Short abstract
Background
To determine the prevalence and outcomes of intrahepatic cholestasis of pregnancy.
Methods
A review comparing intrahepatic cholestasis of pregnancy pregnancies to all other pregnancies in three tertiary care Australian hospitals over a 36-month period.
Results
There were 43,876 pregnancies. The prevalence of intrahepatic cholestasis of pregnancies (n = 319) was 0.7%. There were differences between intrahepatic cholestasis of pregnancy and non-intrahepatic cholestasis of pregnancy mothers including higher prevalence of South Asian (22.6% versus 3.1%, p < 0.001), Indigenous Australian (3.8% versus 1.8%, p < 0.05), and Asian ethnicity (8.4% versus 5.7%, p < 0.05), mothers with a body mass index >35 kg/m2 (10.6% versus 5.5%, p < 0.001), those with diabetes mellitus (25.7% versus 9.8%, p < 0.001), and those with twin births (8.7% versus 2.2%, p < 0.001). The primary clinical outcomes of intrahepatic cholestasis of pregnancy included a median gestational age at delivery of 36.4 (SE 0.09) weeks compared to 38.6 (SE 0.01) weeks (p < 0.001), a lower birth weight (3.12 (SE 0.03) versus 3.31 kg (SE 0.03), p < 0.001), and an increase in special care nursery admissions (44.5% versus 15.3%, p < 0.001).
Conclusion
Treated intrahepatic cholestasis of pregnancy in the population described here had similar mortality outcomes although increased special care nursery admission as compared to the general population.
Keywords: Intrahepatic cholestasis of pregnancy; liver function tests, obstetric cholestasis, pruritus, ursodeoxycholic acid
Background
Intrahepatic cholestasis of pregnancy (ICP) is a medical condition associated with increased pregnancy risk. Although ICP is uncommon, the risk of stillbirth can be a source of anxiety and depression for the mother.1 ICP is characterised by pruritus in the absence of a skin rash and abnormal liver function tests, specifically deranged hepatic enzymes, in the absence of an alternative cause and with resolution following/post-delivery. The epidemiology of ICP is not well understood within Australia, although in English multi-ethnic pregnancies the incidence is believed to be 0.7%,1 and 1.2–3.1% in patients of South Asian origin.2–4 It appears the incidence is also influenced by genetics and environmental factors, with 2.4% of pregnancies in Chile affected, and a 5% prevalence in women of Araucanian-Indian origin.5
Classically the condition presents with an unremitting pruritus, typically of the palms of the hands and soles of the feet and the diagnosis is confirmed biochemically with liver transaminase and/or bile acid elevation. The pruritus can occur for weeks before liver biochemistry becomes deranged, and as such liver biochemistry needs to be measured regularly in the presence of ongoing symptoms.6 Fetal ultrasound and cardiotocography can provide reassurance and reduce anxiety in the mother, although evidence concerning the predictive value of this is limited. Additionally, since the suspected pathophysiology of fetal demise is acute anoxia and not related to placental insufficiency, these investigations are of little benefit for risk stratification.7 The diagnostic criteria for, and management of, ICP are not well defined7–9 and vary within Australia.10 It is unknown what obstetric or medical comorbidities coexist most commonly within Australian-diagnosed ICP women. These limitations are concerning as ICP, and specifically a high bile acid level, has been associated with increased fetal risks including preterm birth, iatrogenic preterm birth, and fetal death.8,11,12 Furthermore, the mental well-being of the mother is associated with maternal morbidity relating to severe pruritus,1,7 sleep deprivation, and stress and anxiety13–15 associated with linkages to preterm stillbirth in patients with ICP.8,13,16–19
This research has the following aims: determine the prevalence and pregnancy outcomes of ICP in Canberra, Gold Coast, and South Brisbane pregnancies; it is hypothesised that the prevalence of ICP pregnancies will be low (<1.0% of all pregnancies); and ICP pregnancy outcomes will be statistically similar to those without ICP.
