Urea cycle disorders in pregnancy
In the face of increased metabolic demands, and requirements for protein, amino acids and energy there is a risk of decompensation where these are not met and/or catabolism is excessive overwhelming already limited capacity for ureagenesis and ammonia consumption.
Decompensation is riskiest where the diagnosis is unrecognized and/or treatment is delayed or not given. Conversely, better outcomes are observed where the UCD (and pregnancy) diagnosis is known.
In 1990 a seminal New England Journal of Medicine case series [
40], reported post-partum coma and death in previously undiagnosed OTC-deficient female carriers. Subsequent numerous publications described various pregnancy outcomes in OTC [
4,
41‐
55] and other urea cycle disorders: citrullinaemia type 1 [
56‐
61], ASA/ASL deficiency [
62‐
64], CPS deficiency [
65] and lysinuric protein intolerance [
66‐
68]. Currently, no reports of pregnancy outcome in either NAGS deficiency, Arginase deficiency, Citrin deficiency (citrullinaemia type 2) or Hyperornithinaemia-Hyperammonaemia-Homocitrullinaemia (HHH) syndrome are published.
Adverse pregnancy outcomes reported have been principally neurological, psychiatric or hepatic. The importance of acute hepatic failure as a manifestation of metabolic decompensation has been not been fully appreciated until recently [
38]. Such presentations, occurring at any stage in pregnancy, may have gone undiagnosed. Whether they are represented in referrals to liver transplant units is worthy of investigation. Mitochondrial dysfunction [
69] and liver disease will be discussed further with fatty acid oxidation disorders in pregnancy.
Complications of hyperammonaemia in pregnancy can masquerade as more common problems. Nausea, vomiting, headaches, mood disturbance and seizures may be attributed to hormonal changes. Mental status change post-partum has been diagnosed as post-partum psychosis or depression [
53,
58,
59,
70]. Hyper-ammonaemic liver failure initially attributed to fatty liver of pregnancy, was considered unusual presenting in
early pregnancy with hyperemesis, weight loss and prominent depression of synthetic function, [
56,
57,
60,
71]. Hyperemesis gravidarum (HG) a risk factor for metabolic decompensation, due to caloric deficit, may be both a cause, and consequence, of hyperammonaemia. Late first trimester pregnancy weight loss from hyperemesis, malnutrition and institution of parenteral nutrition in an undiagnosed OTC heterozygote has caused fatal hyperammonaemic encephalopathy [
46]. Glucocorticoids recommended for HG [
72], an intercurrent condition [
56] or anticipated pre-term delivery [
42], may aggravate a catabolic state.
Understanding the metabolic adaptations to pregnancy provides a framework for understanding and anticipating the impact on an IEM.
Most reported complications occur in early pregnancy and post-partum. Progressive foetal and maternal second trimester anabolism generally confers greater metabolic stability. However, we have seen second trimester decompensation in OTC deficiency (G Wilcox unpublished observations), manifest by psychiatric disturbance, and responsive to intravenous arginine infusion; deficiency of this conditionally essential amino acid likely coincided with increased protein requirements.
Third trimester protein tolerance is generally greater due to increasing protein requirements, but, failing adequate intake
1 and/or catabolic stressors [
42] metabolic decompensation may occur. This is consistent with accelerated maternal catabolism in late pregnancy.
Peripartum multidisciplinary planning in known patients includes clinical observation, ammonia monitoring and avoidance of prolonged fasting, using protein-free nutrition orally, or if necessary, parenterally.
Most hyperammonaemic decompensations have been reported post-partum. Uterine involution takes 6 weeks but occurs rapidly in the first two weeks. The strength of catabolic drive from days 3–11 is such, that metabolic instability may still occur despite proactive appropriate management [
4] Table
1. Additional catabolic stress may result from caesarian section, birth trauma, infection e.g. wound infection, mastitis (Fig.
3b). Blood transfusion may represent an added protein load. Breast feeding is possible so long as caloric intake is adequate. Table
1 summarizes largely previously unpublished experience from an historical case series.
Table 1
Historical case series of pregnancies in women with urea cycle disorders
1 | 40 | OTC | 2 | ‘Psychosis’ day 3 post-partum | Protein aversion | 1° Trimester coma; Ammonia 288 | 117 day 5 | – | Yes |
2aa | 33 | OTC | 1 | Elective termination for affected foetus | Protein aversion decompensation | Post-partum hyperammonaemia | 226 day 4 246 day 8 | zinc selenium vitamin B12, iron protein | Yes |
2b | 35 | OTC | 2 | As above | Protein aversion decompensation | Post-partum & 3° Trimester hyperammonaemia | 105 day 2 150 day 4 125 day 9 | zinc selenium vitamin A vitamin B12 protein essential fatty acids | Yes |
3a | 32 | OTC | 3 | No | Protein aversion | – | – | vitamin D, vitamin B12, iron magnesium | Yes |
3b | 35 | OTC | 4 | As above | Protein aversion | Gestational diabetes | – | As above | Yes |
4a | 37 | OTC | 1 | N/A | Protein aversion | Mild post-partum hyperammonaemia | 105 day 3–4 107 day 9 | vitamin D, vitamin B12 iron | Yes |
4b | 39 | OTC | 2 | As above | Protein aversion | – | – | As above | Yes |
5 | 25 | OTC | 1 | N/A | Protein aversion anxiety depression | 2° & 3° Trimester altered mental status very low arginine normal ammonia | – | vitamin D iron | Yes |
6b,c | 19 | Citrullinaemia | 1 | Past miscarriage | Nil | 1–2° Trimester hyperemesis, ↓8Kg, weight loss, acute liver failure & hyperammonaemia: NH3 165 | – | vitamin D | Yes |
Phenylketonuria (PKU) – an example where the main impact is on the developing foetus.
