The HAPO Study: The Risks of High Blood Sugar in Pregnancy

What was the HAPO Study?

‘HAPO’ is short for Hyperglycaemia and Adverse Pregnancy Outcomes. The HAPO study ⁵ was set up to look at the link between high blood sugar levels (hyperglycaemia) in pregnant mums and potential risks to themselves and their babies around the time of birth. During pregnancy, changes in a woman’s body can make it difficult to control blood sugar levels. Due to factors such as genetics, weight and medical history, some women are better able to cope with these changes than others. Gestational Diabetes Mellitus (GDM) happens in pregnancy when the body cannot keep blood sugar levels in a normal range. There are already many studies which show that GDM, as well as Types 1 and 2 diabetes are associated with problems for mum and baby ^{(1, 2, 3, 4)}

Previous research had established the blood sugar values used to diagnose GDM. However, the HAPO researchers were interested in studying pregnant women with raised blood sugar levels that were less severe than those levels traditionally used to diagnose GDM, to understand what risks these lower blood sugar levels carried, if any, for mums and babies at delivery.

A cooperative research group made up of researchers and clinicians based in 15 different hospitals across Europe, North America, Asia and the Middle East, joined forces to conduct this study. This worldwide team was responding to the need for updated criteria to diagnose GDM. As a result of the HAPO study, the Health Service Executive (HSE) in Ireland published new guidelines for the diagnosis of GDM in 2010 ⁵.

Why did the researchers look at Hyperglycaemia in pregnancy?

Gestational diabetes (GDM), similar to Type 1 and 2 diabetes, involves problems with the body’s ability to control blood sugar, however, guidelines for the diagnosis of GDM have been the subject of considerable controversy. The criteria used in Ireland prior to the HAPO study were developed over 40 years ago, with some minor changes made in the intervening years⁵. These criteria were designed to predict which women were at risk for the development of diabetes after their pregnancy, rather than the risk of poor outcomes for babies and mums. Researchers hoped that results from the HAPO study would help determine whether there was a link between high blood glucose below the criteria for GDM diagnosis, and poor outcomes for mums and babies.

Who was studied and how was the study done?

The HAPO study involved 23,316 pregnant women at 15 hospitals in 9 countries, including the Royal Jubilee Hospital in Belfast. Women in the study received a blood sugar test, known as an Oral Glucose Tolerance Test (OGTT), to study how their body responded to sugar intake.  The OGTT involves testing blood sugar levels while fasting, and then twice again at hourly intervals after a specific dose of sugar is consumed (through a sugary drink for example). This was done between 24 and 32 weeks of pregnancy. Results from the blood sugar tests were compared with maternal and newborn health outcomes at delivery to look for possible links between these measures.

What did the researchers find?

Researchers found significant links between higher levels of blood sugar in pregnant women – within what was previously considered a non-diabetic range – and the risk of certain problematic outcomes.

Strong links were found between high blood sugar in mum and:

• Having a larger than average baby. This can present difficulties during delivery, as it makes passage through the birth canal more challenging, which in turn can lead to a prolonged and risky delivery or shoulder injuries to the baby.
• High cord blood C-peptide: Cord blood C-peptide is a way of measuring insulin production in the baby. If mum’s blood sugar level is too high while pregnant, this can cause the baby’s pancreas cells to produce excess insulin. At birth, high insulin can cause problems with the baby’s blood sugar control.

Weaker links were also found between high blood sugar in mum and:

• Newborn Hypoglycaemia: After birth, the high levels of sugar found in mum’s blood are no longer available to the baby, but because the baby’s insulin levels are still high this can cause a rapid drop in the baby’s own blood sugar.
• Delivery by caesarean section: Complications in mum and/or baby may lead to the need for a caesarean section.
• Preterm delivery: This refers to delivery before 37 weeks gestation.
• Shoulder Dystocia or Birth Injury: Shoulder dystocia occurs when the baby’s shoulder gets ‘stuck’ in the birth canal. This can lead to serious complications and injuries in baby and mum.
• Need for Intensive Care for Baby: Babies may require special care in the intensive care unit to treat conditions such as low blood sugar.
• Hyperbilirubinaemia: Bilirubin is produced when the body breaks down old red blood cells. Bilirubin is usually excreted by the body, but under certain conditions it can build up, resulting in hyperbilirubinaemia. Hyperbilirubinaemia can cause complications in the newborn.
• Pre-eclampsia: Pre-eclampsia is a condition characterized by high blood pressure and protein in the urine. It can occur in mums in the second half of pregnancy and can be dangerous for both mum and baby. 

