Abstract
Introduction
Women with inherited metabolic disorders, including those with previously life-limiting conditions such as MMA, are reaching child-bearing age more often due to advances in early diagnosis and improved pediatric care. Information surrounding maternal and fetal complications associated with the underlying disorders remains largely unexplored.
Methods
Pregnancies affected by maternal MMA were ascertained through study 04-HG-0127 “Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders” (clinicaltrials.gov identifier: NCT00078078) and via literature review. Prenatal and delivery records in study participants were reviewed.
Results
17 pregnancies were identified in women with isolated MMA, including 3 abortions, 1 termination, and 13 completed pregnancies [3 cases with cblA (4 pregnancies), 4 cases of mut- (1 cobalamin responsive, 3 non-responsive), 5 cases with unknown type of MMA]. 17% (3/17) of the pregnancies resulted in a first trimester abortion, while 38.5% (5/13) of the completed pregnancies resulted in preterm deliveries. A cesarean delivery rate of 53.8% (7/13) was noted among the cohort. Fetal distress or nonreassuring fetal status was the indication for 57% (4/7) cesarean deliveries. One patient was reported to have metabolic crisis as well as episodes of mild hyperammonemia. Malformations or adverse outcomes in the progeny were not observed.
Conclusion
Although there have been a small number of pregnancies identified in women with MMA, the cumulative results suggest that the majority of pregnancies can be complicated by cesarean delivery and increased risk of prematurity. A pregnancy registry could clarify perinatal complications and define management approaches needed to ensure optimal maternal and fetal outcomes in this growing patient population.
Introduction
Methylmalonic acidemia (MMA) is a group of inherited metabolic disorders with a common defect in the conversion of methylmalonyl-CoA to succinyl-CoA (Manoli and Venditti 2010). The disorder was first defined clinically in late 1960's in infants presenting with overwhelming acidosis and renal tubular dysfunction (Oberholzer, et al 1967, Stokke, et al 1967). MMA is most commonly caused by mutations in the mitochondrial localized enzyme, methylmalonyl-CoA mutase (MUT) or impaired transport and synthesis of the MUT cofactor, 5′-deoxyadenosylcobalamin due to mutations in the MMAA, MMAB or MMADHC genes. Over the past four decades, treatment with amino acid/protein precursor restriction, along with supportive care and supplementation with cobalamin in responsive patients, has led to improved survival (de Baulny et al 2005, Dionisi-Vici et al 2006, Hörster et al 2007).
With early diagnosis through newborn screening and improved pediatric care, women with inborn errors of metabolism are achieving reproductive age more frequently and are well enough to contemplate pregnancy (Langendonk et al 2011, Jacquemyn 2014). Patients with MMA who are pregnant or interested in becoming pregnant, as well as their health care providers, need information surrounding the risks to maternal and fetal health that may be associated with the disease state during pregnancy and monitoring guidelines to ensure optimal outcomes.
Because some inborn errors have known deleterious maternal or fetal effects in pregnancy (Koch 1993), gestation, parturition, and lactation can be challenging for the fetus, mother, and the medical teams. In urea cycle disorders, there is an increased risk of metabolic decompensation for the mother, especially in the peripartum period (Walter 2000). Maternal phenylketonuria has well-described teratogenic effects on the fetus, including intellectual disability, microcephaly, congenital heart disease, and intrauterine growth retardation, mandating tighter dietary management for women even prior to conception. (Walter 2000). In addition to the inherent exposures from the maternal condition on the fetus, many conditions are treated with medical foods and supraphysiological levels of cofactors, vitamins, even though teratogenicity of these agents have not been studied.
Amongst women with MMA and related disorders, there are nine published cases of pregnancy affected by maternal isolated methylmalonic acidemia (Wasserstein et al 1999, Diss et al 1995, Deodato et al 2002, Boneh et al 2002, Adeyemi et al 2004, Brunel-Guitton et al 2010, Langendonk et al 2011, Lubrano et al 2013, Jacquemyn et al 2014). The paucity of information regarding management and outcomes of pregnancies affected by maternal MMA motivated a critical reappraisal of this topic when we participated in the care of several MMA patients evaluated as part of a natural history study who had previous pregnancies or became pregnant during the course of this study.
