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Maternal and neonatal outcomes of intrahepatic cholestasis of pregnancy after in vitro fertilization

BMC Pregnancy and Childbirth volume 24, Article number: 44 (2024) Cite this article

Abstract

Background

Intrahepatic cholestasis of pregnancy (ICP) is an idiopathic disease of pregnancy. Little is known about how it specifically affects pregnancies resulting from in vitro fertilization (IVF). Our aim is to evaluate the impact of IVF on the perinatal outcomes of ICP.

Methods

A retrospective study of 242 patients with intrahepatic cholestasis of pregnancy, comprising 36 conceived through IVF and 206 spontaneous conceptions (SC), enrolled between 2019 and 2021 was carried out. Data were analyzed from the medical archives of the Huazhong University of Science and Technology, Tongji Hospital.

Results

Numerical values of transaminases (ALT, alanine aminotransferase; AST, aspartate aminotransferase) and serum total bile acid (TBA) are significantly lower in the IVF group than that in the spontaneous conceived group (p < 0.05). The incidence of gestational diabetes mellitus (GDM) was higher in the IVF group than in SC group (30.6% vs. 16%, p = 0.037). The cesarean section (CS) rates are higher in the IVF group (97.2% vs. 85.4%, p = 0.023). On the other hand, the prevalence of premature rupture of membranes (PROM) was higher in the SC group (10.7%) while none was reported in the IVF-ICP group. Other maternal comorbidities and neonatal outcomes were similar between the two groups.

Conclusion

ICP patients who underwent IVF are more likely to suffer from GDM. Therefore, monitoring and management of blood glucose should be strengthened during pregnancy. Fortunately, IVF does not seem to worsen the progression or outlook of ICP, so sticking to standard management practices is recommended.

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Introduction

Intrahepatic cholestasis of pregnancy is an idiopathic pregnancy-related condition characterized by pruritus and elevated concentrations of total bile acids. Patients typically recover after delivery [1]. The incidence rates vary between 0.3 and 5.6% of pregnancies [2]. ICP is associated with a higher incidence of adverse perinatal outcomes in the third trimester, such as spontaneous or iatrogenic premature delivery, meconium staining of the amniotic fluid, foetal distress, neonatal asphyxia and even stillbirth [3]. Women with ICP also have a higher incidence of premature rupture of membranes, postpartum haemorrhage, as well as increased risk of gestational diabetes and hypertension [4, 5].

The pathogenesis of ICP is still not completely understood, though, gestational hormones, environmental factors, genetic variation and lipid metabolism contribute to the development of this disease [6, 7]. Current evidence suggest that assisted reproductive technology (ART) may promote the occurrence and development of ICP [8,9,10]. A significant proportion of women conceiving through assisted reproduction treatments have hormonal dysfunction and multiple metabolic abnormalities, contributing to obstetric complications [11, 12]. Despite the increasing number of births from assisted reproductive technology, knowledge regarding ICP outcomes after IVF remains limited, particularly the specific maternal characteristics and perinatal outcomes. The aim of this retrospective cohort study is to explore the impact of IVF on perinatal outcomes associated with ICP and to determine the optimal management model for IVF-related ICP patients.

Materials and methods

General Information

This study is a retrospective analysis of data from 242 pregnant women diagnosed with ICP, including 36 who conceived through IVF and 206 spontaneous conceptions. All patients delivered between January 2019 and December 2021 at the Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.

Diagnostic criteria

ICP was defined as manifestation of pruritus in the absence of rash, together with raised level of serum bile acids (cut-off level 10 µmol/L) and/or raised level of serum ALT (> 40 U/L), and by normalization of biochemical parameters after delivery [13].

Gestational diabetes mellitus was established following the “one-step” 75-g oral glucose tolerance test [14].

Exclusion Criteria

Incomplete case data, twin pregnancy, multiple pregnancy, extrahepatic biliary tract obstructions, viral hepatitis, autoimmune hepatitis, HELLP syndrome and fatty liver of pregnancy.

Statistical Processing

Statistical analysis was performed using SPSS 20.0 statistical software. Continuous data are presented as mean and standard deviation, while categorical data as number and percentage. The significance of the difference between the mean values of the groups was evaluated using the Student’s t-test and the significance of the difference in the median values was evaluated using the Mann-Whitney U test. Categorical data was compared by the chi-square distribution. The odds ratios (OR) and corresponding 95% confidence intervals (CI) for the risk of GDM were calculated. A p-value of < 0.05 was considered statistically significant.

