SARS-CoV-2 is a virulent pathogen that first emerged in December 2019 in the Hubei province of China. This virus causes severe acute respiratory syndrome and the associated illness was termed coronavirus disease 2019 (COVID-19) by the World Health Organization (2021). As a result of the virulence of this disease and the global movement of infected people, COVID-19 quickly became a global pandemic and crisis (European Centre for Disease Prevention and Control, 2021).
Patients with COVID-19 have exhibited a wide spectrum of clinical presentations, including fever, respiratory symptoms, and extra-respiratory manifestations, such as thrombotic complications (Ahmed et al, 2020). To date, there is no robust evidence linking SARS-CoV-2 viral infection and the symptom of itching (Ahmed et al, 2020; Lai et al, 2020; Stefaniak et al, 2020).
Immune system changes occur during pregnancy, making pregnant women more susceptible to external pathogens; thus, pregnant women are considered a high-risk group in the pandemic (Eltaweel et al, 2021).
Intrahepatic cholestasis of pregnancy (ICP) is a serious liver disorder occurring in late pregnancy, which can lead to life-threatening complications in the fetus, such as premature delivery and stillbirth (NHS, 2019). This multifactorial condition is characterised by itching with abnormal liver function tests and raised bile acids, which usually resolve after delivery. ICP remains a diagnosis of exclusion, as other liver pathologies must be ruled out first before coming to a diagnosis of ICP. A systematic review and meta-analysis from 2019 showed that risk of stillbirth was found to be increased for women with peak serum bile acid concentrations of 100 μmol/L or higher (Ovadia et al, 2019).
In England, ICP affects approximately 0.7% of pregnancies; however, higher rates of 1.2–1.5% are found in women of South Asian origin (Abedin et al, 1999). The incidence and prevalence is influenced by not only genetic but also environmental and seasonal factors, and varies between populations worldwide (Dixon and Williamson, 2016). ICP is more prevalent in women with low levels of vitamin D and selenium, and more common in winter when vitamin D and selenium levels are likely to be low (Gabzdyl and Schlaeger, 2015; Floreani and Gervasi, 2016). The pathophysiology of ICP involves a predilection of women in pregnancy to the cholestatic sequelae of pregnancy hormones in particular oestrogens (Dixon and Williamson, 2016). The genetic association is evidenced by the disease occurring more in families, especially first-degree relatives (sisters), and a higher risk of disease recurrence in following pregnancies (Dixon and Williamson, 2016). The genes linked with the development of ICP include ABCB4, which encodes for hepatobiliary canalicular translocator proteins called multidrug resistance 3 (MDR3) (Dixon and Williamson, 2016). This apparently is transmitted in an autosomal dominant, sex-limited pattern. Other genes implicated include NR1H4, ATP8B1, ABCC2 and ABCB11 (Dixon and Williamson, 2016).
The cholestatic effects of both oestrogen and progesterone have been reported to lead to the development of ICP; increasing levels of these hormones occur late in pregnancy, which would explain the typical presentation of ICP in the late second trimester of pregnancy (Dixon and Williamson, 2016).
Bile acids, especially hydrophobic bile acids, are considered harmful to a developing fetus, and are associated with adverse pregnancy outcomes, particularly stillbirth (Dixon and Williamson, 2016). Ursodeoxycholic acid (UDCA), a naturally occurring hydrophilic bile acid (3% of total bile acids), is commonly used as a treatment for cholestatic liver diseases such as ICP; UDCA was originally proposed as a way to reduce adverse perinatal outcomes by increasing biliary bile acid excretion and thus reducing the impact of harmful hydrophobic bile acids (Paumgartner and Beuers, 2002).
UDCA has also been shown to possess anti-inflammatory properties by inhibiting pro-inflammatory cytokines such as TNF-a and IL-6 at the mRNA and protein levels, and could benefit patients with the SARS-CoV-2 infection (Ko et al, 2017; Talebian et al, 2020).
However, the findings of the major ‘PITCHES’ trial concluded that UDCA treatment does not reduce maternal bile acid levels and/or adverse perinatal outcomes in women with ICP, though the trial did observe a modest reduction in maternal itching (Chappell et al, 2019). Furthermore, a recently published systematic review showed that UDCA treatment had no significant effect on stillbirth rates in women with ICP (Ovadia et al, 2021).
Clinical case study
This article presents the case of a 28-year-old South Asian woman in her first pregnancy with no past medical history and no family history of ICP. She provided written consent for the publication of this clinical case study. At antenatal booking, blood tests were negative for syphilis, HIV and Hepatitis B. The booking blood pressure was normal, but she had low vitamin D levels and received Vitamin D treatment. She was also started on aspirin 150 mg daily to reduce her risk of developing preeclampsia.
