Insulin pump use does not lower risk of congenital malformations
Poor glycaemic control before and during pregnancy can increase the risk of congenital malformations and perinatal death among the offspring of women with type 1 diabetes. A new analysis of real-world data, reported in Diabetologia, shows that use of an insulin pump during pregnancy does not alleviate this risk, despite being associated with better glycaemic control. Dr Susan Aldridge reports.
Congenital malformations and perinatal mortality are two to four times more frequent in the offspring of women with type 1 diabetes than they are in the general population. The most important modifiable risk factor contributing to this increased risk is poor periconceptual glycaemic control.
Meanwhile, higher maternal educational level and folic acid supplementation are associated with a lower prevalence of malformations, while diabetic complications such as retinopathy and nephropathy have been associated with a higher prevalence. Perinatal mortality risk in women with type 1 diabetes is multifactorial in origin but, again, poor glycaemic control is a key modifiable factor that increases this risk.
Studies outside of pregnancy have suggested that continuous subcutaneous insulin infusion via a pump gives better glycaemic control than insulin delivered by multiple daily injections (MDI). Pump use is therefore on the increase throughout Europe, Canada and the USA.
Given the importance of glycaemic control for avoiding congenital malformations and perinatal mortality, it might be expected that pump use in pregnancy would improve outcomes for the offspring. However, this has not yet been demonstrated by the research. The low overall incidence of malformations and perinatal death means that randomised controlled trials are hard to perform for meaningful results and researchers must instead turn to large cohort studies of pump users in real-world settings.
Accordingly, Ida Thorius of the University of Copenhagen and colleagues have drawn on the Diabetes Pregnancy Registry to evaluate the risk of women with type 1 diabetes having a baby with congenital malformations or perinatal or neonatal death while using either a pump or MDI during pregnancy.
The Diabetes Pregnancy Registry
The Diabetes Pregnancy Registry is a large, multinational, prospective, non-interventional cohort including more than 2000 women with type 1 diabetes. It was set up to carry out the EVOLVE (EValuation Of LeVEmir in Pregnancy) study, which aims to assess the safety of insulin detemir in this cohort.
Large-scale data collection through the registry allows comparisons and analysis between different insulin regimens in pregnant women with type 1 diabetes. A secondary analysis of Registry data was used in the current study to test the researchers’ hypothesis that insulin pump treatment in real-world conditions would lead to a reduced risk of congenital malformations and perinatal death.
Data were collected at the enrolment visit, during pregnancy and up to one year after birth. The primary endpoint was offspring with any congenital malformation – major or minor – diagnosed either at birth or up to one year, including those occurring in foetuses following medical termination of the pregnancy. Secondary outcomes were spontaneous miscarriages and medical terminations, stillbirth (from 22 weeks gestation to delivery), perinatal death (from 22 weeks to seven days after birth) and neonatal death (death of a liveborn infant up to 28 days after delivery).
The study involved 750 pump users and 1338 women using MDI. They came from 15 countries in Europe, Israel and Malaysia, with the most participants coming from Denmark (551), the UK (268) and Croatia (226). The pump and MDI users were similar, save that pump users had a higher educational level, a higher BMI, longer diabetes duration and higher prevalence of retinopathy. They were also more likely to have taken folic acid, were less likely to smoke and had a lower HbA1c on enrolment (mean 51 mmol/mol versus 54mmol/mol for the MDI users).
Pump versus MDI
In total, 251 babies had any kind of malformation, including 63 with at least one major malformation. The proportions of offspring with at least one malformation, major and/or minor, were 13.5% in pump users and 11.2% in MDI users. The proportions with at least one major malformation were 2.8% and 3.1%, respectively. And a total of 12 offspring had more than one major malformation, which is 0.5% in both pump and MDI users. Finally, pump users had more offspring with at least one minor malformation (but no major malformation) than MDI users – 10.7% versus 8.1%.
The proportions of pregnancies resulting in stillbirth were 1.3% versus 1.1%; perinatal death 1.6% versus 1.3% and neonatal death 0.3% versus 0.3% – overall, no significant difference between the pump and MDI groups.
So this prospective study of 2088 pregnant women with type 1 diabetes reveals that there is no significant difference in the risk of having a baby with a congenital malformation between those using insulin pump therapy and those using MDI. This is despite women using a pump having a higher educational level, more frequently reporting folic acid supplementation and having better glycaemic control on enrolment in the study. There was even a numerically higher prevalence of any or minor malformations in pump users. Poor glycaemic control cannot account for these findings, so other factors are likely to be involved.
Folic acid, higher socioeconomic status and avoiding smoking are factors that help avoid congenital malformation in the general population. These factors also applied to the pump users in the current study, suggesting a generally healthier lifestyle than for the MDI group. This might be expected to lead to a lower prevalence of malformations. However, pump treatment is often started in women with poorer glycaemic control, so maybe the pump users are women with more challenging diabetes, which in itself may counter their improved control on the pump. This is supported by the finding that the pump users were more likely to have developed retinopathy.
As there were a low number of stillbirths and low neonatal mortality, this could not be statistically tested, but there was no numerical difference between the groups. The perinatal mortality risk was driven mainly by stillbirth and is higher than the prevalence of perinatal mortality among the Danish population, which is around 0.4%.
More research is needed
The strengths of this study lie in its collection of real-world data from women with type 1 diabetes during pregnancy from many nationalities and healthcare systems, thereby increasing the generalisability of the findings.
On the other hand, the women were recruited from selected sites with routine care, ensuring relatively good glycaemic control, which might make the findings less applicable in other settings. Data were collected between 2013 and 2018 and, since then, insulin pump technology has improved, so it is possible that more modern pumps could have a different impact on the risks of congenital malformation. Further studies of pregnancy outcomes, involving users of newer insulin pumps and closed-loop systems are now needed.
In conclusion, the finding of no significant difference in the prevalence of congenital malformations in the offspring of women using either a pump or MDI and even a non-significant increased prevalence of any or minor malformations in pump users was surprising. It suggests a need for further studies to evaluate the impact of pump therapy on the development of malformations. Population-based studies will be needed to assess the impact of pump treatment on such rare events.
Investigation of other factors that could influence malformations such as HbA1c, treatment modality, folic acid and complications is needed. Meanwhile, the prevalence of other poor pregnancy outcomes, such as foetal overgrowth, pre-eclampsia and preterm delivery are to be analysed by these researchers based on data from the Diabetes Pregnancy Registry.
To read this study, go to: Thorius IH, Husemoen LN, Nordsborg RB, Alibegovic AC, Gall M, Petersen J, Mathiesen ER. Congenital malformations among offspring of women with type 1 diabetes who use insulin pumps: a prospective cohort study. Diabetologia online 14 January 2023.
Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.