Maternal Intrahepatic Cholestasis in Pregnancy Risks

Early Metabolic Profile in Neonates with Maternal Intrahepatic Cholestasis of Pregnancy

MDPI Children 2025 | 12(12) | 1655

Bengisu Guner Yilmaz, Saygin Abali, Ariorad Moniri, Umut Kilinckaya, Ekin Altinbas, Beril Ay, Bengisu Karakose, Yusuf Sahinoglu, Melis Sahinoglu and Bugra Yilmaz

Introduction

Intrahepatic cholestasis of pregnancy, or ICP is the most common pregnancy-specific liver disorder. Approximately 0.1–4% of pregnancies worldwide will demonstrate incidence of the disorder. Typically, it presents in the second or third trimester, with symptoms including elevated maternal total bile acid (TBA) levels and unexplained itching. Factors that have been known to elevate the risk of ICP include; hepatitis C infection, advanced maternal age and multiple gestations i.e. twins, triplets etc. [1,2]

Intrahepatic, means “within the liver” and cholestasis refers to a condition where the flow of bile from the liver is reduced or blocked. Disruption to this flow can have drastic effects on the foetus, with perinatal complications such as premature birth, foetal distress and possible metabolic consequences. The most serious risk associated with ICP; demonstrably linked to high levels of bile acid transfer between parent and child, is the tragic instance of stillbirth.

It is not altogether known what pathophysiological mechanisms trigger ICP, however the obstructive effects of reproductive hormones, such as 17β-oestradiol and sulphated progesterone metabolites during pregnancy can potentially impair hepatobiliary transport, thereby resulting in an increase in TBA levels. Elevated TBA level is often the only biochemical abnormality; however, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, and serum lipid levels have also been known to be observable contributors [2,3].

Early Metabolic Profile in Neonates with Maternal Intrahepatic Cholestasis of Pregnancy

The objectives of the study by Guner Yilmaz, B. et al were to:

Assess the amino acid, carnitine, and acylcarnitine profiles of neonates born to mothers with ICP.
Compare these metabolic profiles with those of healthy term neonates to identify potential metabolic differences.
Provide novel insights into the possible metabolic consequences of maternal ICP on the offspring. [4]

Carnitine, acylcarnitine, and amino acid measurements derived from dried blood spots obtained immediately postpartum, form the cornerstone of newborn screening (NS) assessment. These analytes reflect molecular and phenotypic alterations, thereby facilitating prompt detection of heritable biochemical disturbances in newborns. NS metabolite profiles have also been employed for detecting secondary metabolic anomalies, typically associated with gestational diabetes mellitus and preeclampsia.

Individual dried blood spot samples were combined with a total of 200 µL of standard solution containing methanol and a mixture of isotope-labelled internal standards for amino acids and acylcarnitines. Isotope-labelled standards for amino acids (Set A, Cat. No: NSK-A-1) and acylcarnitines (Set B, Cat. No: NSK-B-1) were obtained from Cambridge Isotope Laboratories Inc.

Quantitative analysis was performed using flow injection analysis–tandem mass spectrometry (FIA–MS/MS). This method is favourable due to rapid direct detection of analytes without chromatographic separation. Quantification was achieved by calculating the signal intensity ratio of each analyte to its corresponding internal standard.

Discussion

Intrahepatic cholestasis of Pregnancy is heavily associated with placental disfunction, and consequently can lead to nutrient deficiency and growth restriction during pregnancy. The above study demonstrated significant instances of preterm birth amongst the ICP cohort. Findings also signify that higher maternal bile acid levels were associated with lower gestational age and an increased rate of preterm birth. [4]

Furthermore, gestational age has been demonstrated to influence neonatal metabolic profiles, with distinct variations amongst amino acids and acylcarnitines. [5] A small number of studies have investigated neonatal metabolite profiles to identify metabolic abnormalities. For instance, evidence of insulin resistance in newborns of diabetic mothers is often characterised by elevated short-chain acylcarnitines and free carnitine. Similar occurrences have been observed in neonates born to hypertensive mothers. [6,7] Collectively, these findings suggest that maternal metabolic disturbances can alter acylcarnitine patterns during pregnancy, supporting the concept that maternal metabolic or hepatic dysfunction may influence neonatal energy metabolism.