She subsequently presented at 25 weeks gestation with a 3-day history of worsening itchiness in addition to a dry cough. Her blood pressure was 140/89 mmHg, oxygen saturation on air was 98% and respiratory rate was 16 breaths per minute. Her symptoms began with a cough, followed by intense itching. A few days prior to the onset of her symptoms, all members of her household had tested positive for SARS-CoV-2 infection, and nasal and throat swabs confirmed the infection. Her symptom of intense itching prompted liver investigations. Bile acid was grossly abnormal at 174 μmol/L (a normal level is <10µmol/L; Egan et al, 2012) along with an elevated alanine transaminase (100 U/L). She was immediately started on UDCA 250 mg thrice daily and was advised to self-isolate at home. Over the next 10 days, she was regularly monitored by a COVID-19 surveillance team.
She subsequently developed fever, loss of sense of smell and taste without any respiratory symptoms. However, her itchiness largely subsided following UDCA treatment. Maternal liver and fetal ultrasound (biophysical profile) was normal. Remaining liver investigations such as liver autoimmune screen (LKM antibodies, mitochondrial antibodies, smooth muscle antibodies) and hepatitis serology (hepatitis A, B, C, cytomegalovirus, Epstein Barr Virus, parvovirus) were also negative. Her bile acid and ALT blood levels significantly reduced after 10 days and normalised after 17 days of UDCA treatment (Table 1). A week later, at 27 weeks and 4 days gestation, an oral glucose tolerance test confirmed a diagnosis of gestational diabetes mellitus, and she received oral hypoglycaemic therapy (metformin). There were no further complications and she continued UDCA treatment until delivery. She had a spontaneous vaginal delivery of a healthy baby weighing 3.4 kg at 37 weeks gestation. Blood tests including bile acid and liver function were performed 6 weeks postnatally and were all normal (Table 1).
Table 1. Results of investigations
| Gestation | ||||
|---|---|---|---|---|
| Liver function tests (normal range) | 25 weeks (started UCDA) | 25 weeks + 5 days | 27 weeks + 4 days | Postnatal (6 weeks) |
| Alanine aminotransferase (0–55 IU/L) | 100 | 29 | 15 | 17 |
| Alkaline phosphatase (30–150 IU/L) | 123 | 93 | 75 | 69 |
| Bilirubin(<21 μmol/L) | 24 | 5 | 7 | 10 |
| Albumin (35–50 g/L) | 28 | 28 | 28 | 38 |
| Bile acid (<10 μmol/L) | 174 | 26 | 3 | 3 |
| Full blood count (normal range) | ||||
| Haemoglobin (115–154 g/L) | 117 | 118 | ||
| White cell count (3.9–10.9 x109/L) | 5.11 | 7.85 | ||
| Platelet (150–400 x109/L) | 266 | 320 | ||
Conclusions
In conclusion, this case study presents a woman with SARS-CoV-2 infection complicated by ICP, treated with UDCA, with rapid resolution of symptoms and liver function. On the one hand, the SARS-CoV-2 infection could have resulted in the elevated bile acids and abnormal liver function, and these returned to normal as the infection resolved; this would mean that the use of UDCA was coincidental. Alternatively, the UDCA was beneficial in resolving the SARS-CoV-2 infection, as suggested by a recent publication (Subramanian et al, 2020).
Key points
- Pregnant women are considered a high-risk group during the COVID-19 pandemic.
- Intrahepatic cholestasis of pregnancy affects approximately 0.7% of pregnancies, with higher rates of 1.2–1.5% found in women of South Asian origin.
- Intrahepatic cholestasis of pregnancy is potentially a serious liver disorder occurring in late pregnancy, which could lead to life-threatening complications in the fetus, such as premature delivery and stillbirth.
- It is characterised by itching with abnormal liver function tests and raised bile acids, which usually resolve after delivery.
- Bile acid is considered harmful to the developing fetus, and is associated with adverse pregnancy outcomes, particularly stillbirth.
- Ursodeoxycholic acid is used to treat women with intrahepatic cholestasis of pregnancy; however, recent robust evidence has showed that this treatment does not reduce maternal bile acid levels and/or adverse perinatal outcomes in these women.
- Ursodeoxycholic acid treatment in a woman with SARS-CoV-2 infection complicated by intrahepatic cholestasis of pregnancy appears to be associated with a rapid resolution of symptoms and liver function.
CPD reflective questions
- Could SARS-CoV-2 infection predispose women to developing intrahepatic cholestasis of pregnancy?
- Could ursodeoxycholic acid benefit concurrent SARS-CoV-2 infection and intrahepatic cholestasis of pregnancy?
- How should training of front-line staff be undertaken?
- What has been the care experience of pregnant women with COVID-19 complicated by intrahepatic cholestasis?
- What are the best ways to care and support pregnant women with COVID-19 complicated by intrahepatic cholestasis?