Phenylketonuria, is well known, with widespread neonatal screening pioneered by Robert Guthrie and others, since the 1960s [
73].
PKU is due to absent or dysfunctional phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Untreated, it leads to severe mental retardation and marked mood and behavioural disturbances [
73]. Excess phenylalanine is toxic to the developing brain and completes with other large neutral amino acids e.g. tryptophan crossing the blood brain barrier. Together with deficient tyrosine, this causes marked neurotransmitter derangement, with deficiencies of dopamine, noradrenaline and serotonin [
74]. Excess phenylalanine increases oxidant stress [
75], impairs cholesterol synthesis [
75] and activates osteoclasts [
76].
PKU outcome was revolutionized by Horst Bickel’s therapeutic diet, still used today. Extreme natural-protein restriction, supplemented with micronutrient-fortified phenylalanine-free amino acid-based supplements to meet nutritional requirements was instituted neonatally [
74]. Close blood-spot monitoring of phenylalanine levels, maintained throughout development, has enabled attainment of near-potential IQ [
73]. Adherence to such dietary stringency is difficult for many; alternative therapies e.g. tetrahydrobiopterin (BH4) or Kuvan®, co-factor for PAH, may be limited to those with residual enzyme activity and/or access [
74,
77‐
79]. Many adults, including women of childbearing age, are lost to follow-up, often due historically, to ceasing in adolescence or earlier [
73,
74] This is concerning as excess maternal blood phenylalanine is highly teratogenic throughout gestation. Active placental phenylalanine transport further elevates foetal blood levels [
16].
Maple syrup urine disease
Maple syrup urine disease (MSUD) is an inborn error of branched chain amino acid (BCAA) metabolism due to deficiency of the intra-mitochondrial thiamine-dependent enzyme complex, Branched Chain Keto Acid Decarboxylase. This converts the BCAA derived keto-acids into their respective Coenzyme A derivatives for subsequent mitochondrial energy production [
98‐
100].
Decompensation may occur with catabolic stress and/or excess protein intake, manifesting elevated BCAA, allo-isoleucine, and their respective keto-acids [
101]. Of the BCAA, leucine is particularly neurotoxic [
102], with isoleucine and valine significantly attenuating this [
102]. The urine may have a characteristic ‘maple syrup’ odour, attributed to isoleucine-derived sotolone [
103]. Clinical severity varies depending on the degree and type of enzyme deficiency. The most severe forms present neonatally, before newborn screening results return. Milder cases including ‘intermittent’ MSUD may not be diagnosed until adulthood. Newborn screening (NBS) programs should improve this outcome, long-term [
101]. However, most women currently of childbearing age may not have been screened neonatally for MSUD. Presentations may vary according to age of symptom onset. Ketosis with raised BCAA, nausea, vomiting and progressive encephalopathy are characteristic: irritability, ataxia, hyponatraemia, brain oedema, coma and death may occur if untreated [
104].
Management is by dietary restriction of natural protein, supplemented with BCAA-free fortified amino acid and valine supplements with strict monitoring of BCAA levels. Milder forms of MSUD may be thiamine responsive [
99]. Long term suboptimal outcomes may be manifest by varying degrees of intellectual impairment and/or executive dysfunction [
104].
In pregnancy, the risk periods are in the first trimester, where nausea and vomiting may result in catabolism from inadequate calorie intake, and post-partum when uterine involution increases the free amino acid pool. Intercurrent infections at any stage, and delivery by labour or caesarian section represent additional catabolic stressors.
Death with cerebral oedema has been reported 51 days post-partum, confounded by concurrent physical trauma [
105], but successful pregnancies have been reported in the literature [
106‐
109] as well as others (G Wilcox unpublished observations). Though rats, leucine-exposed neonatally, display long-term neuro-behavioural disturbance [
110], no adverse outcomes are yet described in the children of mothers with MSUD, despite poor compliance and suboptimal metabolic control in some [
108]. Leucine requirements increase disproportionately during late pregnancy [
17], which may be protective. Clearly longer-term follow-up of such offspring is warranted.