Methods
A retrospective clinical audit review was performed at The Canberra Hospital (TCH), the Gold Coast University Hospital (GCUH), and the Mater Mothers’ Hospital (MMH), all of which are large tertiary teaching hospitals, within geographic diverse regions of Australia including Canberra (ACT), the Gold Coast, and South Brisbane (Qld), between 1 January 2014 and 31 December 2016 (36 months).
Raw data collection
Raw data were gained from the hospital’s Birth Outcomes System at TCH and the Maternity Information System at the GCUH and the MMH. The researchers conducted an electronic search of all records that contained the key words: obstetric cholestasis and abnormal liver function. The premise of selecting these key words included the term obstetric cholestasis capturing all believed diagnosis and abnormal liver function highlighting those without a clear diagnosis. These raw data were then used during an audit of patient medical records, as detailed below.
Patient note audit
Raw data collected were used in further analysis of the patient record and key information recorded during the audit included demographic information, pathology results, and diagnostic terms.
Prevalence, management, and pregnancy outcomes
Following the audit of medical records, further data analysis was conducted aimed at confirming/diagnosing ICP, including pruritus with non-pregnancy causes excluded. Data concerning management and pregnancy outcomes were collected. The main outcome measures investigated were mode of delivery, preterm delivery, stillbirth, and neonatal unit admission. This information was then used to compare the overall prevalence rate in normal pregnancies to those with ICP.
Exclusion criteria
Exclusion criteria included women with pruritus but without deranged liver biochemistry or elevated bile acids and pregnancies ending before 24 weeks' gestation.
Statistical analysis
Comparisons between incidence of variables in ICP pregnancies and all other pregnancies were made, using Chi-square and independent t-tests with significance determined at p < 0.05.
Results
A total of 43,876 pregnancies were included in the study, with a mean maternal age of 30 (SE 0.04) years. The overall prevalence of ICP was 0.7% (n = 319). Detailed study site comparisons are shown in Table 1.
Table 1.
All other pregnancies and ICP prevalence by study site.
| Study site | All other pregnancies (n) | ICP (n) | Prevalence (%) |
|---|---|---|---|
| TCH | 10,424 | 66 | 0.6 |
| GCUH | 14,673 | 91 | 0.6 |
| MMH | 18,460 | 162 | 0.9 |
| Total | 43,557 | 319 | 0.7 |
GCUH: Gold Coast University Hospital; ICP: intrahepatic cholestasis of pregnancy; MMH: Mater Mothers’ Hospital; TCH: The Canberra Hospital.
Ethnicity was not reported in all pregnancies, and therefore the prevalence of ICP for each ethnicity cannot be generated. We provide the percentage of each ethnicity in the ICP pregnancy and non-ICP pregnancy populations. Amongst pregnancies where ethnicity was reported, 53.6% of women in the ICP population were of Caucasian origin, compared with 72.1% of women in other pregnancies (p = <0.001). In contrast, nearly 23% of women in the ICP population were of South Asian origin, compared with only 3% of other pregnancies (p < 0.001). Indigenous Australian women (p = <0.05) and Asian women (p = <0.05) were also over-represented in the ICP population. Women in the ICP population had a higher BMI (mean (SE) 25.5 (0.3) versus 24.4 (0.03) kg/m2, p = <0.01), and a higher prevalence of morbid obesity (BMI >35 kg/m2) (10.6% versus 5.5%, p < 0.001), indicating that obesity increases risk.
Average gestational age at delivery (36.4 (0.09) versus 38.6 (0.01) weeks, p < 0.001) and mean birth weight (3.1 (0.03) versus 3.3 (0.03) kg, p < 0.001) were significantly lower amongst infants born to women in the ICP population. There were more special care nursery (SCN)/neonatal intensive care unit (NICU) admissions in the ICP population (44.5% versus 15.3%, p < 0.001). There was an increased rate of induction of labour (79.9% versus 31.2%, p < 0.001) and an increased likelihood of twin pregnancy (8.7% versus 2.2%, p < 0.001) and diabetes mellitus (all types) (25.7% versus 9.8%, p < 0.001) in the ICP population group.