Patients and Methods
A retrospective analysis was performed of patients enrolled through a natural history study at the National Institutes of Health, 04-HG-0127 “Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders” (clinicaltrials.gov identifier: NCT00078078) and conducted in compliance with the Helsinki Declaration. Prenatal and delivery records were obtained for review and used to supplement patient assessments. The subtypes of MMA were determined by cellular biochemistry and/or genetic testing for all participants (Baumgartner et al 2014).
Two women enrolled in the natural history study were found to have three unpublished pregnancies. Additionally, another woman enrolled in the natural history study became pregnant and was followed prospectively. Two first trimester miscarriages were also identified; including one in a patient with another completed pregnancy.
To supplement the experience of our participants, a comprehensive literature review of reports indexed in PubMed describing pregnancies affected by maternal MMA was performed using the terms methylmalonic acidemia, pregnancy, and inborn errors of metabolism. The searches yielded 28 reports; upon further evaluation, 3 were relevant to our study for further review. Additional case reports were also identified after examining the citations within relevant papers. Only cases of isolated MMA were considered in subsequent analyses. The same literature search was repeated in October 2014 prior to final submission. The results of the published cases and the NIH patients were combined with the previously published reports to generate the case series presented here.
Results
Nine pregnancies affected by isolated MMA were previously published (Adeyemi 2004, Boneh 2002, Deodato 2002, Diss 1995, Jacquemyn 2014, Langendonk 2011, Lubrano 2013, Wasserstein 1999). In the review of patients enrolled in our clinical research protocol, four pregnancies in three women with forms of isolated MMA were identified, as well as two first trimester miscarriages. These latter pregnancies have not previously been reported. The results from the literature review and the retrospective chart review were combined for a total case series of thirteen completed pregnancies (Table 1, Table 2); three first trimester miscarriages and one first trimester termination of pregnancy were also documented (Table 3).
Table 1.
Published and unpublished pregnancies complicated by maternal isolated methylmalonic acidemia. (MMA)
| Patient | Year of publi- cation or delive ry |
Age | Enzymolog y/complem entation group |
Molecular genetics |
B12 resp onsi ve |
Protein intake (trimester) |
Treatments | Methylmalonic acid serum μM (trimester) |
Methylmal onic acid urine mmol/mol Cr |
Renal function Serum Cr umol/L (trimester) |
Complications of MMA |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 (Diss 1995) | 1995 | 23 | NR | NR | No | 3.6 g/kg/day (1) 4.1 g/kg/day (2) 1.6 g/kg/day (3) |
