HNF4A is a type of diabetes that runs in families, is diagnosed at a young age (often before 25 years) and may be treated with sulphonylurea tablets rather than insulin. HNF4A diabetes is one of the types of diabetes referred to as maturity onset diabetes of the young (MODY). The HNF4A gene acts as a switch which turns on and off other genes in the body. Changes in the HNF4A gene cause diabetes by reducing the amount of insulin that is produced by the pancreas but unusually has different effects on insulin secretion at different ages. People carrying the changes produce excess insulin secretion in the womb and during the first months of life, there is normal insulin secretion in early childhood and then this reduces with age resulting in diabetes due to too little insulin secretion in late childhood or early adulthood. Further information can be found on www.diabetesgenes.org
Babies with a change in the HNF4A gene produce increased amounts of insulin when in the womb; this increases the growth of the baby making them on average 800g (just under 2lbs) heavier than normal babies. Most of these babies have macrosomia, which is defined as a birth weight of more than 4kg (9lbs). In addition some individuals with HNF4A have low blood sugar levels (hypoglycaemia) at, or shortly after birth, which may require treatment. The low blood glucose is also a result of excessive insulin secretion. When either parent is known to have HNF4A diabetes there is a 50% chance that a baby will inherit the genetic change. Therefore close monitoring is required both during pregnancy and after birth to reduce any complications of having a large baby or the baby having low blood glucose after birth.
When the mother has HNF4A diabetes, her high blood sugar in pregnancy can also increase insulin secretion of the baby resulting in an additional increase in birth weight on top of the direct effect of the HNF4A genetic change in the baby. Even if the baby does not inherit the genetic change they may still be large as a result of mother’s blood sugars being higher than normal.
Individuals with HNF4A diabetes usually have good control of their blood sugars (a good HbA1c) with sulphonylurea tablets. However, during pregnancy sulphonylurea crosses the placenta and increases the risk of macrosomia and neonatal hypoglycaemia. For women with HNF4A diabetes that have good glycaemic control who are on a sulphonylurea pre-conception we recommend they either transfer to insulin before conception (at the risk of a short-term deterioration of glycaemic control) or continue with sulphonylurea (Glibenclamide) treatment in the first trimester and transfer to insulin in the second trimester. This will help with achieving good glycaemic control in the first trimester to minimise the risk to the baby’s development, and avoid the effect of sulphonylurea on the baby’s growth in the third trimester.
For information on the management of HNF4A diabetes during pregnancy see our review article at http://onlinelibrary.wiley.com/doi/10.1111/dme.13388/abstract. The way that insulin secretion is affected in HNF4A diabetes means that glucose levels may be difficult to control after meals, so using fast acting insulin with meals may need to be considered. If an individual already has good diabetes control on insulin then continuing this treatment would be appropriate.
Close monitoring of a pregnancy when either parent has a change in the HNF4A gene is recommended to know if the baby is large for their gestational age as a result of inheriting the genetic change. If the size of the baby is known before birth, delivery can be planned and the possible complications avoided. Serial ultrasound scans are recommended in the last trimester of HNF4A pregnancies to assess the baby’s growth in the womb even if the blood glucose control has been excellent or the affected parent is the father. There has not been any way of knowing if the baby is affected unless genetic tests are done for another reason, however we are now conducting a study measuring ‘cell free fetal DNA’ – this is a blood test that can be taken from the mother and we are investigating if we can accurately use this blood sample to determine whether or not the baby has inherited the same genetic change and is at risk of macrosomia or hypoglycaemia after birth. We would be interested in contacting any families with HNF4A who are planning pregnancy or currently ‘expecting’ to discuss this study further (please contact Dr Ali Chakera – details below – for further information).
Due to the increased risk of large babies early delivery should be considered. Elective Caesarean section may be considered appropriate to avoid problems of delivering a very large baby.
All babies of pregnancies where either parent has HNF4A diabetes should have their blood glucose tested at birth, and also 24 hours after birth, to make sure the blood glucose is not low. Intravenous glucose and tube feeding is sometimes needed and prolonged treatment with diazoxide and chlorthiazide has also been reported.
So we can understand more about HNF4A pregnancies we would be very grateful if patients or their doctors could contact us when there is a pregnancy where either the father or mother has HNF4A diabetes. We still have a lot to learn about these pregnancies. We are also very happy to be contacted for further discussion of individual pregnancies and we can be contacted on the numbers and e-mail below:
Professor Andrew Hattersley (a.t.hattersley@exeter.ac.uk) or Maggie Shepherd on 01392 408261 (m.shepherd1@nhs.net).
Details about the evidence for this guidance can be found in:
Shepherd M, Brook AJ, Chakera AJ, Hattersley AT (2017). Management of sulphonylurea-treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer. Diabet Med. 34: 1332-1339.
Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT (2007). Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PloS Med. 4, 4, e118. This paper is freely available and can be downloaded from the internet directly.
A second reference with details about the occasional child who has prolonged low blood glucose values is:
Kapoor RR, Locke J, Colclough K, Wales J, Conn JJ, Hattersley AT, Ellard S, Hussain K (2008). Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations. Diabetes 57:1659-63.
