Overt diabetes mellitus during pregnancy is associated with significantly increased risks of adverse perinatal outcomes. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study in 2008 showed that hyperglycemia in pregnancy, less severe than overt diabetes, is independently associated with increased risk of adverse maternal and neonatal outcomes.1 HAPO was a blinded observational study in which pregnant women and their clinical caregivers were not made aware of their glucose status. Thus, child outcomes were not confounded by treatment of maternal hyperglycemia. Second, the large number and racial/ethnic diversity of participants included in the HAPO make the findings broadly applicable. This study led to new diagnostic criteria for gestational diabetes mellitus (GDM) proposed by the International Association of the Diabetes and Pregnancy Study Groups.2
The Ministry of Health of China accepted the International Association of the Diabetes and Pregnancy Study Groups criteria and published the uniform diagnostic criteria for gestational diabetes on July 1, 2011.3 The criteria quickly gained acceptance throughout China. In a 2013 cohort study of 17,186 pregnant women from 13 hospitals throughout China that applied these criteria, the incidence of gestational diabetes was 17.5%.4
The aim of this article is to summarize recent updates about long-term adverse effects to GDM mothers and children.
Updates in long-term maternal adverse effects
GDM is well-known to be associated with increased future maternal risk of type 2 diabetes mellitus. A meta-analysis of 675,455 women with up to 28 years of follow-up showed that women with GDM have a more than seven-fold increased risk of developing type 2 diabetes.5
In recent years, more studies have shown that there are other long-term medical complications associated with GDM.
Cardiovascular disease (CVD), including coronary artery disease and stroke, is the leading cause of death in women.6 In 2006, Carr et al.7 first demonstrated the relationship between GDM and future maternal CVD risk. They did a cross-sectional study of 994 women with a family history of type 2 diabetes (332 with history of GDM and 663 without history of GDM), and found those with prior GDM were even more likely to not only have CVD risk factors, including metabolic syndrome and type 2 diabetes, but also to have experienced CVD events, which occurred at a younger age.
In 2008, Shah et al.8 from Canada conducted a population-based retrospective cohort with 8191 women with GDM and 81,262 women without GDM. At follow up at 11.5 years, they found young women with GDM have a substantially increased risk for CVD. In 2009, the same group9 further stratified the population into 3 cohorts: women with gestational diabetes (13,888); women with an abnormal 50g glucose challenge test but a normal OGTT (71,831); and women with a normal 50g glucose challenge test (349,977). They found that both women with GDM and women with an abnormal 50g glucose challenge test had a higher risk of CVD over 12.3 years of median follow-up.
Different research group around the world in the following years showed similar results. In 2013, Kessous et al.,10 a group from Israel, did a population-based study of 4928 women with GDM and they found at follow-up period of more than 10 years, women with GDM had higher rates of cardiovascular morbidity. In 2014, Fadl et al.,11 from Sweden, conducted a population-based matched case-control study. They found the adjusted odds ratios for the association of CVD with GDM are 1.51. In 2017, Shostrom et al.12 from US, had a population-based study of 8127 women. It showed women with a previous history of GDM have significantly higher risk for developing CVD and lower serum level of HDL cholesterol. Tobias et al.13 from US, by a large Prospective Cohort of nearly 90,000 US women older than 26 years, women with a history of GDM had 43% greater risk of CVD. In 2018, Daly et al.,14 a group from UK, by studying a retrospective cohort with 9118 women diagnosed with GDM and 37,281 control women, and found women diagnosed with GDM were at very high risk of developing type 2 diabetes and had a significantly increased incidence of hypertension and ischemic heart disease. McKenzie-Sampson et al.15 from Canada, with a retrospective cohort study of 67,356 women with gestational diabetes and 1,003,311 without gestational diabetes for a maximum of 25.2 years. It showed women with GDM had a higher cumulative incidence of hospitalization for CVD 25 years after delivery (190.8 per 1000 women) compared with no gestational diabetes (117.8 per 1000 women).
To summarize above studies, there are two systematic reviews in the past year. In 2018, Jing et al.16 retrieved seven cohort studies with 3,417,020 pregnant women including 14,146 incident CVD events. In the pooled analysis, women with prior GDM were at 1.74-fold risk of CVD of those without. In 2019, Caroline et al. did a pooled analysis of nine studies from 5,390,591 women (101,424 cardiovascular events). It showed that pregnant women with GDM have a twofold higher risk of cardiovascular events postpartum compared with their peers.17 American Heart Association includes history of GDM in their classification of cardiovascular risk factors in women.18
Chronic kidney disease
Chronic kidney disease is a common condition, with an estimated global prevalence of 13.4%.19 Early evidences showed women with GDM have a higher prevalence of microalbuminuria than women without any history of diabetes.20,21 Emerging evidence reported an association between GDM history and subsequent renal morbidity. Beharier et al. conducted a population-based study and found women with GDM had higher rates of total renal morbidity.22 In 2018, Rawal et al. did a long-term follow-up of women with GDM within the Danish National Birth Cohort and the Nurses’ Health Study II. They found women who develop GDM in pregnancy were more likely to show increased eGFR levels 9–16 years postpartum, which could indicate early stages of glomerular hyperfiltration and renal damage.23
There is some controversy about the relationship between gestational diabetes and breast cancer. A systemic review in 2014 included nine articles documented, five cohort, and 4 case-control studies containing 10,630 cancer cases and 14,608 women with a history of GDM and the pooled odds ratio between GDM and breast cancer risk was 1.01.24 Another systemic review in 2017 included five case-control studies and six cohort studies and it did not find significant associations between GDM and breast cancer.25
In 2019, a cohort study in Taiwan shows women with GDM had increased risk of cancers, including cancers of nasopharynx, kidney, lung, bronchus, breast, and thyroid gland.26
Updates in long-term fetal adverse effects
Obesity, overweight, and insulin resistance
It is known that intrauterine exposure to maternal pre-existing diabetes or GDM is associated with a higher risk for offspring abnormal glucose metabolism and adiposity.27 Early evidences demonstrated the association of maternal glucose levels during pregnancy with abnormal glucose metabolism and adiposity in childhood.28–30
However, whether GDM, independent of maternal body mass index (BMI), is associated with future metabolic disease and obesity in the offspring was controversial, as much of the earlier results did not control for maternal BMI.