NR | 16.4 (1) 7.5 (3) |
2.59 mmol/day (1) 1.02 mmol/day (3) |
NR | Convulsions |
| 2a (This report) | 1997 | 18 | mut– | MUT c.2150G>T p.G717V; 2nd mutation unknown | No | 64 g/day | Carnitine | 172 (Postpartum) | NR | Serum Creatinine 70.72 (Postpartum) | Strokes, Seizure |
| 3a (This report) | 1997 | 24 | cblA | MMAA c.450dupG p.P151AfsX 19 homozygous | Yes | up to 45 g/day | N/A | 52 (Postpartum) | NR | NR | None |
| 3b (This report) | 2008 | 35 | cblA | MMAA c.450dupG p.P151AfsX 19 homozygous | Yes | 45 g/day (1-2) 80 g/day (3) | Carnitine, Hydroxocobalamin IM 5mg QOD, protonix, albuterol inhaler | 214 (Preconception) 39 (1) 45 (2) 15 (3) |
N/A |
Serum Creatinine 120.22 (1) 97.24 (3) eGFR: 56 mL/min/A (3) Proteinuria: 280 mg/24hr (3) |
None |
| 4 (Wasserstein) | 1999 | 20 | mut– | NR | No | 40-55 g/day | Oral amoxicillin in first trimester then metronidazole; Cornstarch in overnight formula; oral bicarbonate | 1900 (1) 484 (2) 1059-1192(3) |
NR | eGFR: 51ml/min/1.73m2 (1); 36 ml/min/1.73m2 (2)Proteinuria: 0.7g in 24 hours (2) | Optic atrophy, chronic pancreatitis, anemia |
| 5 (Deodato) | 2002 | 24 | mut– | NR | Yes | NR | Carnitine, Vitamin B12 IM 5mg per week | 280 (D) | 17,049 (1) 4177 (2) 3236 (3) 1148 (D) |
Creatinine clearance: 67.5 ml/min/1.73m2 | |
| 6 (Boneh) | 2002 | 16 | cblA | NR | Yes | NR | Vitamin B12 IM 1mg every 4 weeks increased to 1mg every 2 weeks | 3.7-9.7 (D) | 210-600 (3) 277-1308 (D) |
NR | None |
| 7 (Adeyemi ) | 2004 | 23 | NR | NR | Yes | Low Protein | Oral cyanocobalamin 500 umg BID | NR | NR | NR | Epilepsy |
| 8a (Langendonk) | 2011 | 24 | decreased propionate incorporation | NR | unknown | 45 g/day (1-2) 60 g/day (3) |
Carnitine, Oral vitamin B12 1mg daily, folic acid, iron, calcium, potassium, vitamin D | 758 (Pre) 1700-3886 (?) | Serum Creatinine 50 | None | |
| 9 (Langendonk) | 2011 | 19 | decreased propionate incorporation and methylmalonyl CoA mutase activity; reduced adenosylcobalamin synthesis | NR | No | 35 g/day | Carnitine, Multivitamin, Vitamin B12 IM 1 mg every 4-6 weeks | 120 (1) 37 (3) |
2240 (1) | Serum Creatinine 66 eGFR >90mL/min/1.73 m2 | Intellectual disability (IQ 55) |
| 10 (This report) | 2012 | 29 | mut– | MUT c.2150G>T p.G717V homozygous | No | 47 g/day | Carnitine, Vitamin D, C, folic acid | 133 (Postpartum) | 765 | Serum Creatinine: 85.75 | Peripheral neuropathy, history of coma |
| 11 (Lubrano) | 2013 | 29 | cblA | MMAA c.586C>T p.R196X homozygous | NR | Immunosuppression, Beta-blocker | 72-52 (2-3) | 1208 (Pre); |
Serum Creatinine 114.92 (1) 123.76 (2) eGFR 55 mL/min/1.73m2 (1) |
Kidney transplant, hypertrophic cardiomyopathy | |
| 12 (Jacquemyn) | 2014 | 27 | NR | NR | Yes | 1 g/kg/day | Carnitine, Zinc sulfate, Calcium carbonate, Vitamin B12 IM 1mg once daily | NR | NR | Serum Creatinine 55.69 | None |
D - Delivery. NR – Not reported, N/A – not applicable
Table 2. Published and unpublished pregnancies with maternal methylmalonic acidemia, pregnancy outcomes.
