Hyperglycemia during Pregnancy: Epidemiology and Public Health Relevance

Anil  Kapur

Hyperglycemia during Pregnancy: Epidemiology and Public Health Relevance1

Anil Kapur

INTRODUCTION

Cardiovascular diseases (CVDs), diabetes, cancers, and chronic respiratory diseases are the most common noncommunicable diseases (NCDs), accounting for 63% of global deaths (36 million) in 2008 and projected to claim 52 million lives by 2030. Almost 80% of these deaths occur prematurely in low- or middle-income countries.¹ NCDs become burdensome, costly, and debilitating over time, negatively impacting productivity and family income. In addition, these diseases create a poverty trap as well as reduce chances of preventing escape from it. The World Economic Forum has for 2 years in a row rated chronic diseases amongst the five top threats to the Global Economy including in the low- and middle-income countries.²

The global community is beginning to understand the enormity of the humanitarian, societal, and economic challenge of NCDs as evidenced by the political declaration from the high-level meeting (HLM) of the United Nations (UN) General Assembly on the Prevention and Control of NCDs, New York, 2011.³

When faced with a challenge of this magnitude, we need to carefully consider where we can make the greatest immediate and long-term impact to eventually break the curve of the NCD epidemic. Up to 80% of the NCD burden can be prevented by addressing the common risk factors of tobacco use, unhealthy diet including excessive use of alcohol and physical inactivity—interventions targeting adults at high risk—a strategy fraught with implementation difficulties.⁴

LINKS BETWEEN MATERNAL HEALTH AND NONCOMMUNICABLE DISEASES

Mounting body of evidence from high-quality research shows that prenatal and early-life development through epigenetic programming influences the risks of NCD in later life^5–9 and this might be, especially relevant to low-resource countries.^9–12 Parent's health particularly the mother's diet, body composition, and metabolic status during pregnancy determine fetal environment and affect risk for later NCDs.^13,14 Early intervention to ensure healthy pregnancy, safe delivery, and disease-free early childhood may, therefore, be the most effective means of attaining best future health and preventing NCDs. Fetal environment determines whether one starts life with a “health head start” or a “health handicap” because it is on this foundation that risk factors play out in later life. People starting life with a “health handicap” may be less able to withstand lifestyle risks and prone to develop 2disease early compared to those starting with a “health advantage”. Similarly, lifestyle interventions in adult life to prevent diseases may have variable effects based on early-life programming.¹⁵ The impact of life conditions on health—the social determinants of health is high on the global development agenda, and it is relevant to consider that these determinants get hard wired into the genome of the next generation through epigenetic changes during fetal life. The recognition of early-life influences on chronic diseases, however, does not imply deterministic processes that cannot be overcome by later-life intervention; only that the task becomes more difficult.

In the last one and half decades, a lot of attention and resources have been provided to Maternal and Child Health Programs, especially in the developing world. In order to optimize these resources, Maternal and Child Health Programs have taken the straight and narrow path of focusing on factors that directly lead to maternal, neonatal and infant mortality. These laudable efforts have led to improvements in access to maternity services in many low- and middle-income countries and to improved survival for even the “at risk” small for gestational age (SGA) babies born to undernourished mothers in rural settings and to substantial improvements in both measures with more infants and mothers surviving. Unfortunately this narrow biomedical focus has failed to address the social determinants, or the root causes of mortality; moreover, the very individuals saved—the low-birth-weight babies or babies surviving obstructed and difficult deliveries are the ones that have the highest risk of future ill health both from communicable and noncommunicable diseases at an early stage of life. Focusing on early survival might not capture outcomes that have long-term implications for adult health, life expectancy, quality of life, and accumulation of human capital.¹⁵ Further, recommendations for nutritional interventions are frequently based on raising birth weight, focusing on gains in stature, or micronutrient status in the short-term.¹⁶ Long-term follow-up data confirm the existence of a narrow window of opportunity for intervention up to 24 months of age, and only limited benefit, or even harm, of feeding strategies thereafter.^17,18 These small babies continuing to be malnourished and stunted during childhood and early adult life, will remain at relatively low risk for NCDs as long as they have subsistence living. With changes in living conditions as a consequence of economic development or urban migration, these individuals manifest diabetes and other NCDs at much lower body mass index (BMI) and central adiposity threshold.^19,20 Studies on survivors of the Dutch^21,22 and Chinese²³ famine show that individuals exposed to intrauterine under nutrition had significantly higher rates of diabetes in adult life and the risk was highest in the subgroup that were relatively well off in adult life.

