Updates for hyperglycemia in pregnancy: The ongoing journey for maternal-neonatal health.

Hyperglycemia in pregnancy, including pre‐existing diabetes and gestational diabetes (GDM), is an important health threat to the pregnant woman and the fetus . In this article, we reviewed recent advances in this field and share our future perspectives.

For pregnant women with type 1 or type 2 diabetes, a recent study from Japan, which included study participants between 1982 to 2020, showed that maternal glycemic control improved in this time period, which was accompanied by a decrease in preterm delivery . A significant reduction in delivering large‐for‐gestational‐age (LGA) neonates was observed in women with type 2 diabetes. However, there was no significant change in other adverse pregnancy outcomes, including primary cesarean section, pre‐eclampsia, major congenital anomaly and neonatal death. In women with youth‐onset type 2 diabetes, a report from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort showed very high rates of maternal and infant complications, including poor glycemic control, pregnancy loss in 25.3% and preterm birth in 32.6% of pregnancies, and LGA in 26.8% and small for gestational age in 7.8% of the offspring . These findings highlight the need for further research and improvement in clinical management in pregnant women with pre‐existing diabetes.

The diagnosis of GDM remains controversial, although it has been a decade since the announcement of the one‐step criteria to diagnose GDM, in addition to the two‐step criteria. Several cohort studies, including our previous report , showed that the one‐step method to diagnose GDM is associated with an improvement in pregnancy outcomes and leads to an earlier diagnosis, at the expense of increased prevalence of GDM. In contrast, a pragmatic, randomized trial comparing one‐step and two‐step methods failed to show any difference in pregnancy outcomes . As the prevalence of GDM diagnosed by the one‐step method was significantly higher than the prevalence of GDM diagnosed by the two‐step method, findings from this study did not support the use of the one‐step method. However, there was a significant non‐adherence in this study. Just 66% of women randomized to the one‐step group received the one‐step method, and the rest of the 34% of women received the two‐step method to screen GDM. This non‐adherence and misclassification would underestimate the effect of the one‐step method on adverse pregnancy outcomes. Indeed, comments from the committee of the International Federation of Gynecology and Obstetrics reported that “whether the additional women considered GDM by the one‐step approach derived benefit from their treatment cannot be determined from the data as presented” . In addition, women with GDM diagnosed by the one‐step method, but not by the two‐step, method had a 39.4% risk of prediabetes and 7.9% risk of overt diabetes during the 11.4 years of follow up after delivery in the Hyperglycemia and Adverse Pregnancy Outcome Follow‐up Study (HAPO‐FUS) . Therefore, another advantage of using the one‐step method is to identify a high‐risk population for diabetes after delivery. Furthermore, offspring born by a mother with GDM diagnosed by the one‐step method was associated with increased risk of adiposity and impaired glucose metabolism , . The potential benefit for the treatment of GDM on the risk of adiposity and impaired glucose metabolism should be considered in the comparison of the two methods to diagnose GDM. In summary, the most appropriate method to diagnose GDM remains unclear. Considering the statistical power required, an international multicenter randomized controlled trial is required to answer the question, which should consider both the risk and benefit during pregnancy, at delivery, and long term after delivery (Table 1).

Table 1

Summary of recent advances in the field of hyperglycemia in pregnancy

Research questions	Findings	Unsolved problems
The consequence of PDM	Improvement in glycemic control in Japanese women with PDM between 1982 and 2020 was accompanied by a decrease in preterm delivery and delivering LGA neonates, but there was no improvement in other adverse pregnancy outcomes 2 In TODAY study, women with pre‐existing type 2 diabetes had poorer glycemic control and a higher rate of adverse pregnancy outcomes 3	Ways to improve the prognosis of pre‐existing diabetes
The diagnosis of GDM	Cohort studies showed that the one‐step method was associated with an improvement in pregnancy outcomes and led to earlier diagnosis, at the expense of increased prevalence of GDM 4 A pragmatic randomized trial comparing one‐step and two‐step methods failed to show any difference in pregnancy outcomes, which might be affected by the high non‐adherence rate (34%) and misclassification 5 The one‐step method identified a high‐risk population for diabetes after delivery, as shown in HAPO‐FUS 7 , 8	This question remains unanswered. An international multicenter randomized controlled trial is required, which should consider both the risk and benefit during pregnancy, at delivery, and long term after delivery
The appropriate timing to diagnose GDM	Cohort studies have shown different clinical characteristics and pregnancy outcomes in women with GDM diagnosed before and after 24th gestational week 9 , 10 A randomized controlled trial failed to show benefits of earlier diagnosis of GDM by the two‐step method on pregnancy outcomes 11	Whether earlier diagnosis of GDM by the one‐step method results in a better pregnancy outcome remains unclear, and there is a randomized controlled trial that is completed and will be published in the near future. (NCT03523143)
Use of aspirin to prevent pre‐eclampsia in PDM	Clinical guidelines suggest the use of aspirin to prevent pre‐eclampsia in women with PDM 12 A cohort study failed to show any benefit of aspirin to prevent pre‐eclampsia and other adverse pregnancy outcomes in women with PDM 13	Randomized controlled trials are required to conclude the effect of aspirin prophylaxis in pregnant women with PDM, such as the ongoing trial in Ireland 14

GDM, gestational diabetes mellitus; HAPO‐FUS, Hyperglycemia and Adverse Pregnancy Outcome Follow‐up Study; LGA, large‐for‐gestational‐age; PDM, preexisting diabetes mellitus; TODAY, Treatment Options for Type 2 Diabetes in Adolescents and Youth.