Results

As Table 1 illustrates, there was no significant difference in age, pregnancy or delivery histories between the two groups (p > 0.05). The mean gestational age at onset of ICP was 35.5 weeks for both groups. Figure 1 shows the flow chart of the participants in the main analysis.

Table 1 Maternal characteristics comparison between the SC and IVF groups
Full size table
Fig. 1
figure 1

Flowchart of participants in the analysis. LBW: Low birth weight

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Woman in the IVF pregnancy cohorts exhibited higher rates of GDM compared to the SC group (30.6% vs. 16%, p = 0.037). In addition, IVF group also had a notably higher cesarean section rates (97.2% vs. 85.4%, p = 0.023).

Conversely, premature rupture of membranes was more prevalent in the SC group (10.7%) while no such occurrence was reported in the IVF-ICP group. Meanwhile, the levels of transaminases (ALT, AST) and TBA are greatly reduced in the IVF group than that in the SC group (p < 0.05) (Table 1).

The severity of ICP, defined as TBA exceeding 100 µmol/L, was 2.8% in the IVF group compared to 9.2% in the SC group. There were no significant differences observed between the two groups in terms of other maternal complications and neonatal outcomes, such as postpartum haemorrhage, gestational hypertension, and preterm labor (Table 2).

Table 2 Analysis of maternal complications and neonatal outcomes
Full size table

Discussion

Interestingly, this study demonstrated that even though ICP incidence is higher, TBA, AST, and ALT mean values are significantly lower in ICP pregnancies resulting from IVF. This difference may be attribute to the benefit of more intensive prenatal care and focused treatment provided to IVF patients. Remarkably, only 1 out of 36 patients of the IVF cohort reported a TBA that surpassed 100 µmol/L. Certain studies have indicated that concentration of serum bile acid correlates to perinatal complications. Once TBA exceeds 40 µmol/L, for each 1 µmol/L increase, the incidence of perinatal complications will go up by 1–2%. If it reaches 100 µmol/L, the risk of stillbirth elevates by 30 times [15, 16]. Although assisted reproduction might induce ICP, no significantly increase in adverse outcomes were detected in this data set. No obvious difference between the two groups in incidence of pre-preeclampsia, postpartum haemorrhage and coagulation disorders was demonstrated. Nevertheless, IVF patients showed a higher likelihood of developing gestational diabetes. In this study, pregnancies conceived by IVF had a higher incidence rate of GDM, OR 1.91 (95% CI 1.06–3.42). Infertility secondary to ovulatory disorders often present with serious endocrinological disorders, such as insulin resistance, or high risk factors for obstetric diseases, for instance, obesity [17]. Excessive progesterone could interfere with the function of major hepatic bile acid receptors, potentially exacerbating the situation in ICP patients [18]. Experimental report indicate that oestrogen could trigger glycemic disorders resulting in liver injury and exacerbating cholestasis [19]. For ICP in patients having undergone IVF, careful attention to gestational glucose status is crucial for early management, potentially alleviating later pregnancy burdens.

ICP is a polygenic disorder, and its specific pathogenesis has not been fully understood. Recent literature report that cholestasis may also be related to mutations in genes encoding bile acid metabolic transporters such as ABCB11, ABCB4, ABCCC2, ATP 8B1, TJP2, which result in the abnormal function of bile salt export pump in hepatocytes [20, 21]. Hormonal imbalances induced by assisted reproductive technology, particularly high oestrogen and progesterone levels, are more likely to contribute to ICP, and lead to adverse pregnancy outcomes [22, 23]. Redundant oestrogen accumulates in liver cells, leading to decreased activity of Na+/K+-ATPase, which can inhibit the synthesis of hepatic biliary proteins, and obstruct of bile salt uptake and excretion [24]. Supplementary progestin administration in IVF patients could trigger bile acid retention, thereby causing adverse events, such as premature birth, respiratory disorders, meconium-stained amniotic fluid and even stillbirth [13]. Serum bile acids stimulate the release of prostaglandins from the uterus and decidua, increase the expression of oxytocin receptors in uterine smooth muscle, and induce preterm delivery [25, 26]. High bile acid concentrations may cause hypoxia which can stimulate foetal vagus nerve, increase intestinal peristalsis, and result in intrauterine meconium passage. As the fetus inhales the tainted amniotic fluid, excessive bile acid accumulation can result in atelectasis, pulmonary edema, neonatal lung injury or even asphyxia [27, 28].

