Organic Aciduria Disorders in Pregnancy: An Overview of Metabolic Considerations

Organic acidurias are a heterogeneous group of rare inherited metabolic disorders (IMDs) caused by a deficiency of an enzyme or a transport protein involved in the intermediary metabolic pathways. These enzymatic defects lead to an accumulation of organic acids in different tissues and their subsequent excretion in urine. Organic acidurias include maple syrup urine disease, propionic aciduria, methylmalonic aciduria, isovaleric aciduria, and glutaric aciduria type 1. Clinical features vary between different organic acid disorders and may present with severe complications. An increasing number of women with rare IMDs are reporting successful pregnancy outcomes. Normal pregnancy causes profound anatomical, biochemical and physiological changes. Significant changes in metabolism and nutritional requirements take place during different stages of pregnancy in IMDs. Foetal demands increase with the progression of pregnancy, representing a challenging biological stressor in patients with organic acidurias as well as catabolic states post-delivery. In this work, we present an overview of metabolic considerations for pregnancy in patients with organic acidurias.


Introduction
Organic acidurias (synonym: organic acid disorders, organic acidemias, (OADs)) are a heterogeneous group of rare IMDs caused by the deficiency of an enzyme or a transport protein involved in the intermediary metabolic pathways. All known organic acidurias are inherited as autosomal recessive traits. There are now considered to be up to 1500 monogenic disorders affecting metabolism. A recent international classification, the International Classification of Inherited Metabolic Disorders (ICIMD described 24 categories. Thirteen groups consist of disorders of intermediary metabolism [1]. Category 1 includes disorders of amino acid metabolism (including organic acidurias), which can be identified by standard metabolic investigations, including plasma amino acid and urine organic acid analysis. Enzymatic deficiencies in amino acid metabolism result in the accumulation of toxic abnormal organic acid metabolites in the body and subsequent organ damage, with the brain being frequently affected. Vitamins are often core elements in amino acid degradation pathways and organic acid metabolism. The severity of symptoms and response to therapy may depend on the extent of the underlying enzyme deficiency.
Ketonuria, Elevated levels MMA and the presence of 3-hydroxypropionate, 2-methylcitrate, and tiglylglycine [11] Plasma amino acids, plasma and urine methylmalonic acid levels, serum acylcarnitine profile and free and total carnitine levels [11] IVA 607036 IVD Metabolic acidosis, Encephalopathy, Developmental Delay, Intellectual disability neutropenia [12] Metabolic acidosis (with elevated anion gap), elevated lactate, hyperammonaemia Increased excretion of 3-hydroxybutyric acid and 3-hydroxy-isovaleric acid [13] Amino acids and carnitine in plasma, urinary isovalerylglycine and plasma isovalerylcarnitine levels Progressive macrocephaly, acute encephalopathic crisis, basal ganglia injury, nonspecific neurologic abnormalities Developmental delay/ Intellectual disability Elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine [14] High plasma glutaryl carnitine [15] Quantitative analysis of plasma amino acids [16] Abbreviations MSUD is characterized by the deficiency of an enzyme, branched-chain α-ketoacid dehydrogenase complex (BCKDC or BCKDHC), in the catabolic pathway of the branchedchain amino acids leucine, isoleucine, and valine. Propionic aciduria (PA) and methylmalonic aciduria (MMA) are characterized by the accumulation of propionic acid and/or methylmalonic acid due to the deficiency of propionyl-CoA carboxylase (PCC) or methylmalonyl-CoA mutase (MCM). PCC is a biotin-dependent mitochondrial enzyme that catalyzes the carboxylation of propionyl-CoA to methylmalonyl-CoA [17]. MCM catalyzes the reversible isomerization of L-methylmalonyl-CoA to succinyl-CoA using adenosylcobalamin (AdoCbl) as a cofactor [18]. Other causes of MMA are a defect in the transport or synthesis of MCM cofactor, adenosyl-cobalamin (AdoCbl), or deficiency of the enzyme methylmalonyl-CoA epimerase [19]. The enzymes deficient in PA and MMA have an indispensable role in the breakdown of the branched-chain amino acids valine, isoleucine, threonine and methionine. IVA is caused by the deficiency of the enzyme isovaleryl-CoA dehydrogenase responsible for the dehydrogenation of isovaleryl-CoA to produce 3-methylcrotonyl-CoA, and is involved in the metabolism