Improvement in glycemic control in Japanese women with PDM between 1982 and 2020 was accompanied by a decrease in preterm delivery and delivering LGA neonates, but there was no improvement in other adverse pregnancy outcomes

In TODAY study, women with pre‐existing type 2 diabetes had poorer glycemic control and a higher rate of adverse pregnancy outcomes

Cohort studies showed that the one‐step method was associated with an improvement in pregnancy outcomes and led to earlier diagnosis, at the expense of increased prevalence of GDM

A pragmatic randomized trial comparing one‐step and two‐step methods failed to show any difference in pregnancy outcomes, which might be affected by the high non‐adherence rate (34%) and misclassification

The one‐step method identified a high‐risk population for diabetes after delivery, as shown in HAPO‐FUS ,

Cohort studies have shown different clinical characteristics and pregnancy outcomes in women with GDM diagnosed before and after 24th gestational week ,

A randomized controlled trial failed to show benefits of earlier diagnosis of GDM by the two‐step method on pregnancy outcomes

Clinical guidelines suggest the use of aspirin to prevent pre‐eclampsia in women with PDM

A cohort study failed to show any benefit of aspirin to prevent pre‐eclampsia and other adverse pregnancy outcomes in women with PDM

The timing to diagnose GDM is another important issue in this field. Several cohort studies found that clinical characteristics and pregnancy outcomes were different in women with GDM diagnosed before (early GDM) and after the 24th gestational week (late GDM) , . In the Japan Environment and Children's Study, pregnant women with early GDM tended to have a higher maternal age, a higher BMI before pregnancy, a higher percentage who received assisted reproductive technology to conceive pregnancy and an increased rate of medical conditions than women with late GDM . Another cohort study showed that hypertensive disorders of pregnancy and cesarean section were more prevalent in the early GDM group than in the late GDM group; whereas the prevalence of LGA was higher in the late GDM group than the early GDM group . These findings show that earlier diagnosis and intervention for GDM might lead to an improved pregnancy outcome. Nevertheless, this is not supported by a randomized controlled trial, which compared the pregnancy outcomes in women who received GDM screening at 14–20 weeks or 24–28 weeks . Early screening of GDM failed to reduce the primary composite outcome, including macrosomia, primary cesarean delivery, gestational hypertension, pre‐eclampsia, hyperbilirubinemia, shoulder dystocia and neonatal hypoglycemia. As this study used the two‐step method to diagnose GDM, we carried out and completed another randomized controlled trial, which used the one‐step method to compare the difference between screening of GDM at 18–20 and 24–28 weeks, and the results will be reported in the future (The Effect of Early Screening and Intervention for Gestational Diabetes Mellitus on Pregnancy Outcomes, the TESGO trial, NCT03523143).

According to the recommendation of the American Diabetes Association, aspirin 100–150 mg/day should be prescribed to pregnant women with pre‐existing type 1 or type 2 diabetes from 12 to 16 gestational weeks to lower the risk of pre‐eclampsia . However, a recent cohort study failed to show a beneficial effect of this recommendation . The study compared the prevalence of pre‐eclampsia after implementation of prophylactic aspirin (150 mg/day) for all pregnant with pre‐existing diabetes with the prevalence in previous risk‐based prophylaxis aspirin (75–150 mg/day). The prevalence of pre‐eclampsia, preterm delivery, preterm pre‐eclampsia, and LGA and SGA infants was similar in the two groups. As there were differences in the percentage of type 2 diabetes and body mass index between the two groups that might confound the results, evidence from randomized controlled trials is required to conclude the effect of aspirin prophylaxis in pregnant women with pre‐existing diabetes, such as the ongoing trial in Ireland .

In conclusion, there have been significant advances in the field of hyperglycemia in pregnancy, from diagnosis to management, in recent years. However, there remains some uncertain issues, such as whether to choose a better cut‐off values of fasting glucose to replace the time‐consuming oral glucose test in clinics? Are there any better markers or risk scores that could help in identifying individuals at high‐risk of gestational diabetes? In addition, recent applications of modern technology with continuous glucose monitoring would certainly add further information in related areas. In consideration of hyperglycemia during pregnancy is not just for pregnancy, but for life for women and the whole family, all those issues demand further studies to explore.

DISCLOSURE

The authors declare no conflict of interest.