Pregnancy in an NTBC‐Treated Patient With Hereditary Tyrosinemia Type I

We report the case of a patient with hereditary tyrosinemia type I (HTI) who carried a pregnancy to term while maintained on (2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione) (NTBC) therapy. To our knowledge, this is the third case (and first in North America) ever reported. HTI is an autosomal-recessive inborn error of tyrosine metabolism, resulting from mutation of fumaryl acetoacetate hydrolase (FAH Figure 1, (1)) and affecting liver, kidneys, and peripheral nerves. Before the liver transplantation era and NTBC pharmacotherapy, HTI was generally fatal, with most patients succumbing in infancy or early childhood. NTBC is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase (Fig. 1), and was developed as HT1 therapy because inhibition of this upstream enzyme prevents accumulation of toxic downstream tyrosine metabolites, including succinyl acetone (Fig. 1). Since the first report describing the effect of NTBC on patients with HTI in 1992 (2), early initiation of this drug has become the mainstay of treatment and dramatically improved the clinical course of HTI. Indeed, a review of HT1 outcomes in Quebec reported abolition of acute complications and absence of detectable liver disease for >5 years in patients initiating therapy before the age of 1 month (3).FIGURE 1: Tyrosine degradation pathway. Enzymes affected by hereditary tyrosinemias and NTBC are indicated. HTII = hereditary tyrosinemia type II; NTBC = (2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione).In 2011, a pregnancy carried to term by a Belgian patient with HTI maintained on NTBC was reported, with no adverse effects of NTBC or maternal HTI noted in the child during the first year of life (4). More recently, a French patient with HTI who delivered an HTI-affected child was described, with the child exhibiting normal growth and development through the age of 7 months (5). Here, we report the third known and first North American case of a pregnancy successfully carried to term in a patient with HTI maintained on NTBC. The mother was diagnosed as having HTI at age 14 months, after presenting with rickets, coagulopathy, and elevated serum tyrosine and methionine levels. The diagnosis was established by detection of elevated urine succinylacetone. She was initiated on NTBC, a phenylalanine- and tyrosine-restricted diet, and a phenylalanine- and tyrosine-free medical food. Her clinical status improved with resolution of rickets and coagulopathy, and normal growth and development. During subsequent years, she was variably compliant with dietary recommendations, and developed painful corneal crystals attributed to and apparently correlated with such dietary noncompliance (6). Her serum tyrosine was persistently elevated (Fig. 2A), which was attributed to a combination of the underlying disease and dietary noncompliance. She was generally compliant with NTBC, although efforts to maintain a dose of ∼1 mg · kg−1 · day−1 were impeded by exacerbated eye pain. Nevertheless, serum NTBC levels generally remained in the recommended target range (Fig. 2B) and serial laboratory and imaging evaluations did not raise concern for hepatocellular carcinoma.FIGURE 2: Maternal serum (A) tyrosine (Tyr; normal range 25–85 μmol/L) and phenylalanine (Phe; normal range 35–90 μmol/L), (B) NTBC (therapeutic target 40–60 μmol/L), and (C) α-fetoprotein before, during, and after pregnancy (reference range in pregnancy reported in reference (7)). Bracket denotes duration of pregnancy. NTBC = (2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione).The patient was 16 years old and at 10 weeks of fetal estimated gestational age when she informed us of her gravid status and intention to carry the pregnancy to term. After consideration and discussion of known and theoretical risks and benefits, she was recommended to continue NTBC therapy. Her dietary prescription was adjusted to account for increased nutrient demands during pregnancy. At serial follow-up visits, our patient reported continued compliance with NTBC therapy and increased compliance with dietary recommendations. Her serum tyrosine remained elevated throughout the pregnancy, although generally in the previously noted range (Fig. 2A). Serum NTBC level declined below the recommended target range during the pregnancy (Fig. 2B), but without the appearance of succinyl acetone in urine or other change in serially monitored metabolic laboratories. Nevertheless, the decreased serum drug level prompted us to increase the NTBC dose, which was tolerated without eye pain and resulted in restoration of the serum NTBC level back into the target range. A rise in maternal serum α-fetoprotein during the pregnancy was noted and within the expected range (Fig. 2(7)). The patient delivered a healthy, well-appearing 2.9-kg infant girl by spontaneous vaginal delivery at 37-week estimated gestational age. The infant's serum tyrosine was elevated on the newborn screen (Fig. 3) and NTBC was detectable in blood at birth (25.3 μmol/L). Mild postnatal indirect hyperbilirubinemia was also noted, with subsequent evaluations showing normalization of serum tyrosine (Fig. 3A) and bilirubin, disappearance of NTBC from serum, and persistently normal serum transaminases, direct bilirubin, glucose, and prothrombin time (data not shown). Urine organic acid evaluation in the infant was negative for succinylacetone at birth and subsequently. The baby was begun on a standard cow's milk–based formula, which she tolerated without difficulty. She was seen in our office in consultation along with her mother at 1, 4, and 12 months of life, with normal development and generally normal growth (Fig. 3B) during that time. After delivery, maternal serum NTBC levels remained in the therapeutic range (with return to the prepregnancy dosage) and serum α-fetoprotein became undetectable (Fig. 2B, C).FIGURE 3: Infant (A) serum tyrosine (Tyr) and phenylalanine (Phe) and (B) growth percentiles. OFC = occipital-frontal circumference.As in the case described here, 2 published descriptions of pregnancies in NTBC-treated patients with HTI reported no evidence of NTBC-induced harm to the developing fetus (4,5). Given the potential for serious risk to the gravid patient with HTI (and, thus, the unborn fetus) of discontinuing NTBC therapy, continuing maternal treatment in pregnancy would seem to be the most prudent approach. Conversely, whether hepatic metabolic function in a developing fetus with FAH haplosufficiency may compensate for complete lack of maternal FAH during pregnancy in HTI is not known. Moreover, maternal serum tyrosine levels or NTBC may have potential to affect the developing fetus; however, in the well-characterized FAH knockout HTI mouse model, NTBC administered to affected pregnant mothers crosses the placenta and is not reported to be associated with teratogenicity (8,9). There are no reported cases of pregnancy in patients with HT type III (mutation of 4-hydroxyphenylpyruvate dioxygenase), which is the site of NTBC action in patients with HTI (Fig. 1). Two pregnancies in patients with HTII (mutation of tyrosine aminotransferase, Fig. 1) have been reported, one unremarkable (10) and the other with markedly abnormal fetal outcome (11). Maternal serum tyrosine levels were reportedly under better control in the former than in the latter case. Those data are intriguing when considered together with a study describing a potential association between serum tyrosine and cognitive outcomes in patients with HTI (12). As additional cases of pregnancy in patients with HTI occur, analyses of infant outcomes in NTBC-treated mothers will be essential for clarification of the risk and benefits of such therapy to the developing fetus. Nevertheless, the case reported here and the ones described previously (4,5) show that continuing NTBC in pregnant patients with HTI does not necessarily disrupt fetal development.

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