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INTRODUCTION
The urea cycle is a set of six metabolic reactions whose main function is to eliminate the excess nitrogen that is formed in the degradation of amino acids and other nitrogen compounds. Of the six enzymes that catabolize these reactions, the deficiency of ornithine carbamoyltransferase (OTC) enzyme is the most common. The underlying cause of OTC deficiency (OTCD, OMIM number #311250) (1) is a gene mutation on the X chromosome, with a prevalence of one in 62,000-77,000 live births (2). Over 400 mutations have been found to result in OTCD. Of the identified disease-causing mutations reported for OTC, the majority are amino acid replacements, followed by RNA splicing defects, premature protein terminations and deletions (2). The mutation can occur de novo in the patient’s genome or is inherited (3). Most of the patients with OTCD are hemizygous males. They can be severely affected, presenting with hyperammonemic coma, in the neonatal period, usually within the first week of life. Neonatal presentation generally correlates with the absence of liver OTC activity and null alleles (2). Partial enzyme activity usually translates to milder symptoms or later age of presentation. These symptoms can include nausea, vomiting, lethargy, confusion, ataxia, seizure, coma, and cerebral edema. The phenotype of carrier females is highly variable, ranging from asymptomatic to neurologic compromise secondary to hyperammonemia (4). Approximately 20 percent of female carriers become symptomatic (2). Reportedly, the degree of symptoms is related to the level of skewed X-inactivation within the liver (4). In females, the deficiency can appear during any period from infancy to adulthood and it can be prompted by triggers such as high protein intake, fasting, intercurrent illness, febrile illness, trauma, surgery, etc. Pregnancy, parturition, and the postpartum period can also be triggers since these situations can produce a major metabolic decompensation.
The diagnosis of OTCD is based on clinical suspicion in patients with elevated ammonia and liver function tests, considering the onset and the symptoms. Historically, the allopurinol test has been used to detect OTC carriers in at-risk females, however, its use is limited, since it has 91 % sensitivity (given by orotidine alone or in combination with orotic acid) and a specificity of 70 % and 65 %, respectively (5). Enzyme analysis and molecular genetic testing can identify OTCD as the underlying disease (3). Similar to other urea cycle disorders (UCDs), OTCD treatment includes a combination of a restriction/supplementation strategy. The restriction part comes from the dietetic treatment which is based on an individualized restriction of proteins (protein tolerance) and also depending on the clinical status. The latter is based on the supplementation with arginine or citrulline (6). Fasting periods longer than overnight time should be avoided.
Regarding the pharmacological treatment, this may include sodium benzoate and sodium or glycerol phenylbutyrate, which reduces ammonia by using alternative pathways for nitrogen elimination. Other modes of treatment include hemodialysis and liver transplantation. Lastly, similar to many metabolic diseases, OTCD is also a compelling candidate for gene therapy. Considering the overall treatment of these patients, it is recommended to avoid hepatotoxic drugs and also anticonvulsants (valproic acid), since they can induce episodes of decompensation (6,7).
Nowadays, UCDs (including OTCD) as well as other inborn errors of metabolism (IEM), represent a growing specialty in adult medicine. Reasons for this include improved diagnosis through expanded new-born screening programs, identification of potentially affected family members and greater awareness of symptomatic presentations in adolescence and in adulthood. Greatly improved survival and reduced mortality from previously lethal and debilitating conditions have enabled survival into adulthood and reproductive age (8).
When women with OTCD wish to become pregnant they will have to be referred to genetic counselling in order to understand the potential impact of pregnancy on their condition and vice versa and the outcome for their children. OTCD-carriers who become pregnant require a regular follow-up, a strict control of ammonia levels, diet or treatment when managing this critical period. There is scarce literature about the management of pregnancy in OTCD-carriers. In this article, a) we report a case of two pregnancies of an OTCD-carrier; and b) we review the literature describing OTCD and pregnancy, parturition and postpartum.