The most tragic outcome of ICP is stillbirth whose exact mechanism has yet to be fully clarified. Fetal cardiomyocytes are more susceptible to bile acids compared to adults. Once bile acids enter systemic circulation, they can directly impair fetal cardiac conduction system, reduce cardiac systolic function and induce fetal arrhythmia [29,30,31]. Additionally, it has also been suggested that bile acids stimulate blood vessels on the chorionic surface of the placenta, causing vasospasm and decreasing placental perfusion, leading to sudden death [32]. Studies report an incidence of stillbirth of 18.3% at 36 weeks, escalating to 33.6% at 39 weeks [33]. Hence, inclusion of all members of the multidisciplinary team involved in the process is recommended, namely, gynecologists, midwives, neonatologists, pediatricians, and physicians. This collaborative approach will definitely reassure and comfort patients that a team is dedicated to everyone’s safety.

Prompt and effective management of severe ICP significantly reduces the risk of adverse perinatal outcomes [34]. For IVF patients with ICP in this study, operative delivery was personally preferred to minimize emergence of adverse perinatal events, reflected as a high rate (97.2%) of cesarean section. However, prenatal monitoring and the timing of delivery must be a comprehensive consideration [23]. Termination of pregnancy around 36 weeks did not increase the incidence of stillbirth in this study. Extending gestational age could reduce the incidence of iatrogenic premature birth. Delivery timing should not only depend on the concentrations of serum total bile acid, but also on feedback from prenatal monitoring such as Non-Stress Test, fetal growth, gestational age and the effectiveness of medical treatment.

This study has analyzed IVF as a modern effective way of achieving pregnancy that does not increase adverse complications in ICP. Therefore, it is advisable to continue routine prenatal check-up. These findings may aid in optimizing medical resources and alleviating emotional tension relating to infertility. Nonetheless, there are two limitations that require improvement. Firstly, the sample size was limited without post-hoc power analysis, an assessment of neonatal prognosis or quality of life. Future studies should aim to include larger samples and provide comparative analyses. The results would help in identifying individuals at risk, particularly with regards to mixed-etiologies, early diagnosis, prevention and possible targeted treatment technologies. Besides, optimal delivery timing for patients with ICP need to be addressed to reduce the burden of prematurity. Secondly, there were no cases of stillbirth, necessitating further research in its etiology and prevention. Despite these limitations, the data presented in this study provides a general evaluation of the impact of assisted reproduction on patients with ICP.

Conclusion

Through this retrospective, hospital-based cohort study, we discovered that ICP patients who underwent IVF did not demonstrate a heightened risk of preterm birth, gestational hypertension, and postpartum haemorrhage compared to cohorts who conceived spontaneously. However, IVF-related ICP may increase incidence of glucose metabolism disorders, artificial reasons-caused prematurity, and cesarean sections. Therefore, it is advisable for women with ICP in post-IVF pregnancies to follow medical advice for proper monitoring and management. This approach guarantees necessary interventions, prevent complications and reduces unnecessary cesarean sections.

Data availability

The datasets used and/or analyzed during the current study will be available from the corresponding author on reasonable request.

Abbreviations

ICP:

Intrahepatic cholestasis of pregnancy

IVF:

In vitro fertilization

CS:

cesarean section

TBA:

Serum total bile acid

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

SC:

Spontaneous conceived

GDM:

Gestational diabetes mellitus

ART:

Assisted reproductive technology

OR:

Odds ratio

CI:

Confidence interval

PROM:

Premature rupture of membrane

LBW:

Low birth weight

References

  1. Geenes V, Williamson C. Liver disease in pregnancy, Best Pract Res Clin Obstet Gynaecol, vol. 29, no. 5, pp. 612 – 24, Jul, 2015.

  2. Basaranoglu S, Agacayak E, Ucmak F, Tunc SY, Deregozu A, Akkurt ZM, et al. The role of vitamin B1-B2 and plasma lipid profile in intrahepatic cholestasis of pregnancy. J Perinat Med. 2017;45(4):461–5.