| Patient | Enzymology /complement ation group |
Metabolic Imbalance in Pregnancy |
Gestational Age at Delivery |
Obstetrical Complications | Method of Delivery |
Indication for Delivery Method |
Birth Weight (%) |
Outcome of Child | |
|---|---|---|---|---|---|---|---|---|---|
| 1 (Diss 1995) | NR | None | Term | Hyperemesis in first trimester | Vaginal | N/A | 3500 g (25%) | At age 3 years, normal development | |
| 2a (This report) | mut– | Hospitalization and IV fluids twice at 24 weeeks | 38 weeks | Postpartum infection | Cesarean | Fetal Distress | 3288 g (50%) | At age 10 years, normal development | |
| 3a (This report) | cblA | None | 42 weeks | Preeclampsia | Cesarean | Fetal Distress | 3714 g (50%) | At age 14 years, normal development | |
| 3b (This report) | cblA | None | 32 weeks | Preeclampsia, PPROM, Gestational diabetes, Placental abruption, Uterine Scar | Cesarean | Fetal distress, repeat cesarean delivery | 1459 g (10%) | At age 3 years, normal development | |
| 4 (Wasserstein 1999) | cblA | None | 36 weeks 4 days | PPROM, preeclampsia | Vaginal | N/A | 3220 g (75%) | At age 1 year, normal development | |
| 5 (Deodato 2002) | NR | None | 38 weeks | None | Cesarean | Scheduled, elective | 2940 g (25%) | At age 2 years, normal development | |
| 6 (Boneh 2002) | decreased propionate incorporation | None | 36 weeks | None | Cesarean | Fetal distress | Not reported | Not Reported | |
| 7 (Adeyemi 2004) | decreased propionate incorporation and methylmalonyl CoA mutase activity; reduced adenosylcobalamin synthesis | None | 34 weeks | PPROM, chlamydia | Cesarean | Failure to progress | 1900 g (10%) | At age 5 months, normal development | |
| 8a(Langendonk 2011) | NR | 2 Episodes of hyperammonemia (49umol/L) | 38 weeks | None | Vagnial | N/A | 2850 g (10-25%) | At age 5 years, normal growth and development | |
| 9 (Langendonk 2011) | mut– | None | 35 weeks | Intrauterine growth restriction (IUGR) | Cesarean | IUGR | 1530 g (<3%) | At age 1 year, normal growth and development | |
| 10 (This report) | mut– | None | 39 weeks | None | Vaginal | N/A | 3095 g (25%) | At age 3 months, normal appearance | |
| 11 (Lubrano 2013) | cblA | None | 37 weeks | None | Vaginal | N/A | 2480 g (10%) | At age 30 months, normal development | |
| 12 (Jacquemyn 2014) | cblA | None | 40 weeks | None | Vaginal | N/A | 3300 g (50%) | Follow up reported as normal | |
Table 3. Pregnancy Loss in first trimester patients with MMA.
| Patient | Enzymology | Timing of Pregnancy Loss |
|---|---|---|
| 2b | Mut – B12 unresponsive | First trimester spontaneous miscarriage |
| 8b (Langendonk) | Not performed. | Miscarriage at 5 weeks gestational age |
| 8c (Langendonk) | Not performed. | Termination of pregnancy at 10 weeks gestational age |
| 13 | Mut – B12 unresponsive | First trimester spontaneous miscarriage |
Of the 12 women with MMA, several subtypes of MMA are represented. Five of the patients were unclassified. Four patients had mut- and three patients had cblA deficiency, one of whom had two completed pregnancies. The women manifested a range of MMA-related complications including optic atrophy, chronic pancreatitis, strokes, seizure disorders, history of coma, intellectual disability, and cardiomyopathy (Table 1).
Renal dysfunction is a common manifestation of MMA (de Baulny 2005, Hörster 2007) and patients in this cohort displayed a range of kidney disease from normal function to renal insufficiency and even renal transplantation (Table 1). As previously noted, but worth emphasized, the woman reported by Wasserstein et al experienced a decrease in renal function during pregnancy from 51 ml/min in the first trimester to 36 ml/min in the second trimester. Serum creatinine values ranged from 0.63 mg/dL to 1.36 mg/dL (Table 1). Renal indices are summarized in Table 1 and were not uniformly reported (n=9).
MMA patients were largely unaffected by metabolic disturbances during the pregnancies. One report mentioned two episodes of mild hyperammonemia (up to 49 μmol/L) during pregnancy (Langendonk et al 2011). Patient 2 had two metabolic crises in pregnancy around 24 weeks gestation, which manifested with nausea, vomiting, and lethargy and resulted in the need for hospitalizations and IV hydration. Fortunately, she was without metabolic crises in the postpartum period.