METHODS
The literature search was carried out in December 2021 and the strategy combined the following key terms: “urea cycle disorders, inborn”, “ornithine carbamoyltransferase deficiency disease”, “ammonia”, “hyperammonemia” with “pregnancy”, “pregnancy outcome”, “gravidity”, “parity”, “labor, obstretic”, “parturition”, “delivery, obstetric”, “postpartum period” both as entry terms and MeSH terms in MEDLINE. There were no filters used and without time limit. We identified 1,049 papers. After screening all titles and abstracts, and eliminating duplicates, 23 papers that corresponded to our inclusion criteria were identified, which were: a) studies written in English, Spanish or French; b) performed in humans; and c) they reported data on women with OTCD during pregnancy, labor, or postpartum period. A thorough review of the references in the retrieved articles was also completed with citations from all searches imported into a reference manager (Mendeley). Informed consent of the patient has been obtained prior to data recollection and publication.
RESULTS
CASE REPORT
In this paper, we report the case of a 33-year-old woman who was sent to our Inherited Metabolic Diseases consult in 2013, in order to determine a possible metabolic disease due to hyperammonemia. Her delivery was normal (3,450 g) and had a normal psychomotor development. She underwent surgery for a liver adenoma in 2005 and has never had a problem with anesthesia. She had no family history of consanguinity or known metabolic diseases. She denied consumption of alcohol, drugs and/or smoking. She was not taking any medication at that time, had a university degree and worked as a teacher in a kindergarten.
The patient presented episodes of sleepiness as an infant that each time improved after fasting. At the age of three, she was treated due to an absence seizure, but she was not given a diagnosis. These episodes happened about two times a year, generally after a heavier meal, especially at noon. They lasted 24-48 hours until she got better. The episode repeated at the age of six and she was admitted again and treated with fluid therapy.
At the age of 17-18-years old, the patient was seen by neurologists. She was diagnosed with epilepsy and was given carbamazepine, but continued with absence seizures. Her crises consisted of drowsiness, decreased level of consciousness and forgetfulness. After trying to decrease the seizures with medications such as Depakine® and Keppra® without improving, she was switched to sodium valproate (Depakine chrono®). After six days taking it, she began with a decreased level of consciousness, behavioral changes, drowsiness, and was admitted to the hospital, where she remained for ten days. She had an ammonia of 300 mcg/dl (normal range, 19-80 mcg/dl). After the withdrawal of the medication and treatment with oral carnitine, she regained the level of consciousness. Three days after admission, she had an ammonia level of 140 mcg/dl (normal range 19-80 mcg/dl).
At diagnosis in our hospital, the patient presented an ammonia level of 74 µmol/l (normal range < 54 µmol/l) (Fig. 1). Plasma aminogram presented slight hypoaminoacidemia with a decrease in citrulline levels, 10 µmol/l (27 + 8) and Arg 12 µmol/l (72 + 26), and increased Gln levels 749 µmol/l (463 + 113). Urinary aminoacids: increased excretion of Gln 122 µmol/mol creatinine (58 + 25) and decreased Arg 1 µmol/mol creatinine (2 + 1). Elevated excretion of cystathionine 9 µmol/mol creatinine (2 + 2). Orotic acid in urine: 7.2 µmol/mol creatinine (0.1-2.9) and orotidine 1.4 µmol/mol creatinine (0.1-2.2). Urine organic acids: slightly increased excretion of homovanillic acid 37 µmol/mol creatinine (1-6) and orotic acid 10 µmol/mol creatinine (3-4). Normal levels of acylcarnitines. The study was completed with the allopurinol test, which was positive. Orotic acid in urine: basal, at 6 h, 12 h, 18 h and 24 h was 3.6 mmol/mol creatinine (normal range 0.1-2.9 mmol/mol creatinine), 24 mmol/mol creatinine, 17 mmol/mol creatinine, 51 mmol/mol creatinine and 5.4 mmol/mol creatinine, respectively.
The genetic test revealed a heterozygous mutation in exon 5 of the OTC gene, variant p.Ala135Pro (c.403G>C). The genetic study of her mother and three siblings showed no genetic mutation. The patient was prescribed citrulline supplementation, a low protein diet and medication for constipation.
