Introduction

Inherited metabolic diseases (IMDs) are individually rare; are clinically widely heterogeneous; can present at any age; and typically, but not always, are associated with abnormal biochemical tests (usually specialist rather than routine biochemistry). Broadly speaking, they can be divided into the following three groups:

• 1.
  

  Disorders of intoxication – these disorders of intermediary metabolism give rise to an acute or progressive intoxication secondary to the accumulation of toxic compounds proximal to a metabolic block, for example, disorders of amino acid metabolism such as phenylketonuria (PKU, Online Mendelian Inheritance in Man ^® (OMIM) #261600), the organic acidurias and urea cycle defects such as ornithine transcarbamylase (OTC) deficiency (#311250).

  
  
• 2.
  

  Disorders of energy metabolism – these give rise to their symptoms chiefly because of an energy deficiency in tissues such as liver, muscle, brain or heart. Examples include mitochondrial respiratory chain defects, fatty acid oxidation defects and glycogen storage disorders.

  
  
• 3.
  

  Disorders of complex molecules – these involve disturbance in the synthesis or catabolism of complex molecules. Symptoms tend to be progressive and not dependent on dietary / energy intake. Examples include the lysosomal storage disorders and the peroxisomal disorders.

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 IMD surviving to adulthood and wishing to have children of their own . Although many women have successful pregnancies, with an excellent outcome, these patients present various challenges from the reproductive perspective. 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 from either isolated case reports or small case series, and no single centre is likely to have enough experience with any single condition to provide definitive guidelines for management. Although in general long-term outcome for these (mostly) autosomal recessive conditions following pregnancy is assumed to be good, there are in fact little data on the long-term follow-up of children born to mothers with IMD.

The aim of this review is not to suggest definitive treatment or provide a review of pregnancy in all potential inherited disorders of metabolism but instead to use specific examples to highlight how these disorders may afffect pregnancy and the puerperium, with emphasis on both the maternal and fetal outcome. One of the most common inherited disorders of metabolism is familial hypercholesterolaemia (#143890), but as this condition is usually managed within adult lipid clinics rather than an IMD clinic and there are a number of published reviews on the management of pregnancy, it is not discussed further in this article . Table 1 , although not exhaustive, lists some of the specific issues that need to be taken into account when a woman with an inherited disorder of metabolism plans a pregnancy. If at all possible, the care of women with an inherited disorder of metabolism in pregnancy should be discussed/managed together with a physician and/or dietitian with expertise in this field. The Society for the Study of Inborn Errors of Metabolism – Adult Metabolic Physicians Group (SSIEM-AMG: http://www.ssiem.org/amp/contact.asp ) can provide contact details for specialist centres worldwide. Similarly, the British Inherited Metabolic Disease Group (BIMDG: www.bimdg.org.uk ) can provide details of centres within the UK.

The preconception period

When women with an inherited disorder of metabolism reach childbearing age, they should be counselled on the potential impact of pregnancy on their condition, as well as the impact of their condition on pregnancy and the outcome for their children. As with any woman planning a pregnancy, prepregnancy advice includes starting folic acid supplementation; stopping smoking; limiting caffeine and alcohol intake; and optimizing weight, diet and general physical health . Many women with an inherited disorder of amino acid or energy metabolism will be treated with a modified diet, which, depending on the specific condition, may be low in protein, high in carbohydrate, low in fat or high in fat. In this context, the nutritional requirements of pregnancy will therefore need to be carefully managed. The goal is to optimize metabolic control and nutritional status if possible prior to pregnancy.

Medications may need to be altered if the patient is prescribed any potentially teratogenic drugs, for example, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or certain anticonvulsants. The impact of these alterations on maternal health needs to be discussed. A decision to stop other specific medications, for example, sodium benzoate and sodium phenylbutyrate in women with symptomatic urea cycle disorders, enzyme replacement therapy in Gaucher disease (#230800) or biotin in biotinidase deficiency (#253260), is likely to have significant detrimental effects on maternal health. Successful pregnancies have been described with the use of these and other specialist medications (including enzyme replacement therapies for the lysosomal storage disorders, Fabry disease (#301500) and acid maltase deficiency (#232300)) . Table 2 presents specific treatments used in a number of lysosomal storage disorders, with data on animal toxicity and use in human pregnancy. Many manufacturers will keep a registry of pregnancies occurring on their product, and it is advisable to contact them directly for further advice if no specific information is available in the literature.