Protein restriction continued to represent the mainstay of treatment for patients with MMA during pregnancy. Depending on the severity of the underlying enzyme deficiency, a variety of protein restriction methods were employed starting as low as 40 grams of natural protein per day up to 80 grams. Patient 2a was maintained pre-pregnancy on protein restriction at 64 grams per day, which was maintained during pregnancy This patient is mut- and clinically vitamin B12 unresponsive. Her metabolic course was significant for repeat hospitalizations from age 6 months to 7 years for metabolic crises but was unremarkable after that. Pregnancy 3a and 3b, who are the same patient, had protein intake during pregnancy of 76-80 grams per day.
Patient 3b preconceptionally was prescribed 40 grams of protein per day, which as pregnancy progressed was gradually increased to 80 grams per day although actual intake based upon her recall was about 70 grams per day. Her plasma amino acids were evaluated each trimester and the diet was adjusted based upon those data. Serum methymalonic acid concentrations ranged from 66.23 micromol/L in the serum in the first trimester to 210 micromol/L in the third trimester.
In addition to protein restriction, the use of supplements such as vitamin B12 and carnitine were continued throughout pregnancy. Patients who have been previously successfully managed with supraphysiological doses of vitamin B12 have been maintained on their dosage throughout pregnancy. Patient 3b was maintained on hydroxycobalamin 5 mg intramuscular every other day throughout pregnancy and during labor and delivery (Table 1).
Specific to the experience with patient 3b in labor and delivery during an episode of acute stress due to possible placental abruption and preeclampsia, recommendations were to administer L-carnitine at 50 mg per kg per dose intravenously every 6 hours for 24 hours and then decrease the dosage to 25 mg per kg per dose every 6 hours intravenously until stabilized. Throughout pregnancy, the patient was maintained on a dose of L-carnitine 1500 mg twice per day by mouth. Seven of the 13 pregnancies were supplemented with carnitine.
Gestational diabetes complicated one pregnancy in our cohort. She was managed less vigorously than gestational diabetic patients without MMA would be to avoid hypoglycemia and catabolism. The goals set for the patient were to maintain blood glucose levels at 120mg/dl to prevent catabolism. Despite the laxity in glucoregulation, the birth weight at delivery was 10th centile.
The literature review revealed four of the nine (44.4%) pregnancies resulted in a cesarean delivery as well as four of the nine (44.4%) resulted in preterm deliveries. One case report noted the development of preeclampsia in a patient who was reported to have renal insufficiency (Wasserstein et al 1999). Unpublished cases from the National Institutes of Health demonstrated three of the four pregnancies resulted in cesarean deliveries all with emergent indications of fetal distress. Two of the four pregnancies were complicated by preeclampsia.
Combining our case series with that of the literature review, 38.5% of the completed pregnancies resulted in preterm deliveries. A cesarean delivery rate of 53.8% (7/13) was noted among the cohort, which is higher than the United States national average of 32.8% (CDC 2014). Fetal distress or nonreassuring fetal status was the indication for more than half (4/7) of the cesarean deliveries, and another report documented persistently nonreactive fetal heart tracings with reassuring biophysical profiles (Wasserstein 1999). An additional indication for cesarean delivery in the setting of maternal MMA was intrauterine growth restriction (Langendonk et al 2011).
The postpartum courses for the patients were unremarkable. Patients were hospitalized for 2-10 days postpartum. All were maintained with dextrose containing intravenous fluids. Patients 2a, 3a, 3b, 10 were slowly introduced to protein postpartum as tolerated. To our knowledge, there have been no published reports of metabolic decompensation postpartum in a mother with MMA.
Fetal growth and development appear to be unaffected by maternal elevations of MMA (Wasserstein 1999). Increased MMA levels in amniotic fluid have been reported in patients undergoing invasive prenatal testing. Malformations or adverse outcomes in the babies were not reported although persistence of high concentrations of maternal metabolites was documented in one case report (Wasserstein 1999, Deodato et al 2002).