The rates of caesarean section differed (p < 0.001) with 48.6% in ICP pregnancies versus 26.7% in all other pregnancies. Perinatal mortality did not differ (p > 0.05) with no stillbirths in pregnancies complicated by ICP and 0.8% stillbirths in all other pregnancies. Detailed comparisons are in Table 2.
Table 2.
Overall pregnancy population compared to ICP.
| Description | All other pregnancies (n = 43,557) | ICP (n = 319) | P-value* |
|---|---|---|---|
| Ethnicity (n) | n=10,053a | n=319 | |
| Caucasian | 7247 (72.1%) | 171 (53.6%) | <0.001 |
| South Asian | 310 (3.1%) | 72 (22.6%) | <0.001 |
| Indigenous Australian | 185 (1.8%) | 12 (3.8%) | <0.05 |
| Middle- Eastern | 85 (0.8%) | 6 (1.9%) | >0.05 |
| South-American | 59 (0.6%) | 4 (1.2%) | >0.05 |
| African | 31 (0.3%) | 2 (0.6%) | >0.05 |
| Asian (excluding South Asian regions) | 570 (5.7%) | 27 (8.4%) | <0.05 |
| Other | 1566 (15.6%) | 25 (7.8%) | – |
| Mother characteristics at delivery | |||
| Average mother age (standard error) | 30.0 (0.04) | 30.0 (0.3) | >0.05 |
| Average mother BMI kg/m2 (standard error) | 24.4 (0.03) | 25.5 (0.3) | <0.01 |
| Mother BMI >35 kg/m2 | 2389 (5.5%) | 34 (10.6%) | <0.001 |
| Diabetes (GDM, T2DM, T1DM) | 4254 (9.8%) | 82 (25.7%) | <0.001 |
| Hypertension | 1200 (2.7%) | 7 (2.2%) | >0.05 |
| Birth characteristics and outcomes | |||
| Mother | |||
| Induction of labour (IOL) | 13,605 (31.2%) | 255 (79.9%) | <0.001 |
| Number of forceps-assisted deliveries | 2264 (5.2%) | 21 (6.5 %) | >0.05 |
| Number of vacuum deliveries | 3267 (7.5%) | 15 (4.7 %) | >0.05 |
| Number of c/s deliveries | 11,625 (26.7%) | 155 (48.6%) | <0.001 |
| Baby | |||
| Average gestational age at deliveries (standard error) | 38.6 (0.01) | 36.4 (0.09) | <0.001 |
| Special care nursery admission | 6658 (15.3%) | 142 (44.5%) | <0.001 |
| Special care nursery admission of gestation (36.0–42.1) | 3846 (8.8%) | 93 (29.1%) | <0.001 |
| Average birth weight – kg (standard error) | 3.31 (0.03) | 3.12 (0.03) | <0.001 |
| Stillbirths (gestational age range 24.0–39.5) | 349 (0.8%) | 0 (0.0%) | >0.05 |
| Twin births | 947 (2.2%) | 28 (8.7%) | <0.001 |
| Triplet births | 32 (<0.1%) | 1 (0.3%) | >0.05 |
BMI: body mass index; GDM: Gestational Diabetes Mellitus; ICP: intrahepatic cholestasis of pregnancy; T1DM: Type 1 Diabetes Mellitus; T2DM:Type 2 Diabetes Mellitus; c/s: caesarean section.
*Chi-square tests were used to compare: vaginal births, BMI >35kg/m2, forceps-assisted delivery, caesarean section, IOL, stillbirth, twin births, HT, NICU, SCN, and DM. Independent t-tests were used to compare average mother age, average gestational age, average birth weight, and average BMI.
aAll other pregnancy ethnicity data were not routinely collected at the study sites, although ICP ethnicity was collected throughout the study sites.
Amongst multiparous women in the ICP population, 50 (25.6%) had an ICP diagnosis during her last pregnancy. Nearly all ICP patients had pruritus (99.6%), and the vast majority of ICP patients had deranged liver biochemistry (83.5%), and elevated bile acids (77.9%) with 47 (13.5%) bile acid tests being severe (defined as >40 µmol/l). Details of pathology testing collected on the ICP pregnancies, including the pathology test description, mean results, and per cent deranged are shown in Table 3. Management data were also collected, including whether the patient’s symptoms were treated, and specifically whether the patient received pathology and imaging monitoring (Table 4). Results indicated that the majority of decisions concerning diagnosis and management of ICP patients were made by the treating consultant (86.4%), followed by the registrar (13.6%).