All patients with known cardiac disease should have a review with a cardiologist to define risk plan surveillance during pregnancy. If there is severe cardiomyopathy, pregnancy may even be contraindicated . Similarly, women with epilepsy, respiratory disease or other issues such as significant skeletal disease need specialist prepregnancy advice, and they may require additional support and monitoring.

Many disorders of metabolism are autosomal recessive in inheritance; in non-consanguineous families there is a very low risk of having an affected child but patients are often anxious regarding the risks to their children, and genetic counselling can be offered at this stage. Preimplantation genetic diagnosis is now widely available for a number of (usually) X-linked inherited disorders of metabolism, for example, OTC deficiency, adrenoleukodystrophy (#300100) and Fabry disease. Antenatal diagnosis is also available, and it may have a role in detecting autosomal recessive conditions in communities where there is a founder effect or a high rate of consanguinity. Similarly, patients with IMD 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.

Maternally inherited mitochondrial disorders affect approximately one in 8000 people . These heterogeneous conditions can cause variable phenotypes including heart and liver failure, defects in energy metabolism, blindness, deafness, loss of motor skills and premature death. Their management is largely supportive and specific treatment is limited to coenzyme Q ₁₀ supplementation in individuals with defects of CoQ ₁₀ biosynthesis. In 2013/2014, the Human Fertilisation and Embryology Authority provided advice to the UK government regarding the use of enucleated donated oocytes with normal (wild-type) mitochondria to be used as recipients of nuclear DNA from intending mothers to overcome transmission of mitochondrial disorders ( http://www.hfea.gov.uk/docs/Mitochondria_replacement_consultation_-_advice_for_Government.pdf and http://www.hfea.gov.uk/docs/mitochondria_scientific_review_update_-_call_for_evidence_2014.pdf ). In February 2015, the UK Parliament approved regulations to allow mitochondrial donation treatment. These regulations are expected to come into force from October 2015.

The preconception period

When women with an inherited disorder of metabolism reach childbearing age, they should be counselled on the potential impact of pregnancy on their condition, as well as the impact of their condition on pregnancy and the outcome for their children. As with any woman planning a pregnancy, prepregnancy advice includes starting folic acid supplementation; stopping smoking; limiting caffeine and alcohol intake; and optimizing weight, diet and general physical health . Many women with an inherited disorder of amino acid or energy metabolism will be treated with a modified diet, which, depending on the specific condition, may be low in protein, high in carbohydrate, low in fat or high in fat. In this context, the nutritional requirements of pregnancy will therefore need to be carefully managed. The goal is to optimize metabolic control and nutritional status if possible prior to pregnancy.

Medications may need to be altered if the patient is prescribed any potentially teratogenic drugs, for example, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or certain anticonvulsants. The impact of these alterations on maternal health needs to be discussed. A decision to stop other specific medications, for example, sodium benzoate and sodium phenylbutyrate in women with symptomatic urea cycle disorders, enzyme replacement therapy in Gaucher disease (#230800) or biotin in biotinidase deficiency (#253260), is likely to have significant detrimental effects on maternal health. Successful pregnancies have been described with the use of these and other specialist medications (including enzyme replacement therapies for the lysosomal storage disorders, Fabry disease (#301500) and acid maltase deficiency (#232300)) . Table 2 presents specific treatments used in a number of lysosomal storage disorders, with data on animal toxicity and use in human pregnancy. Many manufacturers will keep a registry of pregnancies occurring on their product, and it is advisable to contact them directly for further advice if no specific information is available in the literature.

All patients with known cardiac disease should have a review with a cardiologist to define risk plan surveillance during pregnancy. If there is severe cardiomyopathy, pregnancy may even be contraindicated . Similarly, women with epilepsy, respiratory disease or other issues such as significant skeletal disease need specialist prepregnancy advice, and they may require additional support and monitoring.

Many disorders of metabolism are autosomal recessive in inheritance; in non-consanguineous families there is a very low risk of having an affected child but patients are often anxious regarding the risks to their children, and genetic counselling can be offered at this stage. Preimplantation genetic diagnosis is now widely available for a number of (usually) X-linked inherited disorders of metabolism, for example, OTC deficiency, adrenoleukodystrophy (#300100) and Fabry disease. Antenatal diagnosis is also available, and it may have a role in detecting autosomal recessive conditions in communities where there is a founder effect or a high rate of consanguinity. Similarly, patients with IMD 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.