The patient got pregnant spontaneously in October 2017. The ammonia levels of the patient pre-pregnancy and during pregnancy are shown in figures 1 and 2, respectively. The fact that in our case the fetus resulted in an unaffected female could have contributed to decreased levels of ammonia during pregnancy. The treatment of our patient was a combination of citrulline supplementation, reduced protein intake, ensured caloric intake and ensured hydration. We also developed a protocol of treatment that covered from the pre-pregnancy counselling to the postpartum and lactation (9,10) (Table I).
Table I. Protocol for the management of pregnant women with OTCD.
OTCD: ornithine carbamoyltransferase deficiency; ICU: Intensive Care Unit.
The patient delivered at 39.2 weeks by vacuum extraction. At delivery, the patient was asymptomatic and had normal levels of ammonia (Fig. 3). The treatment received during labor was intravenous 10 % glucose, ensured caloric intake, ensured hydration, citrulline supplementation and low protein diet. The fetus was an unaffected female who presented a weight of 3,300 g.
During postpartum, the patient was asymptomatic. On day 4 postpartum, she presented a maximum ammonia level of 122 µmol/l (normal range, < 54 µmol/l) (Fig. 3).
The treatment of our patient was a combination of intravenous 10 % glucose, ensured caloric intake, ensured hydration, citrulline supplementation and low protein diet. However, during the episode of hyperammonemia (day 3-5 postpartum) she followed a protein free diet. She was discharged on day 18 postpartum. Our patient has also successfully breastfed her baby girl, with the exception of the days when hyperammonemia occurred. With the exception of citrulline supplementation, the patient was not prescribed any OTCD-specific medication during lactation. To ensure an adequate calorie intake, a maltodextrin module was prescribed.
In June 2019, the patient had a spontaneous abortion of a male fetus. A non-invasive prenatal testing (NIPT) was performed.
In December 2019, the patient got pregnant again. Invasive prenatal testing determined the fetus was a female. The ammonia levels of the patient pre-2nd pregnancy and during the 2nd pregnancy are shown in figures 4 and 5, respectively. The treatment included L-arginine and L-citrulline, L-carnitine, vitamin D supplementation, reduced protein intake, ensured caloric intake and ensured hydration, as well as medication for constipation. During this second pregnancy the same protocol we had developed previously was followed (Table I). The follow-up of this pregnancy happened during the COVID-19 pandemic (February-August 2020), which impacted the number of blood tests performed, and the telematic follow-up, to avoid unnecessary visits to the hospital.
The patient delivered at 39.1 weeks by spontaneous vaginal delivery. At delivery, the patient was asymptomatic and had normal levels of ammonia (Fig. 6). The treatment received during labor was intravenous 10 % glucose, ensured caloric intake, ensured hydration, L-arginine and L-citrulline and low protein diet. The fetus was an affected female who presented a weight of 3,430 g. Genetic study showed the same mutation as the mother’s.
During postpartum, the patient was asymptomatic. On day 1 postpartum, she presented a maximum ammonia level of 131 µmol/l (normal range, < 54 µmol/l) (Fig. 6). The treatment of our patient was a combination of intravenous 10 % glucose, ensured caloric intake, ensured hydration, L-arginine and L-citrulline supplementation and low protein diet. Our patient has also successfully breastfed her baby girl. Two months later, the patient had an ammonia level of 40 µmol/l (normal range, < 54 µmol/l). Both mother and daughters are well 4.9 years and 2.6 years later, respectively. The patient is actively followed-up in our outpatient clinic.
LITERATURE REVIEW
As a result of the literature review, 23 articles were retrieved regarding 33 cases of OTCD-carriers and pregnancy (Annex 1). The available evidence on OTCD in pregnancy comes mostly from case reports, small case series or literature reviews, and it dates from the past three decades, with the patients not being over 40-years of age. In these cases, the OTCD was either known prior to pregnancy (16 patients) or was diagnosed during pregnancy or shortly postpartum (18 patients). When the OTCD diagnosis was known, many reports described factors regarding pregnancy management such as the treatment provided, the ammonia levels and whether the mother was symptomatic or not throughout the whole process. During pregnancy, ten patients presented with hyperammonemia (11-19), seven patients with mental confusion (11,13,14,19-22), three patients with hyperemesis gravidarum (11,13,17) and one with acute liver failure (18). The risk of hyperammonemia was higher postpartum, especially between postpartum day 2 and day 11. During this period, 16 patients presented an increase in ammonia levels (9,12,15,20,21,23-31). In eight of the cases there was a fatal outcome, where the mother or the fetus died (11,21,28,31,32).
