The impact of elevated liver enzymes and intrahepatic cholestasis of pregnancy on the course of COVID-19 in pregnant women

doi:10.21203/rs.3.rs-1732973/v1

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The impact of elevated liver enzymes and intrahepatic cholestasis of pregnancy on the course of COVID-19 in pregnant women

https://doi.org/10.21203/rs.3.rs-1732973/v1

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Objective:This study aims to investigate the perinatal outcomes in COVID-19 pregnant women with intrahepatic cholestasis of pregnancy (ICP) and elevated liver enzymes.

Methods: Present study was carried on pregnant women with COVID-19 between March 11, 2020 and August 11, 2021. Patients with liver enzyme levels higher than twice the upper limit of the reference range for Aspartate Aminotransferase (AST) and/or Alanine Transferase (ALT) were included. Cases with elevated Fasting Biliary Acid (FBA) levels were regarded as ICP. Remaining cases were used as the control group. A receiver operating characteristics (ROC) analysis was performed to assess the predictive value of ALT and AST for ICP.

Results: There were a total of 1751 patients in the study period. Among them 126 had elevated liver enzymes. Nineteen of these cases had also ICP. AST and ALT values were statistically higher in the ICP group. Demographic features, clinical characteristics and perinatal outcomes were similar between the groups. The rate of ICP in pregnant women with COVID-19 was similar to the literature in this study. Although the rates of preterm delivery were higher than the current literature for both groups, study and control groups were comparable in terms of preterm delivery. The optimal cut-off values were 109.5 IU/L (specificity: 59.2%, sensitivity: 63.3%) and 89.5 IU/L (specificity: 68.4%, sensitivity: 67.3%) for ALT and AST ,respectively according to the results of the ROC analysis.

Conclusion: Similar perinatal outcomes were observed between the ICP and control groups. However, relatively higher rates of maternal mortality, intensive care unit admission, neonatal intensive care unit admission, and preterm birth were observed for COVID-19 pregnant women with elevated liver enzymes compared to the previous literature. Thus, physicians dealing with pregnant women with COVID-19 should be cautious about the management of cases with elevated liver enzymes.

SARS-CoV-2

COVID-19

Pregnancy

Liver Damage

Cholestasis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) was first reported in the Wuhan State of China in December 2019. In March 2020 World Health Organization declared the disease a pandemic and described it as coronavirus disease (COVID-19) (1). As scientific knowledge on SARS-CoV-2 increases, gastrointestinal symptoms like nausea, vomiting, diarrhea, and abdominal pain have been observed in addition to lower respiratory system symptoms like fever, coughing, dyspnea, myalgia (2, 3). The virus is capable of involving numerous organs due to angiotensin-converting enzyme-2 (ACE-2) receptors found in various systems in the organism (2, 3). Studies have demonstrated the presence of ACE2 receptors in the liver, hepatic tracts and gastrointestinal system ; therefore the virus may also affect these systems (4–10).

The liver serves as the primary center for the production of albumin, acute phase reactants, and coagulation factors. Liver function disorder accompanying acute respiratory syndrome (ARDS) may affect multiple system findings of COVID-19 such as coagulopathy and multiple organ failure. Also, the liver is the primary metabolical and detoxification organ for humans, therefore even a moderate function loss changes the safety profiles and therapeutic effectiveness of the drugs metabolized in the liver (11). Hence, revealing the possible causes of COVID-19 related liver damage is vital fort he establishment of better clinical protocols.

Elevated liver enzymes were observed in approximately a quarter of the cases (12). Studies conducted on pregnant population with COVID-19 reported similar results. Although the liver enzyme elevation levels were minor in most cases, the rate of high liver enzymes might reach above forty percent in pregnant patients (13). The rate of elevated liver enzymes was found in 4.6% of the cases in a previous study from Ankara City Hospital (14).

Although the etiology of intrahepatic cholestasis (ICP) is not completely understood, it is believed to be multifactorial. Genetic predisposition, hormonal factors, and environmental factors were suggested to be responsible. Increased estrogen levels due to pregnancy decrease the expressions of nuclear hepatic bile acid receptors and hepatic biliary canaliculi transport proteins in genetically susceptible women. Consequently, hepatic bile acid homeostasis gets disturbed and biliary acid levels increase (15). The incidence of ICP in pregnant women varies between 0,2% and 2% (16).

