Perinatal outcomes of intrahepatic cholestasis of pregnancy from two birth cohorts: A population-based study

Abstract

Background

Intrahepatic cholestasis of pregnancy (ICP) is a complex liver disease with varying incidence worldwide. We compared ICP incidence and pregnancy outcomes with outcomes for normal pregnant controls.

Methods

We conducted a retrospective data analysis of perinatal registry data for the years 2011 and 2017 to compare the following outcome measures: stillbirths, labour induction, gestational diabetes, pre-eclampsia, antepartum haemorrhage, postpartum haemorrhage, preterm births, low Apgar score, acute neonatal respiratory morbidity, meconium aspiration and in-hospital neonatal death.

Results

The incidence of ICP was 8 per 1000 births from a total 31,493 singleton births with more cases in 2017 than in 2011. Women with ICP were almost six times more likely to have labour induced including significantly more moderate preterm births (defined as between 32 weeks and 36 weeks and 6 days of gestation)) seen more in 2011 than in 2017.

Conclusion

Women with ICP showed higher incidence of moderate preterm birth and induced labour but favourable maternal and neonatal outcomes.

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is the commonest pregnancy-related liver disorder.^1,2 Its pathogenesis remains poorly understood, but hormonal, ³ inflammatory, ⁴ immunological ⁵ and genetic ⁶ influences contribute, as does pre-existing hepatobiliary disease. The reported incidence varies, ranging from less than 1% to 27.6%.^7–9 While the incidence in Western countries is 0.5%–1.5%, ¹⁰ the highest reported incidence was in Chile in a report published in the previous century. ¹¹ Risk factors linked to ICP include chronic hepatitis C, personal or family history of intrahepatic cholestasis and advanced maternal age. ⁷

ICP symptoms usually develop during the late second or third trimester, with the primary indicator being generalised pruritus often starting in the palms and soles; less common symptoms include nausea and poor appetite. Diagnosis is based on presence of pruritus with elevated total serum bile acid, elevated aminotransferases, or both in the absence of confounding diseases.

ICP has been associated with adverse fetal outcomes including intrauterine death. meconium-stained amniotic fluid, preterm delivery (spontaneous and iatrogenic) and neonatal respiratory distress syndrome.^9,12,13 The ICP-attributed incidence of stillbirth is reported to be about 0.9%. ¹⁴ Though some risk appears to increase with higher bile acid levels and advancing gestational age, data are inconsistent regarding fetal risks, possibly attributable to unclear diagnostic criteria for ICP.^8,15 In our group of hospitals, a central management guideline is followed. Following an early and accurate diagnosis, a multidisciplinary approach involving the gastrointestinal unit is utilized to help alleviate maternal symptoms and improve fetal prognosis. These medical and pharmacologic modalities include dietary modification, weekly monitoring of liver function tests and bile acid levels, coagulation test before labor or if liver function tests are abnormal and the use of ursodeoxycholic acid (UDCA), antihistamines or topical emollients. For our study, we compared pregnancy outcomes among a group of normal pregnant controls with outcomes among women with ICP across two birth cohorts.

Methods:

Setting and participants

Qatar is a peninsula country located in the Middle East It is a fast-growing economy with a population of about 2.5 million people. ¹⁶ Besides the country's citizens, it is home to many other Arabs, Asians and other nationalities which make up the resident population. Health care is highly subsided and universal. Its maternal and neonatal health indices compare with those in developed countries.

This was a retrospective data analysis from a population-based registry of routinely collected perinatal hospital data in Qatar for the years 2011 and 2017, the two phases of the Perinatal Neonatal Outcomes Research Study in the Arabian Gulf (PEARL) project. We retrieved 31,493 singleton births at 24 weeks of gestation and above. We excluded multiple gestations because they differ in fetal growth and duration of gestation and have higher rates of obstetric and neonatal complications. Both phases of the project study were approved by the Hamad Medical Corporation Institutional Review Board.

Comparison groups

The groups for study comparison were pregnant women with ICP and pregnant women without ICP as well as women with ICP in 2011 and in 2017. We defined cases of ICP as clinician-reported diagnosis with the clinical and biochemical picture of ICP in the second or third trimester of pregnancy and the relevant ICD–10 code (O26.6) at discharge from the delivery hospital.