of leucine. GA1 is caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase which plays an important role in the catabolism of L-lysine, L-hydroxylysine and L-tryptophan [20] (Figure 1). The clinical signs and symptoms of OADs vary between different disorders. Depending on the degree of enzymatic deficiency, these may present as intoxication or 'metabolic encephalopathy' in the newborn with cerebral oedema, coma and multi-organ failure, or as chronic intermittent presentations, with symptoms such as recurrent acidosis, lethargy, hypotonia, ataxia, neurological signs and seizures. Chronic progressive presentations may also be associated with failure to thrive, vomiting, developmental delay/regression, hepatomegaly, respiratory distress, cardiac dysfunction, osteoporosis, and recurrent infections. The clinical signs and symptoms of OADs vary between different disorders. Depending on the degree of enzymatic deficiency, these may present as intoxication or 'metabolic encephalopathy' in the newborn with cerebral oedema, coma and multi-organ failure, or as chronic intermittent presentations, with symptoms such as recurrent acidosis, lethargy, hypotonia, ataxia, neurological signs and seizures. Chronic progressive presentations may also be associated with failure to thrive, vomiting, developmental delay/regression, hepatomegaly, respiratory distress, cardiac dysfunction, osteoporosis, and recurrent infections.
The most important diagnostic investigation is organic acid analysis of urine by gas chromatography-mass spectrometry, followed by enzymatic assays and specific gene analysis [13,[21][22][23]. Diagnostic confirmation is achieved by genetic testing.
The common aim of management in each of these conditions is to prevent catabolism by providing sufficient calories and essential amino acids to sustain metabolism and the correction of metabolic acidosis and hyperammonaemia [24]. During decompensation, patients with OADs are prone to metabolic organic acid intoxications, which may result in encephalopathy. The initial measures to prevent or correct metabolic decompensation include restricting intact or natural protein from the diet whilst supplementing with a precursor-free synthetic amino acid formula, where appropriate; the provision of energy either via enteral or parenteral means (intravenous dextrose or lipid); and the use of carnitine to enhance the excretion of toxic metabolites. The treatment aims to correct metabolic acidosis, hyperammonaemia, hypoglycaemia, and electrolyte abnormalities. Associated illnesses (e.g., infections, vomiting, and diarrhoea) also are treated.
In all OADs, commercially prepared low-protein foods and drinks are often necessary to achieve energy requirements and provide variety in the diet, particularly where natural protein is significantly restricted. This, along with ensuring an adequate provision of vitamins, minerals and essential fatty acids required according to age with avoidance of prolonged fasting, is essential. Prompt treatment of inter-current illness with appropriate medical treatment and the use of an emergency management plan to avoid/ameliorate catabolism remain the cornerstone of metabolic management.
An increasing number of women with rare IMDs are achieving healthy pregnancies [5]. Pregnancy represents a challenging biological stressor in patients with OADs. However, the reports of successful pregnancies in women with OAD continue to grow where once this may have been contraindicated. Case reports provide valuable insight into the implementation of dietary therapies during pregnancy and delivery management strategies.
In this overview, we summarise the experience of pregnancy in patients with organic acidurias, with emphasis on treatment strategies used to help inform practice in this area.

Methods
Data collection and interpretation in this review integrated a hybrid methodology combining meta-narrative and realist approaches [25][26][27]. All data and references were extracted from the PubMed engine, which accessed the MEDLINE database. Keywords used for the data search were: organic aciduria, maple syrup urine disease, propionic aciduria, methylmalonic aciduria, isovaleric aciduria, GA1, and pregnancy. For the purpose of this type of review on a subclass of IMDs, no inclusion or exclusion criteria were set. The Helsinki Declaration on Ethical Standards for Medical Research Involving Human Subjects was followed while conducting this evaluation of the literature, especially paragraphs 12 and 25, which govern the gathering and analysis of human data and call for a thorough understanding of the scientific literature.