The knowledge regarding the relation between elevated liver enzymes and ICP in pregnant women with COVID-19 is still limited. Furthermore, the impact of these pathologies on perinatal outcomes in this specific population has not been clarified, yet. This study aims to investigate the perinatal outcomes in COVID-19 pregnant women with intrahepatic cholestasis of pregnancy (ICP) and elevated liver enzymes.

Turkey Ministry of Health Ankara City Hospital is the main pandemic center in Turkey dealing with the most complicated cases. All pregnant women with COVID-19 are managed by an experienced multidisciplinary team according to the current guidelines (14).

This study is a retrospective cross-sectional study conducted on 1751 pregnant women with positive SARS-CoV-2 PCR test results between March 11, 2020, and August 11, 2021. Approvals from the Turkish Ministry of Health and local ethical commission (E2-21-1059) were obtained. Verification of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was made by a positive result of real-time polymerase chain reaction (RT-PCR) of nasopharyngeal and oropharyngeal samples (17).

Patients with levels of AST and/or ALT at least twice the upper limit of reference ranges were included in the study. Patients with a known active or chronic liver disease were excluded. 126 patients were found to be meeting our inclusion criteria, and the elevation of liver enzymes to at least twice the upper limit rate was 7,1% (126/1751) for these patients. Fasting biliary acid (FBA) tests were performed on especially patients reporting nocturnal pruritus of hands and feet, and a result of > 10 µmol/L was considered as diagnostic (18). Of 31 patients whose FBA levels were tested, 12 had normal (< 10 µmol/L) and 19 had elevated (> 10 µmol/L) levels. 15% (19/126) of the patients with elevated liver enzyme levels were diagnosed with ICP. Cases with ICP along with elevated liver enzymes were used as the study group. Whereas, cases with solely elevated liver enzymes were served as the control group (Fig. 1). Demographic features, clinical characteristics and perinatal outcomes were compared between the groups.

Statistical analyzes were performed with the Statistical Package for the Social Sciences (SPSS.22, IBM SPSS Statistics for Windows, Version 22.0 Armonk, NY: IBM Corp.). Medians and interquartile range values were used for the non-normally distributed descriptive parameters. Mann-Whitney U tests were performed for comparing the median values between the groups. Mann-Whitney U test was also conducted for pairwise comparisons using Bonferroni correction. Categorical variables were presented with numbers and percentages. The Chi-square test was used to compare categorical variables. A receiver operating characteristics (ROC) analysis was performed to assess the predictive value of ALT and AST for ICP. A two-tailed P value < 0.05 was regarded as statistically significant.

Gravidity, parity, maternal age, number of living children, previous miscarriages, and body mass index (BMI) values were comparable between the groups as presented in Table 1.

Table 1

Demographic data
	Control (n:107)			Cholestasis (n:19)
	Mean	Median	Std. deviation	Mean	Median	Std. deviation	P
Age	30,4	30,0	5,09	29,0	28,0	4,20	0,323
Gravidity	2,22	2,0	1,50	1,89	2,00	0,80	0,638
Parity	0,91	1,0	1,08	0,52	0,0	0,77	0,119
Living child	0,89	1,0	1,06	0,52	0,0	0,77	0,133
Miscarriage	0,33	0,0	0,79	0,31	0,0	0,58	0,805
Body Mass Index	27,6	26,0	4,5	30,2	29,5	3,5	0,173
Mann-Whitney U

Symptoms like fever, blood pressure, pulse rate, respiratory rate, and oxygen saturation were similar between the groups. While ALT and AST values were statistically higher in the ICP group the other laboratory findings were similar between the groups. Although the length of hospital stay, gestational age at birth, and APGAR scores were similar between the groups, gestational age at diagnosis was statistically higher in the ICP group (Table 2).

Table 2

Vital signs, laboratory results and pregnancy outcome
	control			cholestasis
	Mean	Median	Std. deviation	Mean	Median	Std. deviation	P
Fever	36,7	36,6	0,62	36,7	36,6	0,68	0,937
Heart rate	97,7	96	16,4	98,2	97	16,7	0,979
Systolic blood pressure	112,9	110,0	13,5	112,2	111,5	10,4	0,764
Diastolic blood pressure	66,7	65	12,08	65,9	62,5	9,8	0,847
O2 saturation	94,6	96	3,8	93,6	95,5	3,6	0,065
Respiratory rate	17,6	16	6,4	17,4	16	3,4	0,607
CRP	67,5	31,3	72,1	19,1	19,3	12,2	0,809
Lymphocyte	1137	1040	563	1183	1060	487	0,825
IL-6	234	15,3	890	12	7,7	11,5	0,181
Procalcitonin	0,5	0,08	1,6	0,08	0,1	0,06	0,224
ALT	147	104	114	332	116	369	0,002
AST	159	73	271	372	77	465	< 0,001
Lenght of hospital stay	7,5	5,0	9,4	8,3	6,0	5,5	0,085
GW at diagnosis	23,6	26	10,2	29,4	30	6,2	0,04
GW at birth	35,6	37	4,6	35,4	36	4,5	0,710
APGAR 1	6,7	8,0	2,2	6,7	7,0	1,9	0,440
APGAR 5	8,1	9,0	2,3	8,3	9,0	1,8	0,792
Mann-Whitney U