Limitations of the HAPO study

Importantly, because this was an observational study, we cannot say that high blood sugar in mum caused the adverse outcomes observed. What the HAPO study showed is that high blood sugar in mum was linked to a higher risk of certain adverse outcomes.

The HAPO researchers did not have information on the nutritional status and gestational weight gain of the mums. These factors could have influenced some of the outcomes studied and therefore ideally would have been included in the analysis if the information was available.

Furthermore, the following factors may have influenced clinical decisions, such as the route of delivery:

• Mum’s Body Mass Index (BMI) before pregnancy – this is a measurement that relates weight to height, and gives a general idea of whether your weight is within a healthy range
• Whether mum had gestational diabetes in a previous pregnancy
• Whether mum had previously had a larger than average baby.

From Research to Everyday Practice

Nonetheless, findings from the HAPO study indicated a need to reconsider the current criteria for diagnosing and treating GDM.

A committee of experts was set up to examine the outcomes of the HAPO study and to develop a consensus regarding appropriate diagnostic criteria ⁶. This task was undertaken by the International Association of Diabetes and Pregnancy Study Groups (IADPSG). In Ireland, new guidelines were published in August 2010, which followed the recommendations made by IADPSG ⁷. The new guidelines included using lower blood glucose value criteria to diagnose GDM, allowing for the diagnosis and treatment of patients who may have previously been considered non-diabetic under the older criteria.

The HAPO Study showed that mothers with glucose levels that were high, but not high enough to be considered diabetic at the time, were still at risk of adverse outcomes and paved the way for changes in how these patients are treated and managed.

To read the original research article published on the HAPO study you can visit: http://www.nejm.org/doi/full/10.1056/NEJMoa0707943#t=article

By Grace Conlon

Citations

1. Macintosh Mary C M, Fleming Kate M, Bailey Jaron A, Doyle Pat, Modder Jo, Acolet Dominique et al. Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study BMJ 2006; 333 :177 (http://www.bmj.com/content/333/7560/177.short)
2. Evers Inge M, de Valk Harold W, Visser Gerard H A. Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands BMJ 2004; 328 :915 (http://www.bmj.com/content/328/7445/915.short)
3. Cundy, T., Gamble, G., Townend, K., Henley, P. G., MacPherson, P. and Roberts, A. B. (2000), Perinatal mortality in Type 2 diabetes mellitus. Diabetic Medicine, 17: 33–39. doi:10.1046/j.1464-5491.2000.00215.x (http://onlinelibrary.wiley.com/doi/10.1046/j.1464-5491.2000.00215.x/full)
4. Billionnet C., Mitanchez D., Weill A., Nizard J., Alla F., Hartemann A., Jaqueminet S., Gestational Diabetes and Adverse Perinatal Outcomes from 716, 152 births in France 2012. Diabetologia, 2017 APR;60(4) 636-644 (https://link.springer.com/article/10.1007%2Fs00125-017-4206-6 )
5. The HAPO Study Cooperative Research Group, Hyperglycemia and Adverse Pregnancy Outcomes. N Engl J Med 2008; 358:1991-2002 (http://www.nejm.org/doi/citedby/10.1056/NEJMoa0707943#t=citedby)
6. COUSTAN DR, LOWE LP, METZGER BE, DYER AR. The HAPO Study: Paving The Way For New Diagnostic Criteria For GDM. American journal of obstetrics and gynecology. 2010;202(6):654.e1-654.e6. doi:10.1016/j.ajog.2010.04.006. ( https://www.ncbi.nlm.nih.gov/pubmed/20510967 )
7. HSE guidelines for pre-GD and GD(July 2010): (http://www.hse.ie/eng/services/publications/NursingMidwifery%20Services/onsdguidelinesgestationaldiabetes.pdf)

Other sources

8. Ali, FM; Farah, N; O’Dwyer, V; O’Connor, C; Kennelly, MM; Turner, MJ, The impact of new national guidelines on screening for gestational Diabetes Mellitus, Irish Medical Journal, Feb-2013 (http://www.lenus.ie/hse/bitstream/10147/270477/1/Article6579.pdf)
9. Joyce Leary,, David J. Pettitt, Lois Jovanovič, Gestational diabetes guidelines in a HAPO world, Best Practice & Research Clinical Endocrinology & Metabolism Volume 24, Issue 4, August 2010 (https://www.ncbi.nlm.nih.gov/pubmed/20832745)
10. https://www.wikijournalclub.org/wiki/HAPO
11. http://www.iadpsg.org/