Results (Background Review)
The search for 'Organic Aciduria' and 'Pregnancy' returned 44 results. The search for 'Maple Syrup Urine Disease' and 'Pregnancy' returned 90 results. The search for 'Propionic Aciduria' and 'Pregnancy' returned 42 results. The search for 'Methylmalonic Aciduria' and 'Pregnancy' returned 108 results. The search for 'Isovaleric Aciduria' and 'Pregnancy' returned four results. The search for 'Glutaric Aciduria Type 1 and 'Pregnancy' returned 25 results. To capture all reported cases of OADs and pregnancy, we also searched 'Inherited Metabolic Disorders', 'Organic Acidemia', 'Isovaleric Acidemia', and 'Pregnancy'. The search returned 1417, 45, and 14 articles, respectively. Thirty-nine articles were pregnancy case reports in OADs . Some of these articles included a number of pregnancy case reports; all successful pregnancies are discussed and detailed in Table 2.

Energy Balance and Caloric Adaptations to the Increased Demands of Pregnancy: Metabolic Considerations for Patients with OADs
Pregnancy is a dynamic state that involves profound anatomical, biochemical and physiological changes with considerable physiological and metabolic adaptations to meet the evolving caloric demands and growth of the foetus. These changes are driven by the increased physical and metabolic demands of pregnancy. The foetal demands increase with the progression of pregnancy. The energy requirement of basal metabolism is influenced by maternal prenatal nutrition and by foetal size [62]. Protein requirements are increased from early pregnancy with incremental changes during the course of the pregnancy to the time of delivery [63][64][65][66].
The overall anabolic phase occurs in the first two trimesters of human gestation with enhanced insulin sensitivity and increased maternal fat and fat-free mass [6,67]. The catabolic phase occurs in the third trimester, which is characterized by an accelerated breakdown of fat deposits. The glucose transporter (GLUT1) is considered to be the primary glucose transporter in the human placenta. Expression of GLUT1 increases during pregnancy [68,69]. Amino acids are transported across the placenta to support foetal growth, with an increased maternal-foetal gradient. There is a gradual increase in protein requirements during pregnancy, while maternal plasma amino acid levels are subsequently progressively decreased [70]. Protein deposition in maternal and foetal tissues increases throughout pregnancy, with most occurring during the third trimester [63]. From around 30 weeks gestation, placental hormones and adipocytokines drive increasing insulin resistance, favouring maternal catabolism and releasing glucose, fatty acids, and amino acids to meet increased foetal growth demands [69].
For the OADs, the first trimester of pregnancy may be particularly challenging. Metabolic decompensation may occur with nausea, poor appetite, 'hyperemesis gravidarum', and inter-current illnesses, making it difficult to achieve an adequate intake of calories and essential supplements. Labour and delivery are times of increased energy and protein requirements [71,72]. The postpartum period is the third high-risk period. It is a time of catabolism with the involution of the uterus and the breakdown of protein, associated with additional metabolic stress. Excess amino acids generated during this period can increase nitrogen load and could theoretically precipitate metabolic decompensation in a pregnant patient with an OAD [45,73]. In terms of teratogenic risks, there is no evidence that OADs influence the selection of regularly used antiemetics or vitamin supplements during pregnancy. Although there have been a limited number of cases, the administration of amino acid supplements and carnitine during pregnancy has not been reported to be teratogenic or to cause significant side effects.
Pregnancy presents a challenge to both the patient and the multidisciplinary team when trying to achieve the main aims of treatment. There is limited information about target metabolite biochemical ranges in pregnancy for patients with OADs and overall specific amino acid requirements during the different stages of pregnancy [56]. There is also no specific guidance on frequency for review and/or metabolic and obstetric care plans. Therefore, close monitoring of biochemical profiles, clinical judgement and treatment of catabolic episodes, in particular during the first trimester and immediate postpartum period, is required to prevent and to pre-emptively manage decompensation.
Breastfeeding of the neonate has been reported in affected women with OADs, with most cases being described in women with MSUD and MMA [74]. The benefits of breastfeeding are manifold, including the reduced risk of sudden infant death, allergic diseases, asthma, obesity, and type 2 diabetes [75]. Therefore, breastfeeding should be actively promoted and supported by the metabolic team. They will be best placed to provide dietetic support for successful and safe breastfeeding. Specific diet and monitoring guidelines to support breastfeeding currently exist only for MSUD. These guidelines recommend dietary monitoring and adjustment to support the extra energy and protein demands of lactation [74]. Insufficient caloric intake at this time could be a risk factor for metabolic decompensation, and this should be closely monitored.