Discussion
As more patients with inborn errors of metabolism not only reach child bearing age but feel well enough to pursue pregnancy, the clinical challenges of counseling and management will continue to become more common. In MMA, the information used to manage patients during pregnancy has been derived from case reports and assumptions made from the experiences of other inborn errors of metabolism. Although in some inborn errors of metabolism, such as phenylketonuria, elevated levels of biochemical precursors are clearly teratogenic, the same information is not yet been established for MMA. It should be noted that one infant born to a mother with MMA had IUGR (Langendonk 2011) and that protein limitation during pregnancy might be associated with serious iatrogenic complications, given that a low protein intake is associated with poor fetal growth in mothers who have malnutrition (Godfrey 1995). In addition to risk to the developing fetus, proper counseling needs to include any potential complications impacting maternal health, such as pregnancy related complications including pre-eclampsia and GDM.
A variety of subtypes of MMA were identified including three cases with cblA (four pregnancies), four cases of mut- (one cobalamin responsive, three non-responsive), two historical cases confirmed with only enzymology, and three cases with an unknown type of MMA (two B12 responsive and one unresponsive). The cases span several decades and therefore include varying methods of management of MMA as well as changing methods of pregnancy management. Although limited in its numbers, this case series presents published experiences along with a number of new cases to create the most comprehensive description of MMA in pregnancy to date and helps to provide the foundation for improved understanding, management, and counseling of MMA patients desiring pregnancy.
When reviewing all the cases together, we observed some possible trends. Pregnancy complications such as late preterm birth, preterm premature rupture of membranes, cesarean delivery, nonreassuring fetal status, and preeclampsia all have been documented in this small cohort, while birth weight and development despite exposure to methylmalonic acid in utero appears to be tolerated without incidence in the offspring.
In support of this concept, there have been no reports of birth defects or intellectual disability related to exposure to elevated levels of methylmalonic acid in utero; in fact, eleven of the thirteen children, ranging in age between three months to 14 years, born to mothers with MMA have reported normal developmental outcomes..
In the postpartum period, no episodes of decompensation have been reported, although in theory this period may present the window of highest risk for metabolic decompensation based upon experiences with urea cycle disorders (Walter et al 2000, Langendonk et al 2011). The postpartum period is a time of catabolism with the involution of the uterus and the breakdown of protein. In theory, the excess amino acids generated during this time can increase BCAA oxidative flux and increase nitrogen load, and could contribute to the precipitation of a metabolic crisis.
Pregnancy is an anabolic state, which for some patients with inborn errors of metabolism might make control of their disease slightly easier. Dietary needs of protein increase naturally as the pregnancy progresses and increased dietary intake of protein would need to be maintained postpartum if the patient were to breastfeed. Although all cases but one thus far have reported normal fetal growth despite protein restriction, the risk of protein malnutrition for the mother and the fetus necessitates careful metabolic management. It has been our recommendation to serially follow fetal growth with ultrasounds throughout the pregnancy, and to adjust maternal and fetal protein needs using maternal biochemical parameters.
Vitamin B12 responsive patients are treated with supraphysiological doses of cobalamin. Although vitamin B12 deficiency can be adequately treated in pregnancy without adverse consequences related to treatment, it is not known where the upper limit of vitamin B12 treatment in pregnancy lies, if such a ceiling exists, and whether cofactors in high doses could contribute to an adverse pregnancy outcome. Of the pregnancies, 7/13 were supplemented with carnitine. Patients ingested high doses of carnitine with the same caveats that very little is known about carnitine supplementation in pregnancy (Winter SC et al 1995). The effect of carnitine supplementation on birth parameters needs to be studied further.
Optimization of the maternal condition prior to pregnancy and close dietary management combined with regular surveillance of maternal serum amino acids is important to ensure maternal nutrition and minimize dietary risk of catabolism. Delivery plans should be discussed with the patient especially in light of the increased rate of late preterm birth and cesarean deliveries. In the intrapartum period, avoidance of catabolism with intravenous dextrose should be maintained in labor and delivery. The most prudent approach to a pregnancy complicated by a maternal inborn error of metabolism is via a multi-disciplinary team that includes a biochemically trained geneticist, metabolic dietitian, and maternal-fetal medicine specialist working together with an obstetrician.