Covariates and outcomes

We classified maternal age at delivery into four groups: 13–24, 25–29, 30–34 and 35 or above years. Ethnicity was grouped into Arab or Non-Arab and parity status was classified as nulliparous or parous. the presence or absence of essential hypertension or diabetes mellitus (Type 1 or 2) was recorded. The main outcome measure was stillbirth, while the secondary outcomes were gestational diabetes, pre-eclampsia, antepartum haemorrhage, postpartum haemorrhage, prematurity, macrosomia, low Apgar score at 5 min, respiratory distress syndrome, meconium aspiration and in-hospital neonatal death.

We defined gestational diabetes as diabetes first diagnosed during pregnancy and pre-eclampsia as the new onset of hypertension and proteinuria or of hypertension and significant end-organ dysfunction with or without proteinuria in the last half of pregnancy or postpartum. We defined antepartum haemorrhage as abnormal uterine bleeding after 20 weeks of gestation and postpartum haemorrhage as excessive vaginal bleeding with estimated blood loss (EBL) of500 ml or more after vaginal birth or EBL of 1000 ml or more after caesarean section within 24 h of delivery. Induced labour referred to the use of either medical or mechanical means to stimulate uterine contractions to accomplish delivery; data for induced labour were available for only vaginal births. We defined preterm birth as delivery at less than 37 weeks of gestation and further subclassified it into moderate (32 weeks to 36 weeks and 6 days ofgestation) or very (before 32 weeks) preterm birth.

We defined stillbirth as fetal death after 24 weeks of gestation and macrosomia as a birthweight of 4000 g or more. We considered a score of less than 7 at 5 min to be a low Apgar score, and we defined in-hospital neonatal death as the death of an infant from 0 to 27 days after birth. The presence of respiratory distress syndrome or transient tachypnoea of the newborn and meconium aspiration was obtained by diagnosis at discharge from delivery or neonatal care hospital.

Statistical analysis

We estimated the overall incidence of ICP in the whole population and in each year, comparing the maternal characteristics and pregnancy outcomes within comparison groups using chi-square or Fisher's exact test as appropriate. For the overall population, we estimated the risk of adverse pregnancy outcomes in relation to ICP using logistic regression, with crude and adjusted odds ratios considering possible confounding factors. We adjusted for parity, ethnicity, and year of delivery. We used IBM SPSS 22 to perform all statistical analysis, setting statistical significance at 95% confidence intervals (CIs) and p <.05.

Results

Overall, there were 263 cases of ICP among 31,493 singleton births, giving an incidence of 8:1000; there were more cases in 2017 (n  =  205) than in 2011 (n  =  58; 1.3% vs. 0.4%, p < 0.001; Table 1). There were more non-Arab women in the group of women with ICP than in the non-ICP control patients (39.5% vs. 28.7%, p < 0.001). There were no differences between the ICP and non-ICP groups in maternal age or pre-existing diabetes; however, women with ICP were more likely to be nulliparous than were the non-ICP controls (respectively, 40.3% vs. 25.1%, p < 0.001).

Table 1.

Maternal characteristics for singleton pregnancies in women with and without ICP.

	Total (n = 31,493)		No ICP (n = 31,230)		ICP (n = 263)		χ2 p-value
	n	%	n	%	n	%
Maternal age
≤24 years	6281	19.9	6236	20.0	45	17.1	0.138
25–29 years	10,164	32.3	10,070	32.2	94	35.7
30–34 years	9087	28.9	9002	28.8	85	32.3
≥35 years	5960	18.9	5921	19.0	39	14.8
Parity
Nulliparous	7917	25.2	7811	25.1	106	40.3	<0.001
parity ≥1	23,512	74.8	23,355	74.9	157	59.7
Hypertension a
No	31,031	98.5	30,775	98.5	256	97.3	0.106
Yes	462	1.5	455	1.5	7	2.7
Diabetes a
No	30,408	96.6	30,153	96.6	255	97.0	0.719
Yes	1085	3.4	1077	3.4	8	3.0
Ethnicity
Non-Arab	9075	28.8	8971	28.7	104	39.5	<0.001
Arab	22,418	71.2	22,259	71.3	159	60.5
Year of Birth
2011	15,391	48.9	15,333	99.6	58	0.4	<0.001
2017	16,102	51.1	15,897	98.7	205	1.3

^a History of Essential hypertension or Diabetes (Type 1 or 2).

