Impact of pregnancy on inborn errors of metabolism

Abstract

Once based mainly in paediatrics, inborn errors of metabolism (IEM), or inherited metabolic disorders (IMD) represent a growing adult medicine specialty. Individually rare these conditions have currently, a collective estimated prevalence of >1:800. Diagnosis has improved through expanded newborn screening programs, identification of potentially affected family members and greater awareness of symptomatic presentations in adolescence and in adulthood. Better survival and reduced mortality from previously lethal and debilitating conditions means greater numbers transition to adulthood. Pregnancy, once contraindicated for many, may represent a challenging but successful outcome. Successful pregnancies are now reported in a wide range of IEM. Significant challenges remain, given the biological stresses of pregnancy, parturition and the puerperium. Known diagnoses allow preventive and pre-emptive management. Unrecognized metabolic disorders especially, remain a preventable cause of maternal and neonatal mortality and morbidity. Increased awareness of these conditions amongst all clinicians is essential to expedite diagnosis and manage appropriately. This review aims to describe normal adaptations to pregnancy and discuss how various types of IEM may be affected. Relevant translational research and clinical experience will be reviewed with practical management aspects cited. Based on current literature, the impact of maternal IEM on mother and/or foetus, as well as how foetal IEM may affect the mother, will be considered. Insights gained from these rare disorders to more common conditions will be explored. Gaps in the literature, unanswered questions and steps to enhance further knowledge and systematically capture experience, such as establishment of an IEM-pregnancy registry, will be summarized.

Keywords: Fatty acid oxidation; Inborn errors of metabolism; Metabolic disorders; Mitochondrial; Pregnancy; Urea cycle.

Fig. 1

a Foeto-placental growth across pregnancy. Adapted from King JC, Reference [7]: Physiology of pregnancy and nutrient metabolism. Am J Clin Nutr. 2000;71(5 Suppl):1218s–25s. b Maternal body composition changes across pregnancy and the puerperium. Adapted from Kopp-Hoolihan et al in Reference [6]: Widen EM, Gallagher D. Body composition changes in pregnancy: measurement, predictors and outcomes. Eur J Clin Nutr. 2014;68(6):643–52. c Protein requirements in pregnancy by method. Recent methodology by in vivo amino acid oxidation (IAAO) suggests protein requirements, whether by Estimated Average Requirement (50th percentile) or Recommended Daily Allowance (97th percentile) are significantly higher than previous estimates. Source: adapted from content in (reference [8]): Elango R, Ball RO. Protein and Amino Acid Requirements during Pregnancy. Adv Nutr. 2016;7(4):839s44s. https://academic.oup.com/advances/article/7/4/839S/4568693

Fig. 2

Amino acid concentrations across pregnancy trimesters. Barplot comparing plasma amino acid concentrations across trimesters among pregnant women. Median (+ Interquartile range/2) was plotted. * p-value <0.00017, p-value was calculated by Mann-Whitney U Test between trimesters. Source: (Reference [17]) Lindsay KL, Hellmuth C, Uhl O, Buss C, Wadhwa PD, Koletzko B, et al. Longitudinal Metabolomic Profiling of Amino Acids and Lipids across Healthy Pregnancy. PLoS One. 2015;10(12):e0145794

Fig. 3

a The urea cycle. In hepatocytes, the rate-limiting, ATP-dependent enzyme carbamoyl phosphate synthetase 1 (CPS1), which is allosterically activated by N-acetyl glutamate (NAG), produced by N-acetyl glutamate synthase (NAGS), not shown, and ornithine transcarbamylase (OTC) are located in the mitochondria; argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and arginase (ARG) are in the cytoplasm. Inherited defects in any of these enzymes can cause recurrent episodes of hyperammonemia. Defects in two mitochondrial transporters, not shown, may also result in hyperammonemia. Source: Adapted from reference [33]: Laemmle A, Gallagher RC, Keogh A, Stricker T, Gautschi M, Nuoffer JM, et al. Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD). PLoS One. 2016;11(4):e0153358. b Post-partum course of term OTC pregnancy. Complicated post-partum course in a female with OTC due to partial X chromosome deletion. Abbreviations: CHO – carbohydrate; CS – Caesarian Section; NH₄ – ammonia; OTC - ornithine transcarbamylase; IV – intravenous. Source: Goldstein R, Smith N, Strauss BJG & Wilcox G. Protein aversion and disordered eating in OTC deficiency: a challenge for pregnancy and post-partum management in a female heterozygote. 25th DMIMD, London, UK April 2011

Fig. 4

Mitochondrial fatty acid β oxidation pathway & interplay between foeto-placental and maternal metabolism in LCHAD. Classical β-oxidation pathway involves: dehydrogenase by acyl-CoA dehydrogenase and hydration, dehydrogenation and thiolyic cleavage is catalyzed by the -mitochondrial trifunctional protein (MTP, highlighted in red color). MTP consists of: enoyl-CoA hydratase,hydroxy acyl-CoA dehydrogenase & thiolase activity. The straight arrows represent products and bent arrows represent the involvement of co-factor in this enzyme-catalyzed reaction. Fetal long chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) deficiency results in accumulation of 3-hydroxy fatty acids in the placenta, since the fetal part of placenta is identical to the genetic makeup of the fetus. Increased accumulation of placental free fatty acids and 3-hydroxy fatty acyl-CoA cause oxidative stress, mitochondrial dysfunction and placental lipotoxicity. Further, lipolysis induced in the third trimester of pregnancy would also trigger the accumulation of fatty acid intermediates, which are shunted from the placenta to the maternal circulation, where they can promote oxidative and nitrosative stress. These fatty acid intermediates reach the maternal liver resulting in microvesicular steatosis, hepatic mitochondrial dysfunction and hepatocyte lipoapoptosis. Source: Adapted from Natarajan & Ibdah (reference [29]) Int J Mol Sci. 2018 Jan; 19(1): 322. Published online 2018 Jan 22. doi: 10.3390/ijms19010322