    Article  CAS  PubMed  Google Scholar 

  3. Batsry L, Zloto K, Kalter A, Baum M, Mazaki-Tovi S, Yinon Y. Perinatal outcomes of intrahepatic cholestasis of pregnancy in twin versus singleton pregnancies: is plurality associated with adverse outcomes? Arch Gynecol Obstet, vol. 300, no. 4, pp. 881–887, Oct, 2019.

  4. Furrer R, Winter K, Schaffer L, Zimmermann R, Burkhardt T, Haslinger C. Postpartum Blood Loss in Women Treated for Intrahepatic Cholestasis of Pregnancy, Obstet Gynecol, vol. 128, no. 5, pp. 1048–1052, Nov, 2016.

  5. Puljic A, Kim E, Page J, Esakoff T, Shaffer B, LaCoursiere DY et al. The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age. Am J Obstet Gynecol, vol. 212, no. 5, pp. 667 e1-5, May, 2015.

  6. Abu-Hayyeh S, Papacleovoulou G, Lovgren-Sandblom A, Tahir M, Oduwole O, Jamaludin NA, Ravat S et al. Feb,. Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype, Hepatology, vol. 57, no. 2, pp. 716 – 26, 2013.

  7. Tang M, Xiong L, Cai J, Fu J, Liu H, Ye Y et al. Intrahepatic cholestasis of pregnancy: insights into pathogenesis and advances in omics studies. Hepatol Int, Nov 13, 2023.

  8. Wood AM, Livingston EG, Hughes BL, Kuller JA. Intrahepatic Cholestasis of Pregnancy: A Review of Diagnosis and Management, Obstet Gynecol Surv, vol. 73, no. 2, pp. 103–109, Feb, 2018.

  9. Wang J, Liu Q, Deng B, Chen F, Liu X, Cheng J. Pregnancy outcomes of Chinese women undergoing IVF with embryonic cryopreservation as compared to natural conception. BMC Pregnancy Childbirth, vol. 21, no. 1, pp. 39, Jan 9, 2021.

  10. Zhu L, Zhang Y, Liu Y, Zhang R, Wu Y, Huang Y et al. Maternal and live-birth outcomes of pregnancies following assisted Reproductive Technology: a retrospective cohort study. Sci Rep, vol. 6, pp. 35141, Oct 20, 2016.

  11. Yu HF, Chen HS, Rao DP, Gong J. Association between polycystic ovary syndrome and the risk of pregnancy complications: a PRISMA-compliant systematic review and meta-analysis. Med (Baltim), vol. 95, no. 51, pp. e4863, Dec, 2016.

  12. Vannuccini S, Clifton VL, Fraser IS, Taylor HS, Critchley H, Giudice LC et al. Infertility and reproductive disorders: impact of hormonal and inflammatory mechanisms on pregnancy outcome, Hum Reprod Update, vol. 22, no. 1, pp. 104 – 15, Jan-Feb, 2016.

  13. Piechota J, Jelski W. Intrahepatic Cholestasis in pregnancy: review of the literature. J Clin Med, vol. 9, no. 5, May 6, 2020.

  14. ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. On behalf of the American Diabetes, 2. Classification and diagnosis of diabetes: standards of Care in Diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S19–S.

    Article  CAS  Google Scholar 

  15. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates, Hepatology, vol. 40, no. 2, pp. 467 – 74, Aug, 2004.

  16. Rezai S, Lam J, Henderson CE. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels, Am J Obstet Gynecol, vol. 213, no. 1, pp. 114, Jul, 2015.

  17. Lei LL, Lan YL, Wang SY, Feng W, Zhai ZJ. Perinatal complications and live-birth outcomes following assisted reproductive technology: a retrospective cohort study. Chin Med J (Engl), vol. 132, no. 20, pp. 2408–16, Oct 20, 2019.

  18. Abu-Hayyeh S, Ovadia C, Lieu T, Jensen DD, Chambers J, Dixon PH et al. Apr,. Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum, Hepatology, vol. 63, no. 4, pp. 1287-98, 2016.

  19. Du Q, Pan Y, Zhang Y, Zhang H, Zheng Y, Lu L et al. Placental gene-expression profiles of intrahepatic cholestasis of pregnancy reveal involvement of multiple molecular pathways in blood vessel formation and inflammation. BMC Med Genomics, vol. 7, pp. 42, Jul 7, 2014.

  20. Sticova E, Jirsa M, Pawlowska J. New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications, Can J Gastroenterol Hepatol, vol. 2018, pp. 2313675, 2018.