Carnitines and acylcarnitines are significantly involved in fatty acid oxidation, with recent discoveries demonstrating their involvement far beyond this, emphasising the contribution they make in a diverse range of biological processes [8]. Both vital metabolites serve as intermediates and signalling molecules that are actively exchanged between tissues. This influences the regulation of several metabolic and physiological pathways across organs. Carnitines and acylcarnitines modulate insulin sensitivity within the endocrine system, and a consensus exists amongst researchers that elevated long-chain acylcarnitine levels are associated with insulin resistance, and their build-up is becoming increasingly recognised as a possible biomarker for insulin sensitivity. [9]

Consistent with similar studies, the above study noted an increased level of alanine, glycine, ornithine, and tyrosine. This would suggest impaired mitochondrial respiratory chain function and a possible predictive tool for altered metabolic pathways. Elevated levels of amino acids may lead to a higher risk of developing metabolic syndrome-related conditions later in life.

Analysis of the metabolite network has revealed that the disturbances attributed to ICP do not occur in isolation, but rather organised coordinated clusters. Studies such as this, have provided valuable insights into foetal adaptiveness and the body’s metabolic response to the cholestatic intrauterine environment. It is heavily suggested that clinicians should consider maternal ICP when interpreting newborn screening results as a potential contributing factor. These important stages in life require the ability to detect abnormalities via newborn screening at the earliest opportunity. Any deviation from standard metabolic processes, may have long-term implications for overall health and supports the concept that the origins of adult-onset diseases begin at a much earlier developmental stage.

close up photo of the feet of a newborn baby

Full Article

Early Metabolic Profile in Neonates with Maternal Intrahepatic Cholestasis of Pregnancy

Guner Yilmaz, B.; Abali, S.; Moniri, A.; Kilinckaya, U.; Altinbas, E.; Ay, B.; Karakose, B.; Sahinoglu, Y.; Sahinoglu, M.; Yilmaz, B.; et al. Early Metabolic Profile in Neonates with Maternal Intrahepatic Cholestasis of Pregnancy. Children 2025, 12, 1655.

Children|2025, 12(12) | 1655

References

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[2] Williamson, Catherine, and Victoria Geenes. “Intrahepatic cholestasis of pregnancy.” Obstetrics & Gynecology 124.1 (2014): 120-133.

[3] Pillarisetty LS, Sharma A. Pregnancy Intrahepatic Cholestasis. [Updated 2023 Jun 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.

[4] Guner Yilmaz, B.; Abali, S.; Moniri, A.; Kilinckaya, U.; Altinbas, E.; Ay, B.; Karakose, B.; Sahinoglu, Y.; Sahinoglu, M.; Yilmaz, B.; et al. Early Metabolic Profile in Neonates with Maternal Intrahepatic Cholestasis of Pregnancy. Children 2025, 12, 1655.

[5] Liu, Q.; Wu, J.; Shen, W.; Wei, R.; Jiang, J.; Liang, J.; Chen, M.; Zhong, M.; Yin, A. Analysis of amino acids and acyl carnitine profiles in low birth weight, preterm, and small for gestational age neonates. J. Matern. Fetal Neonatal Med. 2017, 30, 2697–2704.

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[7] Ryckman, K.K.; Shchelochkov, O.A.; Cook, D.E.; Berberich, S.L.; Murray, J.C. The influence of maternal disease on metabolites measured as part of newborn screening. J. Matern. Fetal Neonatal Med. 2013, 26, 1380–1383.

[8] Xiang, F.; Zhang, Z.; Xie, J.; Xiong, S.; Yang, C.; Liao, D.; Xia, B.; Lin, L. Comprehensive review of the expanding roles of the carnitine pool in metabolic physiology: Beyond fatty acid oxidation. J. Transl. Med. 2025, 23, 324.

[9] Ringseis, R.; Keller, J.; Eder, K. Role of carnitine in the regulation of glucose homeostasis and insulin sensitivity: Evidence from in vivo and in vitro studies with carnitine supplementation and carnitine deficiency. Eur. J. Nutr. 2012, 51, 1–18.