Developmental effects operate through a gamut of subtle influences which provide the fetus the cues (via the intrauterine environment) to predict the external environment it will be born into; as well as the flexibility to adjust its growth trajectory to match that environment. Termed as developmental plasticity, these influences operate through epigenetic changes^24,25 across the entire range of environment, from under nutrition to excessive nutritional environments associated with gestational diabetes mellitus (GDM) or maternal obesity,^26,27 or other maternal health insults like malaria, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), etc. leading to multigenerational cycles of disease.²⁸ The mismatch between the predicted environment for survival 3programming and the actual environment in adult life may be a critical factor driving the type 2 diabetes and obesity epidemic.

In young women, themselves born small, the effects of pregnancy-induced weight gain, insulin resistance, and increased insulin requirements are exaggerated by the preexisting insulin resistance and the lower ability to produce insulin as a consequence of early-life programming, resulting in higher rates of GDM and/or pregnancy-induced hypertension. Seshiah et al.²⁹ reported prevalence rates of 8–10% for GDM among women of low socioeconomic status who had a prepregnancy BMI of less than 19. Undiagnosed or poorly managed GDM sets off a cycle of future obesity and type 2 diabetes in the offsprings and the cycle may repeat in subsequent generations with ever growing risk accumulation.

Compared to a decade ago, in nearly all parts of the world, the number of women of reproductive age who are overweight now exceeds the number of women who are underweight.³⁰ The rising level of overweight and obesity amongst women of reproductive age makes them even more vulnerable to GDM than their mothers. Between 1999 and 2005, age, race, and ethnicity adjusted prevalence of pre-GDM amongst pregnant women in southern California doubled.³¹ Over the last 20 years, the age of onset of diabetes has been declining; at the same time the age of marriage and child bearing is increasing; as a consequence in the future we may see more women entering pregnancy with preexisting diabetes.^1,32 Offsprings of mothers with uncontrolled diabetes, either preexisting or originating, during pregnancy are 4–8 times more likely to develop diabetes themselves in later life^33,34 compared to their siblings born to the same parents in a non-GDM pregnancy. This shows that the uterine environment contributes significantly to the higher risk for diabetes than can be explained by genetic inheritance alone. A recent study suggests that a significant proportion (47.2%) of diabetes and obesity in the youth can be attributed to maternal GDM and obesity.³⁵ Another study suggests that GDM may be responsible for 19–30% of all type 2 diabetes seen among Saskatchewan First Nations people in Canada.³⁶ GDM thus creates a vicious cycle in which diabetes begets more diabetes.

According to the International Diabetes Federation (IDF), Diabetes Atlas, 6th edition,³⁷ there are now an estimated 382 million people (184 million women) with diabetes. In addition, there are about 316 million with prediabetes. The number is likely to grow to over 592 million people with diabetes and almost 471 million with prediabetes by 2035. Asia-pacific region is at the center of this rising trend for diabetes and accounts for about half the global burden with China, India, Indonesia, Pakistan, and Bangladesh figuring amongst the top ten countries with the highest number of people with diabetes.³⁷

HYPERGLYCEMIA DURING PREGNANCY AND ITS CONSEQUENCES

Worldwide, one in six pregnancies may be associated with hyperglycemia, 84% of which involve GDM.³⁷ The IDF estimates that 21.4 million out of the 127 million live births, i.e., 16.8% of live births in 2013 were associated with hyperglycemia in pregnancy. An estimated 16% of those cases were due to diabetes in pregnancy. This does not take into account the number of pregnancies ending in spontaneous abortions, still births, or intrauterine deaths that may have been associated with 4hyperglycemia proven or otherwise. In South-East Asia, one in four live births may occur in the setting of maternal hyperglycemia during pregnancy.³⁷ In high-risk groups, up to 30% of pregnancies may involve diabetes.^38,39 The age-adjusted prevalence of GDM in women in United States shows that the rates are higher for women with Asian or Pacific Island origin, but more so (almost threefold compared to non-Hispanic whites) for migrant women born in the country of their origin.³⁶ A staggering 91.6% of cases of hyperglycemia in pregnancy are in low- and middle-income countries, where access to maternal care is often limited.³⁷