GENETIC MUTATION
Few studies described the mutations causing the disease, probably since many studies are historical and the possibility of studying it was low (11,15,17-19,32) (Annex 1). For those naming it, Weiss et al. mentioned their case as being a heterozygous c.919 A>G mutation in exon 9 of the OTC gene and also being a de novo mutation, since none of the parents had it (18). On the other side, Blair et al. found no pathogenic mutation. This occurs in approximately 30 % of biochemically confirmed OTCD cases and is likely due to intronic or promoter mutations. The genetic mutation of our patient (c.403G>C, p.Ala135Pro) has never been reported. Caldovic et al. have recently published the fifth mutation update for human OTC. After examination of publicly available genomic data and examination of phenotype/genotype correlations from patients participating in the Urea Cycle Disorders Consortium Longitudinal Study, they reported 417 disease-causing mutations in the OTC gene, fifty-two patients with OTCD due to deletions, duplications or complex rearrangements involving the OTC gene and also 44 rare sequence variants in the OTC gene (2). Additionally, the authors found no correlation between the type of mutation and severity of disease measured by either number of hyperammonemic episodes or liver dysfunction in patients with late onset OTCD.
PREGNANCY DESCRIPTION
Clinical presentation
Similar to our patient, some of the included studies described no symptoms of OTCD during pregnancy, while others reported a manifestation of the disease as early as seven weeks into pregnancy (18). The adverse pregnancy outcomes reported have been mainly neurological, psychiatric, or hepatic (19) (Annex 1). In the study by Weiss et al., at seven weeks pregnant, the patient affected by hyperemesis gravidarum (intractable vomiting, weight loss and mildly elevated transaminases) developed acute liver failure and coma (18). In pregnancy, UCDs must be included in the differential diagnosis of hyperemesis gravidarum or acute liver failure, which must prompt plasma ammonia determination. A careful medical and family history is mandatory and should include questions about unexplained neonatal deaths, neurological or psychiatric disorders in the family, evidence of protein avoidance in patient and family members and drug intake by the patient (6). Pregnancy-related issues (nausea, vomiting, and anorexia) can lead to acute metabolic decompensation due to reduced calorie intake and difficulties taking essential supplements and medications. Although rare, if prompt treatment is not given, such decompensation can be sufficiently severe so as to lead to maternal and/or fetal death (11,15,33).
Ammonia levels
Since in many cases the OTCD was unknown until postpartum (in some cases postmortem), many patients did not have determinations of ammonia levels during pregnancy (15,20-22). The lack of ammonia levels determinations combined with an ostensibly healthy patient conducted in many cases for the OTCD to go unnoticed during the pregnancy period. On top of that, given the increased nitrogen demands during this time, the pregnancy period was unremarkable for some patients. On the other side, several studies reported hyperammonemia during pregnancy (12-19). The potential deleterious consequences of hyperammonemia on the fetus at an early term of pregnancy are uncertain. Compared to other metabolic diseases, in OTCD, data regarding the possible fetal toxicity of high levels of ammonia is not completely known (18). For instance, in phenylketonuria, high maternal phenylalanine levels are teratogenic to a developing fetus in utero (33). Ammonia levels should be checked regularly during pregnancy in patients with OTCD. Our patient presented normal levels of ammonia during pregnancy, something confirmed in some of the published cases (9,26).
Treatment
Pregnant women with OTCD should maintain the prescribed dietary treatment, according to the individual protein tolerance, and aminoacids supplements. Plasma amino acids should be checked regularly during pregnancy. The increased energy and protein requirements during pregnancy should be considered to avoid endogenous catabolism. Fasting periods longer than overnight time should be avoided. There are few reports on the use of specific medications (sodium benzoate and sodium phenylbutyrate), to control the ammonia levels during pregnancy (11-16,18,19,21). None of the articles described any teratogenic effects of the drugs and neither manufacturers’ data do not provide substantial information on their use in pregnancy. Annex 1 describes the outcomes of these cases. Additional treatment used to lower the ammonia levels included hemodiafiltration (13,17), hemofiltration (19) and hemodialysis (18) described in four of the clinical reports.