Management of MSUD
A leucine-restricted diet is recommended, achieved by limiting natural protein intake. The total protein requirements are achieved by supplementing with a Branched Chain Amino Acids (BCAA) free synthetic amino acid supplement. Isoleucine (Iso) and valine (Val) supplements may be given to achieve appropriate target blood levels. A trial of thiamine supplementation should be documented (usually pre-pregnancy) [74,76]. Carnitine depletion is not a recognised feature in MSUD [34].

MSUD and Pregnancy
The main goals of treatment of MSUD during pregnancy are to increase protein intake to support foetal growth while maintaining BCAA levels within acceptable treatment targets [74]. This may require a combination of increased natural and BCAA-free synthetic amino acid, depending on blood levels. Energy intake must also support increased needs associated with pregnancy. Vitamin and mineral supplementation may be required depending on dietary and biochemical assessments, routinely carried out by a metabolic dietitian. Maintaining adequate caloric intake during pregnancy to help meet the additional energy demands of pregnancy is important, as is the need to ensure adequate energy provision during particularly vulnerable periods, such as labour, delivery and the early postpartum period. This can be achieved by infusion of intravenous dextrose +/− intravenous lipids [31].
The first three pregnancies in women with MSUD were reported in 1992 and 1998 ( Table 2). Two of these were successful [34,35], and the third reported a maternal death at day 51 postpartum [35,36]. A favourable outcome of a pregnancy in a 22-year-old Turkish woman (who had only 2% residual branched-chain oxo acid dehydrogenase activity) was reported in 1998. The target plasma levels of the branched-chain amino acids were achieved (between 100 and 300 µmol/L). The patient's leucine tolerance increased progressively from the 22nd week of gestation from 350 to 2100 mg/day [34].
A further two cases of successful pregnancies were documented in 2013 [31]. This patient was managed with a low-protein diet and branched-chain amino acid-free supplements. The leucine levels were persistently 500-1000 µmol/L. The branched-chain amino-acid-free supplements intake was increased from 60 g to 75 g at 15 weeks' gestation. There was no natural protein intake on day 1 postpartum. This was gradually increased by 5 g increments to the usual pre-pregnancy intake of approximately 20 g over 1 week.
The other cases of pregnancy with severe MSUD were reported in 2015. In this case, the natural protein requirement began to increase by the fourth month of pregnancy. The protein and leucine intake (tolerance) peaked during the eighth month of the pregnancy. The mother resumed her pre-pregnancy diet with around 500 mg of leucine per day in the first few days following birth [30].
A report of pregnancy for an intermediate variant of MSUD was reported in 2018. The prior protein tolerance was 30 g of natural protein per day. The exchanges were increased to 60 g of natural protein by the third trimester and supplemented by synthetic proteins [29].
A further favourable outcome of pregnancy in a case of classical MSUD was reported in 2018. The BCAAs levels were maintained at: Leucine 100-300 µmol/L, isoleucine 100-300 µmol/L and valine 200-400 µmol/L. The patient's protein tolerance increased significantly from the second trimester up to 27 mg/kg/d of leucine per day prior to delivery. The leucine intake was reduced to 200 mg/day on the day of delivery [77].
The treatment of an adolescent patient with intermittent MSUD and the resulting positive pregnancy outcome was described in 2021. This patient attended the metabolic clinic at 31 weeks gestation. The patient's protein intake was approximately 30 g/day. Delivery was by emergency caesarean section with intravenous lipids and fluid supplementation [28]. Another similar case was reported from Japan in a thirty-one-year-old individual [37].
Each of these reports describe similar management strategies in terms of biochemical monitoring and dietary manipulation during pregnancy, labour, delivery, and the postpartum period. Each case described increasing natural protein tolerance during pregnancy, the provision of intravenous dextrose and lipids during labour and delivery, and a reduction in natural protein intake initially postpartum [32].