Maternally inherited mitochondrial disorders affect approximately one in 8000 people . These heterogeneous conditions can cause variable phenotypes including heart and liver failure, defects in energy metabolism, blindness, deafness, loss of motor skills and premature death. Their management is largely supportive and specific treatment is limited to coenzyme Q ₁₀ supplementation in individuals with defects of CoQ ₁₀ biosynthesis. In 2013/2014, the Human Fertilisation and Embryology Authority provided advice to the UK government regarding the use of enucleated donated oocytes with normal (wild-type) mitochondria to be used as recipients of nuclear DNA from intending mothers to overcome transmission of mitochondrial disorders ( http://www.hfea.gov.uk/docs/Mitochondria_replacement_consultation_-_advice_for_Government.pdf and http://www.hfea.gov.uk/docs/mitochondria_scientific_review_update_-_call_for_evidence_2014.pdf ). In February 2015, the UK Parliament approved regulations to allow mitochondrial donation treatment. These regulations are expected to come into force from October 2015.

Fertility and miscarriage

In general, fertility is not a major issue in the majority of inherited disorders of metabolism. A well-recognized exception, however, is classic galactosaemia (#230400). This condition, caused by deficient activity of the enzyme galctose-1-phosphate uridyltransferase, has an overall incidence of about one in 16,000 to one in 60,000 . It typically presents in early infancy with hepatorenal failure, cataracts and sepsis. Prompt recognition of the condition with removal of lactose from the diet results in resolution of liver and kidney involvement, but patients remain at a risk of long-term complications including movement disorders, speech delay, cognitive problems and, in the majority of women, premature ovarian insufficiency (POI). POI may manifest as delayed puberty, primary or secondary amenorrhoea or oligomenorrhoea. The precise pathophysiology is currently uncertain.

In a retrospective, cross-sectional survey of the long-term outcome of 270 individuals with classic galactosaemia, 81% of girls and women had signs of POI . Most women developed oligomenorrhoea and secondary amenorrhoea within a few years of menarche. Only five out of 17 women over the age of 22 years had normal menstruation. Hormonal treatment is therefore needed to promote pubertal development and/or to manage secondary amenorrhoea in many women.

However, fertility is possible for some women with classic galactosaemia, and a number of successful spontaneous pregnancies have been reported. In a small cohort of 22 patients, nine tried to conceive and four were successful . Other pregnancies have occurred following follicle-stimulating hormone (FSH) therapy .

To date, there are no data on the use of techniques such as ovarian tissue cryopreservation, or mature oocyte cryopreservation in women with galactosaemia . The majority of women who have undergone these procedures worldwide have done so prior to chemotherapy or other gonadotoxic therapies and so have had normal healthy ovaries. The ovaries of many girls with galactosaemia are probably already damaged at a young age, and so the success rate of these techniques may well be lower. Embryo cryopreservation is a well-established infertility treatment, but it relies on ovarian stimulation, which may be inadequate in many women with galactosaemia.

These options, including alternatives such as the use of donor oocytes or adoption, should be discussed with parents, girls and women with galactosaemia. It is important to be aware that legislation regarding fertility may differ between countries, and the involvement of an institutional ethics committee, particularly if treatment of a child or use of an experimental technique is proposed, is advisable.

Another condition for which reduced fertility has been suggested is glycogen storage disease (GSD) type I. This is an autosomal recessive disorder of glycogen metabolism caused by deficiency either of the catalytic subunit of glucose-6-phosphatase (GSD Ia, #232200) or of the endoplasmic reticulum of glucose-6-phosphate translocase (GSD Ib, #232220). The most common presentation is in the first 3–6 months of life with failure to thrive, hypoglycaemia, lactic acidosis and hepatomegaly. It has been noted that many women with GSD I have polycystic ovaries and irregular menstrual cycles . However, recent data have suggested that this appears to have little impact on fertility .

There is an increased risk of miscarriage, usually associated with maternal poor metabolic control, recognized in maternal PKU (mPKU), and possibly other conditions including those associated with hypertyrosinaemia, hyperhomocysteinaemia, and some disorders of energy metabolism. Regular discussion with women of reproductive age regarding the value of good metabolic control around the time of conception and the early pregnancy period is an important part of the adult IMD clinic. Prompt treatment of intercurrent illness, significant nausea and/or vomiting and avoidance of known triggers of metabolic decompensation are critical in supporting women with a known disorder of energy metabolism through a pregnancy. Similarly, effective and appropriate means of contraception should be discussed with those women who do not wish to plan a pregnancy.