.5 kg. Most neonates required NICU admission (83.78%), primarily due to prematurity and IUGR. There were 7 neonatal deaths (18.91%), consistent with Kondareddy T et al⁹ study where they reported 16.67% neonatal mortality rate. The high rates of preterm delivery and low birth weight are linked to liver dysfunction and jaundice during pregnancy.

In the current study, HELLP syndrome was the most common complication, observed in 10 (19.2%) cases, followed by DIC in 7 (13.5%) cases. HELLP syndrome occurs in 3-10% of preeclampsia cases and is associated with a maternal mortality rate of 20%. Similarly, Joshi et al¹¹ reported HELLP in 30% of cases, while Satia et al¹² noted DIC as the most common complication in 44% of cases. Among the 52 patients, 21 (40.38%) required blood transfusions due to altered blood parameters, emphasizing the need for specialized management in tertiary care facilities with 24-hour blood bank services. The maternal mortality rate in our study was 17.31%, which aligns with reports from other studies, such as 22% by Satia et al¹² and 24.31% by Tripti et al¹⁵. Contributing factors to high maternal mortality include poor nutrition, anemia, delays in seeking medical care, and late referrals, often leaving patients in critical condition upon arrival at the hospital.

In the present study, among 47 patients with serum bilirubin levels less than 10 mg/dl at admission, 40 were successfully discharged, 1 left against medical advice (DAMA), and 6 died despite intensive care management. Among the 5 patients with serum bilirubin levels above 10 mg/dl, 2 were discharged, while 3 died despite treatment. Maternal outcomes were significantly worse for those with bilirubin levels over 10 mg/dl, showing 60% maternal mortality compared to 12.76% in those with lower levels. This indicates that maternal deaths were directly proportional to serum bilirubin levels, with Tripti et al¹⁵ also reporting a 47% maternal mortality rate in cases above 10 mg/dl (p < 0.05). Additionally, of the 44 patients with initial bilirubin levels below 10 mg/dl, 34 had live births, 8 had stillbirths, and 2 had abortions, resulting in a perinatal mortality rate of 40%. In contrast, among the 5 patients with bilirubin levels above 10 mg/dl, 3 had live births, and 2 had stillbirths, accounting for 34% perinatal mortality. The p-value was also less than 0.05, suggesting a significant association between fetal outcomes and maternal serum bilirubin levels.

In conclusion, pregnant patients with abnormal liver function tests require comprehensive evaluation, as viral hepatitis is the leading cause of jaundice in pregnancy. Enhancing public awareness about hepatitis transmission, improving sanitation, and promoting routine antenatal check-ups and viral screenings can reduce jaundice incidence. Symptoms of hepatobiliary diseases may include jaundice, nausea, and abdominal pain. While mild jaundice can be treated conservatively, moderate to severe cases pose serious risks to maternal and fetal health, leading to increased morbidity and mortality. Timely diagnosis and management are essential, and critical cases necessitate expert obstetric care. Effective fetal monitoring during the antenatal period is crucial and should involve a skilled team of obstetricians, neonatologists, and nursing staff, along with well-equipped neonatal intensive care units (NICUs) to ensure optimal maternal and fetal care.

Clinical Significance

The study highlights the critical need for early detection and management of jaundice in pregnancy, particularly due to its association with high maternal and perinatal morbidity and mortality. By raising awareness, incorporating routine screenings, and ensuring multidisciplinary care, healthcare providers can significantly improve outcomes for affected mothers and their infants.

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