  21. Niemyjska-Dmoch W, Kosinski P, Wegrzyn P, Luterek K, Jezela-Stanek A. Intrahepatic cholestasis of pregnancy and theory of inheritance of the disease. Literature review, J Matern Fetal Neonatal Med, vol. 36, no. 2, pp. 2279020, Dec, 2023.

  22. Gao XX, Ye MY, Liu Y, Li JY, Li L, Chen W et al. Prevalence and risk factors of intrahepatic cholestasis of pregnancy in a Chinese population. Sci Rep, vol. 10, no. 1, pp. 16307, Oct 1, 2020.

  23. Smith DD, Rood KM. Intrahepatic Cholestasis of Pregnancy, Clin Obstet Gynecol, vol. 63, no. 1, pp. 134–151, Mar, 2020.

  24. Crocenzi FA, Mottino AD, Cao J, Veggi LM, Pozzi EJ, Vore M et al. Aug,. Estradiol-17beta-D-glucuronide induces endocytic internalization of Bsep in rats, Am J Physiol Gastrointest Liver Physiol, vol. 285, no. 2, pp. G449-59, 2003.

  25. Germain AM, Kato S, Carvajal JA, Valenzuela GJ, Valdes GL, Glasinovic JC. Bile acids increase response and expression of human myometrial oxytocin receptor, Am J Obstet Gynecol, vol. 189, no. 2, pp. 577 – 82, Aug, 2003.

  26. Ovadia C, Seed PT, Sklavounos A, Geenes V, Di Ilio C, Chambers J et al. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses, Lancet, vol. 393, no. 10174, pp. 899–909, Mar 2, 2019.

  27. Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol. 2009;15(17):2049–66.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Campos GA, Guerra FA, Israel EJ. Effects of cholic acid infusion in fetal lambs, Acta Obstet Gynecol Scand, vol. 65, no. 1, pp. 23 – 6, 1986.

  29. Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy, Obstet Gynecol, vol. 124, no. 1, pp. 120–133, Jul, 2014.

  30. Miragoli M, Kadir SH, Sheppard MN, Salvarani N, Virta M, Wells S et al. Oct,. A protective antiarrhythmic role of ursodeoxycholic acid in an in vitro rat model of the cholestatic fetal heart, Hepatology, vol. 54, no. 4, pp. 1282-92, 2011.

  31. Zhan Y, Xu T, Chen T, Deng X, Kong Y, Li Y et al. Aug,. Intrahepatic cholestasis of pregnancy and fetal cardiac dysfunction: a systematic review and meta-analysis, Am J Obstet Gynecol MFM, vol. 5, no. 8, pp. 100952, 2023.

  32. Sepulveda WH, Gonzalez C, Cruz MA, Rudolph MI. Vasoconstrictive effect of bile acids on isolated human placental chorionic veins. Eur J Obstet Gynecol Reprod Biol, vol. 42, no. 3, pp. 211–5, Dec 13, 1991.

  33. Saleh MM, Abdo KR. Consensus on the management of obstetric cholestasis: National UK survey, BJOG, vol. 114, no. 1, pp. 99–103, Jan, 2007.

  34. Yang J, Chen C, Liu M, Zhang S. Women successfully treated for severe intrahepatic cholestasis of pregnancy do not have increased risks for adverse perinatal outcomes, Medicine (Baltimore), vol. 98, no. 27, pp. e16214, Jul, 2019.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Ying Zhu, Le Xu, Rajluxmee Beejadhursing & Fei Li

  2. Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Fei Li

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Contributions

LX and RB were responsible for the collection, arrangement, analysis and conclusion of data. FL was a supervisor, revised the manuscript. YZ contributed to writing, editing, and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Fei Li.

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Ethical approval and consent to participate

Informed consent was obtained before the survey from each participant in the current study. Tongji hospital ethics committee has issued clearance for conduction of this study. All methods were carried out in accordance with relevant guidelines and regulations. All participants gave written informed consent to participate in the study.

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The authors declare no competing interests.

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Zhu, Y., Xu, L., Beejadhursing, R. et al. Maternal and neonatal outcomes of intrahepatic cholestasis of pregnancy after in vitro fertilization. BMC Pregnancy Childbirth 24, 44 (2024). https://doi.org/10.1186/s12884-024-06248-x

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BMC Pregnancy and Childbirth

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