In the case of maternal phenylketonuria, a pregnancy registry has proven invaluable to collect patient experiences and use the aggregate data to adjust practice patterns (Vockley J et al 2014, Koch et al 1993). The information presented here should be useful in the continued surveillance and counseling of future patients, and will help stimulate the formation of a dedicated registry to define the natural history of pregnancy in MMA and related disorders.
Synopsis.
Pregnancies affected by maternal MMA can have complex issues and are at increased risk for obstetrical complications, including preterm delivery and cesarean section despite this the children appear to do well.
Footnotes
Compliance with Ethics Guidelines
Conflict of Interest: Donna Raval, Melissa Merideth, Jennifer Sloan, Nancy E. Braverman, Robert Conway, Irini Manoli, and Charles P. Venditti declare that they have no conflict of interest.
Details of the contributions of the individual authors: Donna Raval: conceived study, literature review, planning, and writing of the manuscript.
Melissa Merideth: guidance on the interpretation of the data, patient care, and edits to the manuscript.
Jennifer Sloan: literature review, interviewed and collected records from the patients in the study, guidance on the interpretation of the data, patient care, and edits to the manuscript.
Nancy Braverman: patient care and edits to the manuscript.
Robert Conway: guidance on the interpretation of the data, patient care, and edits to the manuscript.
Irini Manoli: patient care, literature review, guidance on the interpretation of the data, and edits to the manuscript.
Charles P. Venditti: supervised study, patient care, literature review, guidance on the interpretation of the data, and writing of the manuscript.
References
- Adeyemi OA, Girish T, Mukhopadhyay S, Olczak SA, Ahmed Z. Methylmalonic acidaemia: a rare metabolic disorder in pregnancy. J Obstet Gynaecol. 2004;24(8):927–8. doi: 10.1080/01443610400019070. [DOI] [PubMed] [Google Scholar]
- Baumgartner MR, Horster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet Journal of Rare Diseases. 2014;9:130. doi: 10.1186/s13023-014-0130-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Boneh A, Greaves RF, Garra G, Pitt JJ. Metabolic treatment of pregnancy and postdelivery period in a patient with cobalamin A disease. Am J Obstet Gynecol. 2002 Jul;:225–6. doi: 10.1067/mob.2002.119637. [DOI] [PubMed] [Google Scholar]
- Brunel-Guitton C, Costa T, Mitchell GA, Lambert M. Treatment of cobalamin C (cblC) deficiency during pregnancy. J Inherit Metab Dis. 2010 doi: 10.1007/s10545-010-9202-7. [DOI] [PubMed] [Google Scholar]
- CDC Fast Stats. 2014 http://www.cdc.gov/nchs/fastats/delivery.htm.