DELIVERY DESCRIPTION
Timing and mode of delivery
Regarding the timing and/or the mode of delivery, some of the studies did not contain this data, however the information extracted reports pregnancies going from 31 weeks (the lowest reported) up to term, whereas the mode of delivery varied between a cesarean section, a spontaneous vaginal delivery or an induction of labor. There are no specific recommendations on the mode of deliver for OTCD patients. In the absence of other complications, vaginal delivery is usually possible (33). According to Méndez-Figueroa et al., an induction of labor at 39 weeks should be considered, to ensure the presence of all services and medical specialties for management (9).
Labor description
From a metabolic standpoint, parturition represents prolonged and intense muscular activity where the energy requirements are substantial (8), and women often have poor oral intake for the duration of labor (33). Once admitted to labor and delivery, patients can be classified as low risk or high risk to guide the most appropriate management. A patient is high risk if she has had previous episodes of hyperamonemic coma, recurrent episodes of hyperammonemia as an adult or metabolic decompensation during this or prior pregnancies (9). Depending on the low/high risk patient, an adequate peripheral or central intravenous access should be secured. Euglycemia should be maintained throughout the period of delivery. Blood glucose monitoring should be carried-out every 2-4 h (9,25,26,32,33). The aim is to keep blood sugars 60-100 mg/dl at all times. Hemodynamic stress can be reduced by appropriate analgesia and decreasing patients’ anxiety. Liaison with the obstetrician, obstetric anesthetist and neonatology prior to delivery is advised. Considering these issues, these deliveries should be performed in a hospital setting. Our patient did not present any symptoms of OTCD during labor, similar to many cases described in the literature.
Ammonia levels
Only a few patients had ammonia levels determinations during labor (9). Méndez-Figueroa et al. recommend that, during labor, ammonia levels should be determined upon admission and every six hours (9). However, these determinations should be more frequent if the patient is symptomatic, or the values are above normal (Table I). Our patient presented normal levels of ammonia during labor.
Treatment
According to the literature, the treatment used in these patients during labor was mainly intravenous lactated Ringer’s solution, intravenous 10 % glucose and L-citrulline. The idea behind the treatment was to avoid catabolism during this critical period (Table I). In the case of our patient, a combination of intravenous 10 % glucose, ensured caloric intake, ensured hydration, L-citrulline, low protein diet was used. A scheduled cesarean section preceded by overnight fasting could theoretically precipitate hyperammonemia, therefore intravenous hydration using 10 % dextrose is recommended (9). If epidural anesthesia is used, additional hydration with lactated Ringer’s solution as needed may be used (9,25,26,32,33). However, this solution must be cautiously used, since it can be dangerous in other pathologies that cause increased ammonium, when the disease has not yet been confirmed (34). The patient’s usual treatment with arginine or citrulline should be maintained during this time. Since some of the medications used to treat OTCD patients are not readily available, the hospital pharmacy should be involved early with management plans (9).
POSTPARTUM DESCRIPTION
Clinical presentation
Following delivery of the fetus and placenta, maternal endocrine and metabolic status changes abruptly (8). Postpartum metabolic decompensation is frequent in OTCD, as well as other metabolic disorders. Elevations in postpartum metabolites have also been described in other disorders of protein metabolism such as maple syrup urine disease and methylmalonic acidemia (33). In symptomatic patients, the symptoms appeared between postpartum days 2 to 11. Some of the symptoms included nausea, vomiting, diplopia, ataxia, progressive somnolence (31), and even severe cerebral edema (31) and coma (23). In our review, three of the patients died as a result of OTCD complications (31). In the study by Açikalin et al. the patient was hospitalized on the second postpartum day because of nausea and vomiting, altered mental status, disorientation, and seizure activities. She was diagnosed as postpartum coma due to hyperammonemia related to OTCD and after 14 days of hospitalization, she died in the ICU despite all of the supportive and specific treatment modalities (28). Our patient did not present any symptoms of OTCD postpartum, similar to many cases described in the literature.