Table 3.
Pathology results of ICP pregnancies at diagnosis.
| Pathology test description (normal range) | Number of patients who received test | Number of pathology tests ordered | Mean average resulta | Number deranged (%) |
|---|---|---|---|---|
| Bile acid level (<10 µmol/l) | 319 | 349 | 22.0 (SD 23.9) | 272 (77.9) |
| Severe ICP (defined as bile acid >40 µmol/l) | 47 | 47/349 | 72.4 (SD 24.2) | 47 (13.5) |
| Aspartate aminotransferase (AST) (<40 U/l) | 129 | 129 | 104.6 (SD 87.6) | 61 (47.3) |
| Alanine aminotransferase (ALT) (<35 U/l) | 157 | 157 | 161 (SD 148.7) | 115 (73.2) |
| Gamma-glutamyl transferase (GGT) (<30 U/l) | 157 | 157 | 29.6 (SD 24.5) | 50 (31.8) |
ICP: intrahepatic cholestasis of pregnancy.
aThis result details the combined patient averages into a summed average.
Table 4.
Management of ICP patients.
| Management | (N = 319) |
|---|---|
| Medication | n (%) |
| Ursodeoxycholic acid | 192 (60.2) |
| Antihistamines | 53 (16.6) |
| Emollients | 9 (2.8) |
| Vitamin Ka | 132 (41.4) |
| Monitoring and management | |
| Pathology total (liver biochemistry and bile acid concentrations) | 156 (48.9) |
| IOL booked at diagnosis | 124 (38.9) |
| CTG/weekly | 55 (34.8) |
| CTG/x2 week | 214 (67.1) |
| Fetal U/S | 75 (23.5) |
| Confirmatory pathology following birthb | |
| Liver biochemistry collected following birth | 15 (4.7) |
| Bilirubin deranged following birth | 0 (0.0) |
CTG: cardiotocography; ICP: intrahepatic cholestasis of pregnancy; IOL: induction of labour; U/S: ultrasound.
aVitamin K is co-prescribed with ursodeoxycholic acid at the MMH, as per their internal protocol.
bConfirmation pathology was not routinely completed, as per discharge summaries, patient referred to general practitioners for follow-up pathology.
Discussion
Main findings
This study found that ICP was uncommon with an overall prevalence rate of 0.7%. This figure is consistent with recent 2017 findings from South Australia which found an ICP prevalence of 0.6%,20 although is inconsistent with earlier findings from 1988, which found a 0.1–0.2% prevalence rate.9 This change could in part be due to the increased prevalence of obesity and diabetes mellitus (DM) in the Australian population,21 greater ethnic diversity in Australian communities, greater awareness of the condition, and more frequent biochemical evaluation of pregnant women with pruritus. This study found that there was a significantly higher prevalence in South Asian, Indigenous Australian, and Asian ethnicity women amongst patients with ICP, with women from Indian and Pakistani ancestry representing 22.6% of our ICP population which is consistent with other published articles.2–4
The results from this study indicated that the prevalence of ICP was significantly higher amongst those with a BMI greater than 35 kg/m2 and significantly different when comparing overall group BMI (24.4 versus 25.5 kg/m2). Gestational diabetes mellitus and pre-eclampsia are more common in women who are overweight or obese;22 in our cohort, women with a BMI of greater than 35 kg/m2 were more likely to have ICP. Consequently, overweight and obesity may explain the association between ICP and these pregnancy-related diseases. This result is inconsistent with Shemer et al.,23 who found that women in their cohort were less likely to have a high BMI. As such, this association warrants further investigation. South Asian, Asian, and Indigenous Australian ethnicity, obesity, third trimester of pregnancy, and multiple pregnancies are all associated with increased insulin resistance raising the possibility that this may play a role in the development of ICP. Studies testing the association of increased risk of ICP to polycystic ovarian syndrome may be worthwhile. South Asian, Asian, and Indigenous Australian ethnic groups are also at increased risk of non-alcoholic fatty liver disease (NAFLD), with NAFLD being associated with elevated concentrations of bile acids.24