Management of PA and MMA
The proposed guidelines for the management of MMA and PA recommends regular monitoring of quantitative plasma amino acids, methylmalonic acid in plasma and urine, and acylcarnitine profile in dried blood or plasma [8]. L-carnitine at a dose of 100 mg/kg/day is recommended to maintain normal carnitine and CoA levels. A trial of parenteral B12 is recommended (ideally pre-pregnancy) to assess responsiveness in suspected cases. Some MMA patients may benefit from cobalamin treatment; however, biotin treatment for PA patients is not recommended [8]. Expert opinions advise against the primary use of sodium phenylbutyrate as an ammonia scavenger in MMA and PA during acute metabolic decompensation [8,10]. There is still limited evidence on the long-term efficacy of carglumic acid in MMA [78]. Recent evidence suggests that taking carglumic acid in addition to standard treatment may significantly reduce the number of emergency admissions related to hyperammonaemia in patients with PA and MMA [79].
In MMA and PA, natural protein restriction is advised to reduce the intake of propiogenic amino acids (valine, methionine, isoleucine, threonine). However, intake should not be over-restricted, as this may result in deficiencies in these essential amino acids, which are required to meet the needs for growth and anabolism. Synthetic amino acid formula may be needed to ensure an adequate intake of the unaffected amino acids where natural protein intake cannot be increased. Metronidazole (to reduce bacterial propionate production) may be considered. Acute management requires the temporary cessation or reduction in natural protein [24,80]. Acute illness management should include increased provision of energy via oral, enteral, or parenteral route as tolerated. MMA patients may experience late-onset disease complications such as chronic renal failure, chronic pancreatitis, and osteopenia [8,46,81].

PA/MMA and Pregnancy
Eight successful pregnancies have been described in six women with PA [35,51,82] ( Table 3). In the first documented case of pregnancy in PA, a pregnancy was reported at 6 weeks of gestation. The patient was treated with protein restriction (to 0.8 g/kg) and a propionic aciduria amino acid supplement formula for additional protein. L-carnitine (30 mg/kg) was prescribed [35]. There were no metabolic problems reported for these cases [38]. In general, a protein-restricted diet and carnitine supplementation were successfully employed to manage pregnancy in PA [35,38,[51][52][53]. Complications during pregnancy included growth retardation and preeclampsia [51].
In the literature, seventeen successful pregnancies were described in 14 women with MMA, B12-responsive and non-responsive forms (Table 4) [35,51,82]. The first case report of a patient with MMA who carried a pregnancy to term was reported in 1995 [48]. Complications during pregnancy included hyperammonaemia [51], nausea and vomiting [40,73], hyperglycaemia, anaemia [40,46,47], proteinuria [46], and carnitine deficiency [47]. One infant was noted to have poor foetal growth during the pregnancy with documented poor nutritional baseline prior to conception [38]. One patient had three successful pregnancy outcomes, with complications only in the last pregnancy when she developed acute stress in labour due to possible placental abruption and preeclampsia [73].
There is a report of a woman affected with MMA who delivered two subsequent children who were also affected with MMA. The parents were unrelated. On day 5 of life, the first neonate presented with lethargy, hypothermia, and hyperbilirubinemia. Gas chromatography of a 24 h urine sample showed a high excretion of MMA, and B12responsive MMA was confirmed on cultured fibroblasts. The mother had a subsequent successful affected pregnancy three years later. [49].
The protein restrictions for these case reports were described with increasing natural protein tolerance as the pregnancy advanced [40,42,46,50,73]. Precursor-free amino acids were utilised in two cases where insufficient natural protein intake was tolerated [38,40]. In one reported case, the addition of nocturnal corn starch was used dosing during pregnancy to prevent a fasting state and reduce the catabolism of odd-chain fatty acids [46]. The majority of cases were treated with vitamin B12 and carnitine, often given in higher doses and adjusted with biochemical metabolite monitoring. Nine pregnancies were carried to term. The most common method of delivery was via C-section. In almost all cases, intravenous dextrose was used to reduce the risk of metabolic decompensation. Intravenous carnitine was given during the delivery period in three cases [40,47,73]. There were no long-term complications for the MMA patients in the peripartum or postpartum periods. One case described a successful breastfeeding experience which was supported by a protein intake of up to 1.68 g/kg in addition to extra calories [40]. Cardiac complications and occult cardiomyopathies have been reported in PA patients [83,84]. Metabolic strokes and associated neurologic sequelae, particularly during periods of catabolism, are also reported [82]. Cardiac assessment is recommended at the early stages of pregnancy and during pregnancy [51].