Coughing, dyspnea, and myalgia were the most common symptoms for both groups. The rate of pruritus was significantly higher in the ICP group compared to the control group, while other symptoms have shown no statistically significant difference between the groups. While 71 patients delivered during their hospital stays, 55 patients were still pregnant during the study period. 61 patients delivered in the control group and the preterm birth rate was 43%. On the other hand,10 ICP patients delivered during the study period and the preterm birth rate was 50%. There was no significant difference between the groups in regards to administration of antenatal corticosteroids, systemic steroid therapy, oxygen support, maternal mortality, preterm delivery, admission to ICU, and admission to NICU (Table 3).

Table 3

Symptoms and treatment
	Control	cholestasis	P
Caugh	%37	%47	0,411
Dyspnea	%34	%53	0,120
Chest pain	%5	%11	0,310
Myalgia	%32	%37	0,674
Nasal congestion	%5	%6	0,918
Sore throat	%10	%6	0,555
İnsomnia	%10	% 0	0,216
Headache	%6	% 16	0,116
Diarrhea	% 3	% 0	0,458
Itching	%13	%100	< 0,001
Antenatal corticosteroid	% 18	%37	0,061
Systemic steroid	%30	%32	0,837
O2 support	%37	%53	0,193
Admission to ICU	%17	%21	0,732
Admission to NICU	% 8	%15	0,313
Preterm Delivery	%43	%50	0,961
Maternal Mortality	%7	%15	0,237
Pearson Chi-Square

The optimal cut-off values were 109.5 IU/L (specificity: 59.2%, sensitivity: 63.3%) and 89.5 IU/L (specificity: 68.4%, sensitivity: 67.3%) for ALT and AST ,respectively according to the results of the ROC analysis (Table 4).

Table 4

ROC Curve
	Cut-off	AUC	P	%95 C.I.	Sensitivity	Specificity
ALT	109,5	62,2	0,022	0,521-0,723	63,3	59,2
AST	89,5	73,2	< 0,001	0,643-0,821	67,3	68,4
AUC: Area Under Curve

The present study is to the best of our knowledge, the first study in the literature that focuses on ICP patients with COVID-19 including the highest number of participants from a single pandemic center. SARS-CoV-2 related liver damage is described as the liver damage that occurred during the course and treatment of COVID-19 (10). In SARS-CoV-2 patients overall incidence of elevated liver enzymes range between 2,5% and 76,3%. Furthermore, according to the results of a recent meta-analysis, AST and ALT values were outside the reference ranges for 20–22,5% and 14,6–20,1%, respectively (12). Although the COVID-19 related liver damage is usually reported to be mild in a significant number of the patients, especially the ones who experienced a relatively severe disease course, might be affected adversely (12).

Liver damage has been reported in approximately 60% of patients with SARS, and positive SARS-CoV RT-PCR was detected in liver biopsy specimens of some SARS cases (19). Similar to SARS-CoV, SARS-CoV-2 infiltrates the cells via ACE-2 receptors (2, 3, 20). ACE-2 is expressed in hepatocytes and biliary tract epithelial cells (cholangiocytes). An increase in ACE2 expressions is reported to be higher in hepatocytes (2,6%) compared to cholangiocytes (59,7%) (3). Additionally, cholangiocytes play an important role in liver regeneration and immune response (21). Thus liver damage in COVID-19 patients may stem from not only hepatocyte damage but also from cholangiocyte damage (3, 21). Autopsies performed on COVID-19 patient cadavers have shown irrefutable proof of secondary liver damage. Findings such as microvascular steatosis, hepatomegaly, permanent inflammation findings, increased size of gall bladder are reported as histological findings that show the pathological changes caused by liver damage (22–24).