Bold: statistically significant at p < 0.05.

Regarding obstetric outcomes, the two groups showed similar rates of stillbirth (ICP: 0.4%, non-ICP: 0.7%, p > 0.05). Women with ICP were more than six times more likely to have induced labour than were women without ICP (OR: 6.7, 95% CI: 4.96–8.94; p < 0.001). The association remained strong even after we adjusted for ethnicity, parity, and year of birth (aOR: 5.7, 95% CI: 4.26–7.79; p < 0.001; Table 2). There were more moderate preterm births (gestational age 32–36⁺⁶ weeks) in the ICP group (OR: 3.28; 95% CI: 2.38–4.52, P < 0.001; non-ICP, aOR: 3.08, 95% CI: 2.23–4.26; p < 0.001) and more women with gestational diabetes (OR: 1.33, 95% CI: 1.02–1.73; P  =  0.034), although this finding was attenuated by our adjusting for confounding variables. There were no differences between the ICP and non-ICP groups in other obstetric complications, and Table 3 indicates that there were also no differences in neonatal outcomes.

Table 2.

Adverse pregnancy outcomes in women with and without ICP.

							Crude OR		Adjusted OR
Pregnancy outcome	Total		No ICP		ICP		OR (95% CI)	p	AOR a (95% CI)		p
	n	%	n	%	n	%
GDM	7584	24.1	7506	24.0	78	29.7	1.33 (1.02–1.74)	0.034	1.27 (.97–1.66)	.077
PET	499	1.6	495	1.6	4	1.5	.96 (.36–2.59)	.934	.87 (.32–2.35)	.782
PPH	1654	5.3	1639	5.2	15	5.7	1.09 (.65–1.84)	.742	.99 (.58–1.67)	.962
Caesarean b	8454	27	8372	27.0	82	31.3	1.23 (.95–1.60)	.12	1.1 (.85–1.43)	.475
APH	298	.9	297	1.0	1	.4	.39 (.06–2.84)	.358	.41 (.06–2.91)	.37
IOL c	3245	14.1	3152	13.8	93	51.7	6.66 (4.96–8.95)	<.001	5.76 (4.26– 7.79)	<.001

^a Adjusted for parity, ethnicity and year of delivery.

^b Only live births included.

^c Vaginal deliveries only and adjusted for the effects of pre-existing diabetes and hypertension in the model.

APH: antepartum haemorrhage; GDM: gestational diabetes mellitus; IOL: induction of labour; PET: pre-eclampsia; PPH: postpartum haemorrhage.

Table 3.

Adverse neonatal outcomes in women with and without ICP.

							Crude OR		Adjusted OR
Neonatal Outcome	Total		No ICP		ICP		OR (95% CI)	p	AOR a (95% CI)	p
	n	%	n	%	n	%
Stillborn	218	.7	217	.7	1	.4	0.55 (.08–3.90)	.546	.58 (.08–4.14)	.585
Male gender	16051	51.0	15916	51	135	51.3	1.02 (.79–1.29)	.907	.98 (.77–1.25)	.895
Moderate Preterm b	1998	6.3	1951	6.2	47	17.9	3.28 (2.38–4.53)	<0.001	3.08 (2.23–4.26)	<0.001
Very Preterm b	434	1.4	432	1.4	2	.8	.68 (.17–2.74)	.588	.61 (.152–2.48)	.494
NICU admission b	3691	11.8	3651	11.8	40	15.3	1.35 (.96–1.89)	.085	1.16 (.82–1.62)	.406
Macrosomia b	1769	5.7	1758	5.7	11	4.2	.73 (.39–1.34)	.306	.87 (.47–1.59)	.64
Apgar <7 at 5 min b	84	.3	84	.3	0	0.0	──	─	──	─
RDS/TTN b	1714	5.5	1693	5.5	21	8.0	1.51 (.96–2.36)	.072	1.44 (.92–2.25)	.115
In-hospital Neonatal Death b	107	.3	107	.3	0	0.0	──	─	──	─
Meconium Aspiration syndrome b	124	.4	122	.4	2	.8	1.95 (0.48–7.92)	.352	1.87 (.46–7.67)	.385

^a Adjusted for parity, ethnicity and year of delivery.