Management of IVA
The aim of treatment is to maintain a state of anabolism, reducing the formation of isovaleryl-CoA formation from leucine catabolism. Natural protein restriction is recommended to reduce the isovaleric acid load. Leucine intake should supply the recommended levels of intake. It is recommended to prescribe L-carnitine to maintain an adequate free carnitine level in blood and to add L-glycine in severe types [85,86]. Detoxification of excess isovaleric acid is achieved by conjugation with glycine, hydroxylation, and excretion in urine as 3-hydroxyisovaleric acid. The absence of 3-hydroxyisovaleric acid in the urine suggests metabolic stability [54]

IVA and Pregnancy
Of note, there are no consensus guidelines for the dietary management of pregnancy in IVA. A number of cases of pregnancies in IVA have been described from 1984, with eight successful pregnancies (including one twin pregnancy) (see Table 5) [54][55][56][57]. Treatments included leucine-free formula, protein-restricted diet, L-carnitine or glycine supplementation or a combination thereof, which are comparable to non-pregnancy IVA management strategies. Information on dietary prescriptions used in pregnancy was limited. Interventions required during pregnancies included increased glycine and L-carnitine supplementation in two pregnancies and increased protein intake in the latter part of the pregnancy in another case. Symptom management of malodour from urine in trimester 2 in one pregnancy was attributed to an increase in milk consumption and improved with milk cessation. Protein intakes, in this case, varied hugely, with reported intakes from 32 to 108 g per day. Isovalerylglycine was the only abnormal metabolic detected in the urine at 20, 31 and 36 weeks gestation [54]. Hyperemesis gravidarum was reported in three cases and was managed with intravenous glucose L-carnitine and oral glycine. [55][56][57]. Two of these pregnancies required significant increases in carnitine and glycine doses to manage low levels. Successful pregnancy outcomes were reported in all cases [54][55][56][57].

Management of GA1
Dietary treatment of GA1 varies according to the age of diagnosis and symptom severity. The aim of the treatment is to limit dietary lysine, the most quantitatively relevant amino acid precursor of the neurotoxic glutaric acid and 3-hydroxyglutaric acids [87], while maintaining sufficient intake of protein, energy and essential nutrients to meet requirements [17]. Carnitine supplementation is associated with risk and mortality reduction [88]. Hence, lifelong carnitine supplementation is recommended [89,90]. The recommended dose is 100 mg carnitine/kg/day, to be adjusted to maintain plasma carnitine concentration within the normal range [14]. The international consensus guidelines recommend a relaxation of lysine restriction after six years of age; however, many centres may recommend acute management of intercurrent illness or surgery with increased dextrose intake. The suggested emergency treatment (pre-pregnancy) includes stopping natural protein intake for 24-48 h and supplementing with intravenous dextrose and L-carnitine [59].