In most studies, higher levels of AST and ALT were regarded as the reflection of liver damage (3, 10, 11). Some studies also made use of the parameters such as alkaline phosphatase (ALP), total bilirubin, gamma-glutamyltransferase (GGT), and albumin (25, 26). The present study used the AST and ALT values, which are serum transaminases commonly used in general literature, as liver damage findings. In this study, rather than a minimal transferase elevation, we considered an elevation of twice the upper limit of the normal reference range in AST and/or ALT as a significant increase. Consequently, our reported rate of patients with elevated levels of liver enzymes is lower (7,1%; 126/1751) when compared to literature. We found the ICP patients rate to be 15% (19/126) in subjects with liver damage findings, and 1% in all subjects (19/1751). This incidence was generally found to be similar to the literature, and It was thought that pregnant women with COVID-19 had ICP at a similar rate to other pregnant women (16).

In studies including pregnant patients with COVID-19, similar results for liver damage were reported when compared to the non-pregnant population (27). In pregnant patients with liver damage, worse course of COVID-19 and poor pregnancy outcomes were observed (27, 28). The most important adverse pregnncy outcome is the increased rate of preterm delivery. According to the results of a current meta-analysis, the preterm birth rate was reported to be 23% among pregnant women with COVID-19 (30). Preterm delivery rate was reported to be more common among pregnant women with COVID-19 compared to the pregnant women with negative SARS-CoV-2 results (31). To the best of our knowledge there is no study in the literature investigating the rate of adverse pregnancy outcomes in SARS-CoV-2 positive pregnant women with elevated liver enzymes. Preterm delivery rates were higher both for the study and control groups in the present study. According to this data, we believe pregnant women with liver damage might be at greater risk of preterm births.

A mild course of COVID-19 and relatively favorable outcomes were reported for pregnant women with COVID-19 in the early months of the pandemic. However, recent studies indicated a worse course of COVID-19 and increased rates of complications among pregnant women with COVID-19. Especially the rates of mortality, ICU admission, need for mechanic ventilation and severe disease were higher in pregnant women with COVID-19 compared to the women with COVID-19 in the reproductive age (30, 32). Although two groups were similar with regard to adverse perinatal outcomes in the present study, higher rates of pregnancy complications and a worse course of the disease was observed for both groups compared to the findings of the previous studies including pregnant women with COVID-19.

Intrahepatic cholestasis of pregnancy is a multifactorial condition presented with pruritus and normal/slightly elevated liver enzyme values (15, 16). In the ICP group both AST and ALT levels were significantly higher when compared to the group with only elevated liver enzymes. Furthermore, for the first time in the literature cut-off values for the prediction of ICP in pregnant women with elevated liver enzyme levels were calculated. Considering the potential of increased adverse outcomes in pregnant women with ICP, early prediction of ICP among pregnant women with COVID-19 may help physicians to establish more effective management protocols.

Retrospective design, and lack of information related to the delivery characteristics of some cases were the main limitations. On the other hand, high number of participants, calculation of optimal liver enzyme cut-off values for the prediction of ICP and assessment of the elevated liver enzymes’ impact on perinatal outcomes for the first time in the literature were the main strengths.

Intrahepatic cholestasis of pregnancy should be considered in the differential diagnosis when pruritus and/or elevated levels of liver enzymes accompany COVID-19 infection in pregnant women. Similar perinatal outcomes were observed between the ICP and control groups. However, relatively higher rates of maternal mortality, intensive care unit admission, neonatal intensive care unit admission, and preterm birth were observed for COVID-19 pregnant women with elevated liver enzymes compared to the previous literature. Thus, physicians dealing with pregnant women with COVID-19 should be cautious about the management of cases with elevated liver enzymes.

İ. Funding: Our study is not financially supported.

İİ. Conflicts of interest: There is no conflict of interest.

İİİ. Ethics approval: Approvals from the Turkish Ministry of Health and local ethical commission (E2-21-1059) were obtained.

İV. Consent to participate: Not applicable (Because it is a retrospective study).

V. Consent for publication: All authors agree to publish the article

Vİ. Availability of data and material: The data supporting the analysis of this study can be obtained from the relevant author (R.DENİZLİ) upon request. Raw data is not publicly available due to institutional restrictions.

Vİİ. Code availability: Not applicable

Vİİİ: Authors contributions:

concept: RD, DŞ, AT,ÖMT,SS,BS,NF,MEMP,ÖK

design: RD,AT,DŞ,ÖK

data collecting: MEMP,BS,NF

experiments and procedures; RD,DŞ,AT,ÖMT

writing of article: RD,AT,DŞ

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The impact of elevated liver enzymes and intrahepatic cholestasis of pregnancy on the course of COVID-19 in pregnant women

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