^b Only live births included.

Differences between 2011 and 2017 birth cohorts

The women with ICP in the 2017 cohort were older and more parous, and there were more Arab women in 2017 than in 2011 (Table 4). There were, however, no statistically significant differences between them. There were more moderate preterm births in 2011 than in 2017 (31.0% vs. 14.1, p  =  0.003) and more induced labours in 2017 than in 2011 among women with ICP who delivered by vaginal births (56.1% vs. 36.6%, p  =  0.028). Other differences in ICP outcomes between cohorts were not significant.

Discussion

We have reported a low incidence of ICP in our population with a low incidence of stillbirths from more than 30,000 singleton births in 2011 and 2017. Previous researchers identified similar incidences in other large population-based studies^9,13,17 with generally no major differences between women with ICP and women without. Two studies on the Chinese population however reported incidences greater than 3%.^18,19 We documented more cases of ICP in 2017 than in 2011, which could be attributed to increased physician's awareness about the condition.

There were slightly younger women aged below 35 in the ICP group, but we found no association between maternal age and ICP. Shemer and colleagues ²⁰ and Gao et al. ¹⁸ reported an association between ICP and advanced maternal age. Others however,^{13,14,17,19,21} found no association with age. Two out of every five pregnant women with ICP in our study were nulliparous. This notwithstanding, the pathophysiology of ICP remains unclear, there is no known support for a direct relationship between ICP and parity, and previous researchers report no documented differences in ICP rates according to parity.^9,14,17,21

Other researchers also identified more women with essential hypertension in their ICP group than in the non-ICP group. ⁹ In several published reports, women with ICP showed a three-fold increased risk of gestational diabetes and pre-eclampsia.^9,13,14,22 Although we found more cases of gestational diabetes in the group of women with ICP than in the women without ICP, the findings were not statistically significant after we adjusted for confounding variables. There was no difference in the incidence of pre-eclampsia between the two groups.

Intrapartum, there were more cases of induced labour in the ICP group even after we adjusted for confounding variables. Labour induced at or before 37 weeks of gestation is frequent in ICP cases,^23,24 and another group of researchers suggested no additional risks associated with this management technique. ²⁵ Nevertheless, the evidence is still conflicting regarding the potential decrease in fetal morbidity and mortality.^22,26 Other researchers identified similar low stillbirth rates between women with and without ICP, which likely reflected active antenatal surveillance and approaches to managing the disease. ¹⁷ Current recommendation by The Society for Maternal-Fetal Medicine is to deliver women with ICP based on their bile acid levels. ²⁷ Separately, the Royal College of Obstetrics and Gynaecology ²⁸ considers that evidence is insufficient for uniformly inducing labour and states that instead, the practice should be considered on a case-by-case basis determined by the risk of a preterm delivery versus intrauterine fetal death.

Strengths and limitations

To our knowledge, this is the first examination of ICP in Qatar using a large and representative cohort. The advantages of which include the increase in statistical power of findings, reduction in selection bias and the opportunities for sub-group or cohort studies. Despite this, a limitation of registry-based studies is the absence of important data which may not be captured. A limitation of our study was that important biochemical parameters for diagnosing ICP and ursodeoxycholic acid (UDCA) use were missing. Meanwhile, Ovadia and colleagues’ individual patient data meta-analysis of more than 5000 ICP cases demonstrated that the highest risk for stillbirth was observed in women with total bile acid levels of over100 mmol/L. ¹⁴ In addition, UDCA has been found to be beneficial and recommended especially in reducing preterm birth.^27,29,30 In addition to this, another potential limitation is that our study was retrospective, and the results represent group-level measures. In addition, data for 2011 were retrieved from paper records, in contrast to the electronic health record data from 2017, and measurement bias and misclassification of outcomes cannot be ruled out in measures obtained from hospital records. Despite these limitations, findings from this study are generalisable to women with singleton pregnancies in our population.

Conclusion

Women with ICP have a higher incidence of induction of labour and moderate preterm birth than do normal pregnant controls with no short-term adverse effects on mother and newborn. Further research is required to explore disease severity and the management approach in our setting and region