GA1 and Pregnancy
There are no consensus guidelines for dietary management during pregnancy or breastfeeding. The physiological changes of pregnancy and the catabolism associated with labour and delivery can impose the risk of a neurological 'crisis' in GA1 [58]. Therefore, the vulnerable stages of pregnancy may also necessitate this treatment to minimise catabolic stress and prevent neurological crises. This can be achieved by adequate caloric intake such as IV dextrose and lipid in addition to carnitine supplementation. For most documented reports on GA1 in pregnancy, the patients were mostly asymptomatic or showed only mild neurologic symptoms.
There are a number of successful pregnancies reported in GA1 [58,60] ( Table 6). The outcomes of three pregnancies involving two women who had undiagnosed GA 1 were reported in 2007. Case 1 had a normal pregnancy and was delivered at term. This woman had a previously uneventful pregnancy and delivery. In Case 3, a child was born to a woman who had GA1 following a normal pregnancy and delivery. Although untreated and not supplemented with carnitine, both women had no metabolic decompensation during gestation or in the postpartum period [60]. In another report in 2008, a further two women, the first in her second pregnancy and the second in her third pregnancy, had normal pregnancies, deliveries and healthy newborns. The diagnosis of GA1 in both women was only established following a positive newborn screening test in their babies [61]. To our knowledge, there are five pregnancies reported in four women diagnosed with GA1 [38,59,60]. A 23-year-old primigravid woman with a history of GA1 presented for a scheduled caesarean section at 36 weeks of gestation. Preconception, she was treated with a low protein diet (40 g/d), L-carnitine, and riboflavin supplements. Carnitine supplement was increased from 0.5 g to 2 g daily at 18 weeks of gestation. The delivery management was pre-planned with a detailed emergency C-section protocol (40). Limited information is available on treatments used, and there is no information on dietary treatments employed.
In our practice, we followed a female patient with GA1 who had two clinically uneventful pregnancies. Although asymptomatic at diagnosis (age 11 years), dietary treatment was commenced with restriction of natural protein (tryptophan and lysine) and synthetic protein substitutes were prescribed to meet daily protein and micronutrient requirements according to the Irish practice [91]. In both pregnancies, there were slight increases in natural protein exchanges, with increasing protein requirements across the trimesters achieved with higher synthetic protein intake. Additional energy was provided with glucose polymers, fat supplements, and sugar-based beverages. Carnitine and essential fatty acid supplementation continued with the addition of vitamin and mineral supplementation. The weight gain was acceptable for both pregnancies, and the risk of acute decompensation was proactively managed. Catabolic stress during labour and delivery was mitigated by providing effective pain relief, adequate hydration, calories, and the maintenance of acid-base balance pre-, during, and post-delivery.