Ammonia levels
The exact cause of postpartum hyperammonemia is not well understood. It is hypothesized that when there is an unaffected fetus, the liver detoxifies maternal ammonium and, when this relationship is disrupted at the time of delivery, maternal ammonium increases (24). Following delivery of the fetus and placenta, the uterus undergoes involution (the process in which the uterus decreases in size, following delivery) producing increased protein catabolism. Uterine involution is especially rapid in the first 10-14 days’ postpartum; by six weeks’ postpartum it has returned to pre-pregnancy size. This is therefore a period of exceptionally high risk for decompensation of OTCD in at risk mothers, with many OTCD presenting for the first time in the postpartum period (8). Our patient presented moderate hyperamonemia up to 122 µmol/l (normal range, < 54 µmol/l) and 131 µmol/l (normal range, < 54 µmol/l) during the first and second pregnancy, respectively. In both cases, that responded to dietary modification without the use of any specific drug.
Treatment
In case of postpartum hyperammonemia, the treatment of choice was a low-protein diet (9,12,15,20,23,25,27,30), ammonia scavengers (sodium benzoate and sodium phenylbutyrate) (9,12,15,20,21,23-28,30,31), and hemodialysis/hemofiltration (20,28,30,31).
Discharge day
According to the literature, the most dangerous period for developing hyperammonemia and other OTCD symptoms is postpartum, therefore, this will have to be considered when discharging an OTCD carrier.
Breastfeeding
Only two of the studies reported women who successfully breastfed their baby girls. One of the newborns had OTCD. Both mothers were taking specific medications used to stimulate nitrogen excretion (sodium benzoate and sodium phenylbutyrate) when lactation started. Breastfeeding is a topic that needs to be discussed on an individual basis between women wishing to breastfeed and their physicians. Since breastfeeding places extra energy demands on the mother, with energy and nutrients being diverted to milk production from the third postpartum day (e.g., the uterine involution mobilizes amino acids for lactation), it is important to ensure an adequate calorie intake (8,33). During lactation, the composition of human milk changes dynamically and may vary according to many maternal factors, such as the nutritional status. Maternal undernutrition, producing lack of vitamin B12, vitamin D, calcium, and DHA during lactation may lead to low vitamin content in breast milk, which can cause permanent neurological disabilities in infants or low bone mineralization (35). On top of that, the combination of the catabolic state of the puerperium with the nutritional demands of breastfeeding and a poor calorie intake may be a potential trigger for metabolic decompensation. Moreover, since pregnancy, labor and puerperium can be associated with citrulline or arginine deficiencies, which can increase ammonia build-up, their prescription will have to be ensured, especially if the patient is breastfeeding (9). Currently, there is very little safety information available regarding many of the specific medications used or their content in breast milk (26,33,36). On the other side, there is a need to consider the clinical status of the newborn, whether it is affected by the disease or not, and follow the nutritional guidelines recommended in each case. Overall, both mother and child should be closely monitored during lactation.
FOLLOW-UP AND OVERALL OUTCOME
Women should be monitored in the hospital for at least 72 hours after delivery, and close follow-up in an outpatient metabolic clinic should be recommended.
Limitations
There is scarce literature about the management of pregnancy in OTC carriers and the information available comes from non-analytic studies: single case reports, small case series or literature reviews.
For this reason, it is highly important to develop protocols/clinical guidelines that will guide the physicians in managing this condition during pregnancy. Nevertheless, our work provides relevant information regarding pregnancy managing in OTCD and highlights the importance of protocols ready to follow during pregnancy, labor and postpartum.
CONCLUSIONS
Females with OTCD can certainly plan a pregnancy, but they need a careful management during delivery and particularly during the immediate postpartum period. If possible, a multidisciplinary team of physicians, dietitians, obstetricians-gynecologists, neonatologists, pharmacists, etc. with expertise in this field, should participate in the care of women with OTCD during pregnancy and in their adult life. Increased awareness of these conditions amongst all clinicians is essential to expedite diagnosis and manage appropriately.