This study demonstrated a significant relationship between ICP and DM, which is consistent with other published research.25,26 Prior publications highlighted a potential relationship between bile acid, cholesterol, and glucose homeostasis, in which the primary bile acid receptor farnesoid X receptor (FXR) is reported to influence normal glucose homeostasis as well as pathways involved in cholesterol metabolism.27 It is possible that ICP and an increased GDM prevalence is the result of aberrant bile acid homeostasis.28 To our knowledge this has not been studied beyond a prevalence association. However, a study by Lien et al.29 indicated that metformin treatment induces FXR phosphorylation and perturbed bile acid homeostasis. This is in contradiction to a recently established clinical trial by Shehata and Ali,30 who are proposing to compare the effect of metformin versus ursodeoxycholic acid on lowering of liver enzymes and bile acids, with the ultimate aim of improving maternal morbidity and improving neonatal outcomes. Furthermore, a case study by Elfituri et al.31 found that ICP ‘occurred in five consecutive pregnancies with a different course of the disease in the fifth pregnancy’, with the fifth pregnancy receiving metformin treatment for gestational diabetes mellitus. They concluded that metformin was associated with lowering the effect on bile acid and liver enzymes. As such, we believe that metformin-induced cholestasis is extraordinarily uncommon in treating diabetes mellitus and look forward to future clinical trial findings.
This study demonstrated a significant relationship between ICP and twin birth rates. This association could be related to the role of sex hormones during pregnancy, with evidence suggesting that oestrogens are involved in the pathogenesis of ICP.15 Evidence in this current study that supports this includes the predominant appearance of ICP in the third trimester when oestrogen production reaches its maximum. Furthermore, the prevalence of ICP was four times greater in twin pregnancies, which are characterised by having higher concentrations of oestrogen than control pregnancies, with similar findings reported in other studies.15 Multiple pregnancies are also believed to be associated with greater insulin resistance, although this needs confirmation research. Lastly, ICP resembles the cholestatic picture developed in some women using oral contraceptives with high oestrogen content.32 Of note, the role of oestrogen may also explain the increased prevalence of ICP in women of a higher BMI. To our knowledge this association has not been researched and is a potential gap in understanding ICP.
This study found that there was a significant difference in the median gestational age at delivery of the ICP pregnancies. This result is not surprising as some expert opinion recommends delivery of diagnosed ICP fetuses after 37 weeks, or earlier if there is a deterioration of the maternal liver enzymes.7,33 There have been no randomised studies concerning the optimal timing of induction, due to limitations associated with participant numbers, and as such some clinicians are guided by serum bile acid concentrations.34,35 Many will advise induction when bile acid concentration is over 40 µmol/l at 37 weeks of gestation,34 with others advising to wait until 39 weeks of gestation.12,35,36 Our findings indicated that severely elevated bile acid results (13.5%) resulted in IOL between 36 and 39 weeks. The timing of delivery appears to be clinician-dependent, with some applying a blanket rule to ICP with IOL at 37 weeks, while others preferring to monitor liver biochemistry, serum bile acids and trying to increase gestation to over 38 weeks.
The results from this study indicate that most of the ICP pregnancies are induced at or before 37 weeks’ gestation, based on the belief that fetal risk is reduced and neonatal outcomes improved by delivering early. This belief was not confirmed in this study, with significantly more ICP babies being admitted to the SCN, for complications related to the induction. Other studies indicate that IOL at term gestation can reduce perinatal mortality.37 Results of this study indicated similar perinatal mortality, although more nursery admissions. The long-term effects, reflective of the reason for nursery admission, have not been studied in this population.