Discussion
In this overview, we summarise the metabolic experiences of pregnancy in patients with organic acidurias, with emphasis on treatment strategies used in all stages of pregnancy and the postpartum period. A summary of the reports reviewed with interventions is provided in Table 2. The overall summary of reports (in the absence of pregnancy-related clinical practice guidelines) suggests that catabolism should be prevented or minimized in all stages of pregnancy and the postpartum period with OADs using intensive dietary interventions (enteral or parenteral nutrition when needed) [34,35].
Overall the foetal outcomes were favourable in all the OADs described [31]. However, although there is an increase in reported successful pregnancies in this reported cohort, there is a paucity of data on long-term outcomes for the offspring. In the case of MMA, favourable outcomes were achieved despite high levels of methylmalonic acid in the serum and urine, which may suggest that elevated levels of MMA may not be teratogenic [49]. Additionally, it has been suggested that there may be foetal metabolism of MMA, as a reduction in MMA levels was shown in one case report [46]. Poor foetal development was reported in one case that was most likely caused by insufficient dietary intake [38].
Amino acids cross the placenta by an active transport mechanism. Leucine can rapidly cross the placenta. It has been estimated that toward the latter part of gestation, 90% of foetal plasma leucine is derived from maternal circulation. The exposure of the foetus to a high concentration of leucine might have a negative impact on its growth and development [92]. Similarly, abnormally high maternal organic acid metabolites may potentially cross the placenta and negatively impact foetus development. Therefore, careful monitoring of the mother's metabolic status during pregnancy is essential to minimize potential risks to the foetus. Other complications reported in maternal phenylketonuria (PKU), including congenital heart defects, microcephaly was not reported in this series [93]. In addition to dietary intervention, a number of adjuvant treatments were described.
L-carnitine has an important role in the management of OADs. Carnitine is an important molecule contributing to energy production and the metabolism of fatty acids [94]. It mediates the transport of fatty acids into the mitochondria. It possesses antioxidant properties that might have a role in protecting against the oxidative stress promoted by BCAA [95,96]. L-carnitine may also protect against lipid peroxidation [97]. L-carnitine might have an important role in foetal growth [98,99]. It has been reported that low carnitine levels may negatively influence foetal maturation [100,101]. Carnitine deficiency can lead to muscle weakness and cardiomyopathy [102].
It has been reported that L-carnitine levels are lower in MSUD patients compared with the general population. Studies have shown that oxidative stress may be involved in the neuropathology of MSUD. In vitro studies demonstrated that leucine and α-ketoisocaproic acid may cause DNA damage. In these studies, L-carnitine was able to significantly prevent DNA damage [103]. It has also been reported that L-carnitine supplements may enhance the formation and excretion of short-chain acylcarnitines in PA [104]. The current clinical practice guideline suggests that L-carnitine is useful in the management of patients with MMA and PA [24]. Carnitine supplement to MMA patient can increase the urinary excretion of hippurate and short-chain acylcarnitines, and reduces the excretion of methylmalonate and methylcitrate [105]. Patients with IVA may also have low plasma levels of free carnitine. Studies have shown that L-carnitine conjugated isovaleric acid earlier than glycine. It has been suggested that supplementation with L-carnitine might enhance the excretion of isovalerylcarnitine and reduce or prevent further hospitalizations [85,86].
L-carnitine supplementation also enables physiological clearance of glutaryl-CoA by conjugation with carnitine. In GA1 patients, supplementation with L-carnitine resulted in beneficial effects by reducing levels of toxic intermediate metabolites [106]. Notwithstanding the beneficial effect of L-carnitine therapy, there is still no consensus on the dose and duration of treatment. Furthermore, there are no controlled trials on its safety when high doses are used or when it is prescribed for longer periods.
Another adjuvant therapy is the intermitted use of oral antibiotics (such as metronidazole) to decrease propiogenic anaerobic gut bacteria in MMA and PA [24].
The development of clinical guidelines can directly improve management, bring further insights, and advance research. Guidelines for the management of pregnancies in OADs are limited, consistent with the limited experience to date [107]. Clinicians should be aware of potential complications and carefully consider how best to manage these conditions during pregnancy. Preplanning pregnancy should include consideration of potential complications and detailed monitoring plans throughout the trimesters. Avoidance of catabolism throughout pregnancy, labour, and the postpartum period is very important. This can be achieved by providing adequate caloric, protein, and micronutrient intake in conjunction with close monitoring of metabolic and nutritional status. Patients should be closely followed up by a specialised metabolic and dietetic team, which can implement a planned approach to conception and pregnancy. Close liaison with other specialists, in particular, perinatal specialists, is required for optimal outcomes. In this context, with the increasing number of these high-risk pregnancies expected, increased education in this discipline is required.
Finally, consideration should be given to breastfeeding, and patients should be counselled accordingly [74]. Mothers who have OADs should be encouraged to breastfeed. However, it is important to closely monitor the mother's metabolic control with sup-plemental essential amino acids and to monitor the infant's nutritional status, growth, and development.

Conclusions
The development of shared care guidelines and outcome monitoring of the offspring will aid in continued successful pregnancy outcomes for women with OADs. Further research is required to develop recommendations for amino acid precursor essential requirements at the different stages of the pregnancies, the development of novel predictive biomarkers for early detection of decompensation, and to monitor therapies. Developing new targeted therapies and rescue medication to effectively prevent and treat acute decompensation is another important area for further research. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflicts of Interest:
The authors declare no conflict of interest.