Two systematic reviews have shown the association between maternal diabetes and childhood obesity.31,32 In both reviews, maternal hyperglycemia was shown to be a risk factor for obesity or overweight in offspring, but the association was attenuated or no longer apparent after adjusting for maternal BMI. Another systematic review came out in 2018 included twenty observational studies involving a total of 26,509 children.33 The result shows offspring of GDM mother had higher BMI in childhood, however, after adjustment for maternal pre-pregnancy BMI, this association disappeared.
These are some limitations in those studies. First, many studies focused on women with a high prevalence of diabetes, making it unclear whether mild hyperglycemia in pregnancy could have long-term effects on offspring. Second, maternal treatment during pregnancy has confounded studies on offspring risk of hyperglycemia.
The HAPO follow-up study (FUS) offered a unique opportunity to examine associations of maternal hyperglycemia during pregnancy, less than overt diabetes and not confounded by maternal treatment, with childhood glucose metabolism. A total of 4834 children completed all or part of the HAPO FUS visit. Four study results came from HAPO FUS since last year.
Regarding offspring overweight and obesity, Lowe et al.34 in 2018 initially found among children of mothers with GDM versus those without it, the difference in childhood overweight or obesity was not statistically significant. However, in 2019 article, they are able to find the positive association between maternal glucose levels during pregnancy and measures of child adiposity in HAPO FUS children (aged 10–14 years) and it is independent of maternal BMI.35
In terms of offspring insulin resistance, Lowe et al.36 demonstrated that offspring of mothers with untreated GDM are at high risk for impaired glucose tolerance 10–14 years postpartum. Scholtens et al.37 further demonstrated that the relationship between maternal glucose levels during pregnancy and child glucose levels and related outcomes was generally linear across the spectrum of glucose levels, including levels below those diagnostic of GDM.
The development of GDM coincides with a period of rapid fetal brain development, and recent studies have shown GDM has long-term adverse effects to offspring neurocognitive development.
Nomura et al.38 revealed maternal GDM is associated with an increased risk for attention-deficit/hyperactivity disorder at age 6 years. Tine et al.39 showed offspring of women with GDM had a lower global cognitive score. Cai et al.40 in 2018 found gestational diabetes and maternal blood glucose levels are associated with offspring neuronal activity during an attentional task at both 6 and 18 months. Such electrophysiological differences are likely functionally important, having been previously linked to attention problems later in life.
A systematic review and meta-analysis includes 12 studies involving 6140 infants up to 14 years. This meta-analysis found the association between maternal diabetes and deleterious effects on mental/psychomotor development and overall intellectual function in the offspring must be taken with caution, a direct causal influence of intrauterine hyperglycemia remains uncertain.41 A recent meta-analysis in 2019 includes a total of nine studies with 7,218,903 participants. The result shows combining of the cohort studies demonstrated that offspring of diabetic mothers were at higher risk of attention-deficit/hyperactivity disorder.42
Effects of mild GDM treatment on long-term maternal and fetal outcome
After decades of uncertainty, results from randomized treatment trials confirm that treatment of mild GDM is associated with immediate short-term maternal and fetal benefits.43,44 There is, however, insufficient evidence regarding whether treatment confers long-term maternal and fetal metabolic benefit.
In terms of maternal long-term effect, a recent article in 2019 included 457 women with mild GDM (243 treated; 214 untreated) and evaluated at a median 7 years after their index pregnancy. Result showed there was no statistical significance in frequency of diabetes, metabolic syndrome, and insulin resistance.45
In terms of fetal long-term outcome, one study showed although treatment of GDM substantially reduced macrosomia at birth, it did not result in a change in BMI at age 4–5 years old.46 In a FUS of the offspring of women participating in a randomized controlled trial for the treatment of mild GDM, there is no difference in the overall frequency of obesity or metabolic dysfunction at ages 5–10 years according to whether treatment was undertaken.47
In summary, treating mild GDM with dietary intervention and insulin when necessary is effective in reducing short-term maternal and fetal risks. Whether treatment of mild GDM is associated with future metabolic disease and obesity in the mother and her offspring remains unknown, with the data at present suggesting no such association at least in the first decade since delivery.
There are increasing new evidences demonstrating the relationship between GDM and long-term maternal and fetal adverse outcomes. This review summarized long-term maternal effects including CVD, chronic kidney disease, and cancer, as well as long-term fetal adverse such as obesity, overweight, insulin resistance, and neurocognitive development. Whether treatment of mild GDM could benefit the women and offspring in long-term remains unclear. Future clinical trials are needed to address the question.
Conflicts of Interest
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