The prevalence of hyperglycemia in pregnancy increases rapidly with age and is the highest in women over the age of 45 years (47.7%), although there are fewer pregnancies in that age group. This explains why just 23% of global cases of hyperglycemia in pregnancy occurred in women over the age of 35 years, even though the risk of developing the condition is higher in these women.³⁷

In 2010, there were an estimated 22 million women with diabetes in the reproductive age-group of 20–39 years; an additional 54 million in this age-group had impaired glucose tolerance (IGT) or prediabetes with potential to develop GDM if they become pregnant.⁴⁰ Thus, over 76 million women are at risk of their pregnancy being complicated with pregestational (existing) diabetes or GDM.

Hemorrhage, hypertensive disorders, obstructed labor, and infection/sepsis are among the leading global causes of maternal mortality.⁴¹ High blood pressure and gestational hyperglycemia are linked directly or indirectly to all of them. According to WHO's report on women and health, high blood pressure and high blood glucose are two leading risk factors for death from chronic conditions in women above 20 years of age,⁴² yet women are not routinely screened for hyperglycemia during pregnancy and the diagnosis of GDM is often missed; maternal mortality and morbidity attributable to diabetes in women may, therefore, be actually higher than current estimates.

Diabetes in pregnancy is associated with serious complications for both the mother and child. It has been shown that the negative consequences on the fetus and the mother increase linearly with increasing maternal blood glucose.⁴³ It is now recognized that a proportion of women diagnosed during pregnancy may have had diabetes before pregnancy (type 1 or type 2), also called pre-GDM. Infants of mothers with pre-GDM have higher rates of malformation.^44–46 Good blood-glucose control before conception and throughout pregnancy reduces these risks substantially.^47,48 Major problems related to hyperglycemia during pregnancy are shown in table 1.

Several markers, such as age, race/ethnicity, BMI, history of type 2 diabetes in first-degree relatives, history of GDM, macrosomia, unexplained stillbirth, spontaneous abortion in previous pregnancies, excessive weight gain, presence of polycystic ovary syndrome, metabolic syndrome, polyhydramnios, and suspected macrosomia during current pregnancy, have been described to clinically identify women with high risk of GDM;⁴⁹ in practice, they fail to correctly identify more than half the women with GDM;^50–53 thus universal screening for hyperglycemia during pregnancy must be the standard practice.

Women diagnosed with GDM—are at high risk of developing type 2 diabetes within a few years of the pregnancy compared to women without previous history of GDM. A meta-analysis shows that women with GDM had an increased risk of developing type 2 diabetes [relative risk (RR) = 7.43; 95% confidence interval (CI) = 4.79–11.51].5

Table 1 Risks associated with hyperglycemia in pregnancy

Fetal risks	Maternal risks
• Spontaneous abortion, intrauterine death, and still birth • Lethal or handicapping congenital malformation • Shoulder dystocia and birth injury • Neonatal hypoglycemia • Infant respiratory distress syndrome	• Polyhydramnios • Pregnancy-induced hypertension and preeclampsia • Prolonged/obstructed labor-assisted delivery and Caesarean section • Uterine atonia and postpartum hemorrhage • Infections • Progression of retinopathy

Women within 5 years of a pregnancy complicated by GDM had a RR of 4.69, which is more than doubled to 9.34 in those who were examined more than 5 years postpartum.⁵⁴ The risk can be considerably reduced or the onset of diabetes considerably delayed by taking appropriate preventive steps in terms of postpartum weight loss and a healthy lifestyle.⁵⁵