This study did not find that stillbirth rates in ICP differ from other control pregnancies and this is possibly a direct reflection of established ICP management. Previous research indicated an association between stillbirths and ICP, and this is the primary premise behind literature recommending induction at 37 weeks gestation. Much of the literature that demonstrated an increased stillbirth rate associated with ICP are over 20 years old9,11 and preceded contemporary guidelines. Recent publications demonstrate that the risk of fetal death in ICP still increases by each additional week of expectant management and continues to rise by week of gestation beyond 36 weeks.38 As such, it is reasonable to assume that the ICP stillbirth rates in this study were reduced by induction at 37 weeks of gestation, and that current management practices are achieving good outcomes.9,11,38
Strengths and limitations
This is a large study from multiple sites dispersed across Australia collecting detailed information concerning ICP. This study had the following limitations, including limited to three case hospitals, being retrospective in nature, and the control populations’ ethnicity data not being routinely collected. Future studies will include other case hospitals from different geographical areas including additional hospitals from New South Wales, Victoria, South Australia, and potentially Western Australia and the Northern Territory. These future studies will broaden the research topic to include severity of disease and fetal monitoring and medical treatment of ICP.
Interpretation
The clinical features that led to a diagnosis of ICP in this population were based on the definition of ICP (pruritus and increased bile acids in the absence of another pathology) and accepted guideline recommendations.8
This study found that in the majority of cases ICP management reflected guidelines,8 with the exception of biochemistry monitoring following diagnosis and the use of vitamin K. This included the use of ursodeoxycholic acid (60.2%), symptom relief using antihistamines (16.6%), and the monitoring of biochemistry following diagnosis (48.9%). As per the literature, the management of ICP should predominately be aimed at relief of the maternal symptoms and in high-risk cases, earlier delivery.7,35 Medical therapies such as topical emollients, antihistamines, and ursodeoxycholic acid are advised for the relief of maternal pruritus. Their efficacy can be variable and some adverse effects can occur.15,39 Low-fat diets (i.e. low fat-soluble vitamins) have also been suggested as management options.15,40 Of these interventions, only ursodeoxycholic acid has a direct effect on the liver enzyme and bile acid concentrations, with a recent meta-analysis by Kong et al.41 suggesting that ursodeoxycholic acid results in fewer premature births, reduced fetal distress, fewer neonates in the intensive care unit, and increased gestational age and birth weight in women with ICP.
Conclusion
The results from this study show that the prevalence of ICP in Canberra, the Gold Coast, and South Brisbane is similar to that in other predominantly White populations (0.7%). Furthermore, results indicate that the present treatment methodology of ICP pregnancies results in similar perinatal mortality outcomes as the general population, despite increased IOL and nursery admission. The results confirm the hypothesis that the prevalence of ICP pregnancies will be low (<1.0% of all pregnancies). However, the results do not confirm the hypothesis that ICP pregnancy outcomes will be similar to those without ICP, due to significantly more nursery admissions in the ICP population. Findings from this study could indicate that the ICP management algorithm in Australian hospitals is working in reducing stillbirth rates, although questions should be raised associated with the increased nursery admission rates. Future studies should consider a national cohort looking at severity outcomes, associations of insulin resistance and ICP, and an analysis concerning whether the incidence of postpartum haemorrhage differed in patients who received vitamin K as compared to those that did not.
Acknowledgements
We would like to acknowledge the staff and patients of The Canberra Hospital, the Gold Coast University Hospital, and the Mater Mothers’ Hospital for their support and enthusiasm during this project. We would also like to acknowledge the following individuals for providing external project pre-submission support: Ezekiel Uba Nwose, Phillip Bwititi, Judith Crockett, Lexin Wang, Jo Borrman, and Elli Gardiner.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical approval
This project has received Human Research Ethics Committee (HREC) approval from the ACT Health Research Ethics and Governance Office (ETHLR.17.067), and the Queensland Government Health Research Ethics and Governance Office (HREC/17/QGC/264). Patient written consent was not required for this low-risk retrospective review.
Guarantor
FWG
Contributorship
FWG, RM, CA, TC, AM, JL, TN, BL, and MJP contributed to all aspects of the study design. FWG had overall responsibility for the study and coordinated the running of the study. FWG and TN analysed the data with input from RM, CA, TC, AM, JL, BL, and MJP. All authors were responsible for the drafting of the manuscript. All authors gave approval for the final version of the manuscript.
References
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