Factors including improved medical care, increased awareness of metabolic conditions and newborn screening with early treatment, have led to an increased number of patients with inherited metabolic disease surviving to adulthood and wishing to have children of their own.18,19 Although many women have successful pregnancies, with an excellent outcome, these patients present various challenges from the reproductive point of view and Table 5.1-1 lists some of the specific issues that need to be taken into account at different stages of pregnancy and the post-partum period. The examples given are not exhaustive but illustrate issues that may be encountered.
Table 5.1-1 |Favorite Table|Download (.pdf) Table 5.1-1
| Pre-conception || Examples || During pregnancy || Examples || Post-partum || Examples |
|Fertility || Galactosemia ||Metabolic control || Morning sickness’ - Any disorder of energy metabolism e.g. FAOD, GSD, UCD, MSUD, GA1, disorders of ketone body metabolism ||Metabolic control || Puerperial stress, Involution of the uterus, Lactation |
| || Other conditions with poor metabolic control e.g. HCU || || Worsening of underlying condition e.g. dyslipidemia in lipoprotein lipase (LPL) deficiency; hypercoagulability in HCU, MTHFR deficiency; cardiomyopathy in GSDIII || || |
| || polycystic ovarian syndrome (PCOS) e.g. GSD1 || || Vitamin and mineral deficiencies - any condition associated with dietary restriction || || |
|Medications || Possibly teratogenic e.g. statins, trientine ||Affects on fetus || Maternal PKU syndrome ||Contraception || |
| || || || Anomalies e.g. HCU || || |
| || || || Growth retardation (secondary to protein restriction) || || |
|Genetic counselling || pre-implantation genetic diagnosis (PIGD) e.g. OTC deficiency, ALD ||Affects on mother || Acute fatty liver of pregnancy e.g. FAOD ||Long term fetal outcome || Maternal PKU |
| || Antenatal diagnosis || || Anatomical considerations e.g. Hepatomegaly, bony pelvic disease || || |
|Metabolic control || Time for optimisation e.g. PKU ||Maternal issues || Maternal learning difficulties e.g. HCU, methylmalonic acidemia (MMA), GA1 || || |
| || ||During labour || Energy requirements || || |
| || || || Muscular involvement e.g. GSDIII, mitochondrial disorders || || |
Fertility may be a problem e.g. secondary to ovarian failure in galactosemia.20 Treatment options, including oocyte donation, should be discussed with these women. Women with GSD1 may have polycystic ovaries and hence oligomenorrhea with subfertility.21 Other patients may be at risk of early miscarriage, particularly with poor metabolic control e.g., homocystinuria (HCU), methylene tetrahydrofolate reductase (MTHFR) deficiency. In any woman with an inherited metabolic disease, ideally pregnancy should be planned, with optimization of metabolic control prior to pregnancy to ensure adequate nutritional status including vitamin and mineral supplementation if needed. Some medications prescribed in inherited metabolic disease have been shown to be teratogenic in animal studies (e.g. statins, trientine) and careful counseling needs to be given to female patients regarding the use of these medications in the reproductive period. Most hereditary metabolic diseases do not affect male reproduction or sexual function, but patients themselves may have concerns about their fertility or the inherited nature of their condition and these should be addressed.
Preimplantation genetic diagnosis is now widely available for a number of (usually) X-linked inherited disorders of metabolism e.g. ornithine transcarbamylase (OTC) deficiency, adrenoleukodystrophy (ALD), Fabry disease. Antenatal diagnosis is also available and may have a role in detecting autosomal recessive conditions in communities whether there is a founder effect or a high rate of consanguinity. Similarly, patients with inherited metabolic disease need to understand that, even with a rare autosomal recessive condition, the risks of having a child with the condition are considerably higher than that of the general population.
Apart from PKU, for which there is substantial evidence for management guidelines during pregnancy, information on pregnancy for most of the other inherited metabolic conditions comes either from isolated case reports or small case series. In our experience early pregnancy, if complicated by morning sickness, can be a difficult time for women with inherited disorders of energy metabolism e.g. fatty acid oxidation (FAOD), glycogen storage disease (GSD), urea cycle defect (UCD), maple syrup urine disease (MSUD), glutaric aciduria type 1 (GA1), disorders of ketone body metabolism. Nausea and vomiting leads to problems in taking supplements and medications which may result in episodes of metabolic decompensation. Women and their local hospital (including obstetric services) need to carry an up-to-date copy of their oral and intravenous emergency regimen. Nausea, vomiting and anorexia should be taken seriously and early consideration given to treatment with effective anti-emetic medication. In any woman on a restricted diet vitamin and mineral supplementation should be considered.
Some metabolic disorders worsen in pregnancy e.g. the dyslipidaemia, particularly hypertriglyceridemia, of lipoprotein lipase deficiency. Regular dietetic assessment is crucial to ensure compliance and prevent complications such as pancreatitis. Pregnancy is also a prothrombotic period and presentation of hypercoagulable conditions e.g. HCU during pregnancy with a thrombus is well described. In all conditions with a known thrombotic risk, anti-coagulation (usually with subcutaneous heparin) during pregnancy and the post-partum period needs to be considered. A particular challenge may be women with inherited metabolic disease who also have learning difficulties and may need additional social and psychological support during pregnancy and following childbirth.
Labour and delivery are times of increased energy requirement and women may require additional energy supplementation (usually intravenous dextrose) during this time. Women with skeletal muscle involvement may find the second stage of labour difficult, necessitating caesarean section. Deterioration of underlying organ damage e.g. cardiomyopathy in women with GSDIII or renal impairment in women with GSD1is also possible. Patients with GSD1 may also be at risk of bleeding due to platelet dysfunction.
Following delivery, there is a well recognized risk period for acute decompensation of some disorders, particularly those of protein metabolism.22,23 Classically this decompensation occurs between day 3-14 post-partum. The reasons for this are not entirely clear but are thought to relate to the relative metabolic stress of the changes of the puerperium and an increased protein load for catabolism following involution of the uterus. Care must be taken not to confuse the behavioural changes of hyperammonemia for symptoms of post-partum psychosis or depression. Information on how to manage this period in a patient with known metabolic disease is limited but preventive strategies have included: use of oral or intravenous emergency regimens, hyperalimentation, and bowel sterilization. Similarly, breast-feeding places energy demands on a mother and women with inherited metabolic disease wishing to breast feed need to ensure adequate energy intake.
As regards foetal outcome, again, apart from the larger experience with PKU, the outcomes in women with other hereditary metabolic diseases are largely limited to case reports.24 Therefore, there is little outcome data on the long-term follow-up of children born to mothers with inherited metabolic disease. Although the maternal PKU syndrome is well–recognized, in general long-term outcome for these (mostly) autosomal recessive conditions is assumed to be good.