- Chandler RJ, Venditti CP. Genetic and Genomic Systems to Study Methylmalonic Acidemia. Mol Genet Metab. 2005;86(1-2):34–43. doi: 10.1016/j.ymgme.2005.07.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deodato F, Rizzo C, Boenzi S, Baiocco F, Sabetta G, Dionisi-Vici C. Successful pregnancy in a woman with mut- methylmalonic acidaemia. J Inher Metab Dis. 2002;25:133–134. doi: 10.1023/a:1015632911801. [DOI] [PubMed] [Google Scholar]
- Dionisi-Vici C, Deodato F, Röschinger W, Rhead W, Wilcken B. ‘Classical’ organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis. 2006;29:383–9. doi: 10.1007/s10545-006-0278-z. [DOI] [PubMed] [Google Scholar]
- Diss E, Iams J, Reed N, Roe DS, Roe C. Methylmalonic aciduria in pregnancy: A case report. Am J Obstet Gynecol. 1995;172(3):1057–1059. doi: 10.1016/0002-9378(95)90049-7. [DOI] [PubMed] [Google Scholar]
- de Baulny HO, Benoist JF, Rigal O, Touati G, Rabier D, Saudubray JM. Methylmalonic and propionic acidaemias: management and outcome. J Inherit Metab Dis. 2005;28:415–23. doi: 10.1007/s10545-005-7056-1. [DOI] [PubMed] [Google Scholar]
- Godfrey K, Robinson S, Barker DJP, Osmond C, Cox V. Maternal nutrition in early and late pregnancy in relation to placental and fetal growth. BMJ. 1995;312:410. doi: 10.1136/bmj.312.7028.410. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hörster F, Baumgartner MR, Viardot C, et al. Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB) Pediatr Res. 2007;62:225–30. doi: 10.1203/PDR.0b013e3180a0325f. [DOI] [PubMed] [Google Scholar]
- Jacquemyn Y, Den Hartog M, Eyskens F. Methylmalonic acidaemia in pregnancy. BMJ Case Rep. 2014 doi: 10.1136/bcr-2014-203723. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koch R, Levy HL, Matalon R, Rouse B, Hanley W, Azen C. The North American Collaborative Study of Maternal Phenylketonuria. AJDC. 1993;147:1224–1230. doi: 10.1001/archpedi.1993.02160350098015. [DOI] [PubMed] [Google Scholar]
- Langendonk JG, Roos JCP, Angus L, et al. A series of pregnancies in women with inherited metabolic disease. J Inherit Metab Dis. 2011 doi: 10.1007/s10545-011-9389-2. [DOI] [PubMed] [Google Scholar]
- Lubrano R, Bellelli E, Gentile I, et al. Pregnancy in a Methylmalonic Acidemia Patient with Kidney Transplantation: A Case Report. American Journal of Transplantation. 2013;13:1918–1922. doi: 10.1111/ajt.12282. [DOI] [PubMed] [Google Scholar]
- Manoli I, Venditti CP. Methylmalonic Acidemia. 2010 www.genereviews.org. http://www.ncbi.nlm.nih.gov/books/NBK1231/
- Oberholzer VG, Levin B, Burgess EA, Young WF. Methylmalonic aciduria. An inborn error of metabolism leading to chronic metabolic acidosis. Arch Dis Child. 1967;42:492–504. doi: 10.1136/adc.42.225.492. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ramin SM, Vidaeff AC, Yeomans ER, Gilstrap LC. Chronic Renal Disease in Pregnancy. Obstetrics and Gynecology. 2006;108(6):1531–9. doi: 10.1097/01.AOG.0000246790.84218.44. [DOI] [PubMed] [Google Scholar]
- Stokke O, Eldjarn L, Norum KR, Steen-Johnsen J, Halvorsen S. Methylmalonic acidemia: a new inborn error of metabolism which may cause fatal acidosis in the neonatal period. Scand J Clin Lab Invest. 1967;20:313–28. [Google Scholar]
- Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. ACMG Practice Guidelines. Genetics in Medicine. 2014;16(2):188–200. doi: 10.1038/gim.2013.157. [DOI] [PubMed] [Google Scholar]
- Walter JH. Inborn errors of metabolism and pregnancy. J Inherit Metab Dis. 2000;23:229–236. doi: 10.1023/a:1005679928521. [DOI] [PubMed] [Google Scholar]
- Wasserstein MP, Gaddipati S, Snyderman SE, Eddleman K, Desnick RJ, Sansaricq C. Successful pregnancy in severe methylmalonic acidaemia. J Inher Metab Dis. 1999;22:788–794. doi: 10.1023/a:1005597722237. [DOI] [PubMed] [Google Scholar]
- Winter SC, Linn LS, Helton E. Plasma carnitine concentrations in pregnancy, cord blood, and neonates and children. Clinica Chimica Acta. 1995;243:87–93. doi: 10.1016/0009-8981(95)06148-7. [DOI] [PubMed] [Google Scholar]