Evidence is now emerging that women with past history of GDM also have a higher prevalence of the metabolic syndrome and an increased risk of CVD. In the years following a GDM pregnancy, women exhibit an enhanced cardiovascular risk profile and ultimately an increased incidence of CVD.⁵⁶ Over a median follow-up of 12.3 years women with GDM had a higher risk of CVD [adjusted hazard ratio (HR) = 1.66; 95% CI = 1.30–2.13, p < 0.001].⁵⁷ In another study over a 10-year follow-up period, after adjusting for age, ethnicity and comorbidities, such as preeclampsia and obesity, women with history of GDM had higher rates of cardiovascular morbidity including noninvasive cardiac diagnostic procedures [odds ratio (OR) = 1.8; 95% CI = 1.4–2.2], simple cardiovascular events (OR = 2.7; 95% CI = 2.4–3.1), and total cardiovascular hospitalizations (OR = 2.3; 95% CI = 2.0–2.5).⁵⁸

Without screening and diagnosis in pregnancy, the possibility of reducing risk in these women will be missed and in view of the dramatic increase in obesity and diabetes, we should accept that diagnosing and treating GDM is worthwhile.⁵⁹ Sceptics, however, continue to question whether screening women for GDM is cost-effective. Most cost effectiveness analysis in the past have only assessed benefits related to immediate pregnancy outcomes and not included long-term benefits.⁶⁰ A few recent studies show that GDM screening associated with postpartum lifestyle interventions for type 2 diabetes prevention is cost-effective in both high-income countries (United States, Israel) and low-income countries (India).^61–63

The concept of fetal programming and its consequences is paradigm changing. It highlights that pregnancy offers a window of opportunity to provide maternal care services, not only to reduce the traditionally known maternal and perinatal morbidity and mortality indicators, but also for intergenerational prevention of several chronic diseases, such as diabetes, arterial hypertension, CVD, and stroke. Thus, with one high-quality intervention related to maternal and child health services, it is now possible to achieve several objectives with far reaching health and economic benefits.³⁹

There are several barriers in achieving these objectives. These have been recently studied through a systematic review.⁶⁴ Knowledge of and adherence to existing 6GDM guidelines and procedure for screening and diagnosis seem suboptimal at best and arbitrary at worst, with no clear or consistent correlation to health provider, health system or client characteristics. Most women express commitment and motivation for behavior change to protect the health of their unborn baby, but knowledge about how to change is missing. Compliance to recommended treatment and advice is seen challenging and precious little is known about health system or societal factors that hinder compliance and what can be done to improve it. Immediately following a GDM pregnancy, many women when properly informed desire and intend to maintain healthy lifestyles to prevent future diabetes but find the effort challenging. Adherence to recommended postpartum screening and continued lifestyle modifications seems even lower. Here, some healthcare provider, health system and client related determinants and barriers have been identified. Studies reveal that sense of self-efficacy and social support is important. Noncompliance to screening or nonacceptance of diagnosis of GDM may be due to poor understanding of the consequences or fear of stigmatization and one needs to be careful not to create another platform for women to be blamed for adverse effects on their children's future health.

POLICY RECOMMENDATIONS

What can be recommended as a public health approach for GDM?

The recommendations made at the symposium “Diabetes – A Missing Link to Achieve Sexual and Reproductive Health in Asia-Pacific Region” at the 6th Asia-Pacific Conference on Sexual and Reproductive Health and Rights held in Yogyakarta, Indonesia⁶⁵ aptly sum up the issue.

Building awareness: Considering the magnitude of the problem, the seriousness of the consequences and the opportunity for improving health that it offers, raising awareness of the risks and consequences of diabetes in women including GDM must be given top priority. Awareness needs to be heightened amongst future mothers, general public, health professionals, and policy makers not only about the specific issue, but also about the importance of good health of women in general and during pregnancy, in particular
Advocacy: Ensure due attention is accorded to diabetes among women including GDM and program interventions are put in place. There are several platforms that provide the opportunity for advocacy. These include:
- – The International Conference on Population and Development (ICPD, 1994) recommendations, one of which was “all countries should strive to make accessible through the primary healthcare (PHC) system, reproductive health to all individuals of appropriate age, as soon as possible and no later than 2015.”
- – Millennium Development Goals (MDGs): Although diabetes is not a specific goal in the MDGs, countries are encouraged to implement programs for achieving MDGs according to their own needs and situations, and indeed the issue can clearly be taken up under MDG 5, “improve maternal health”. Besides MDG 5, the management of GDM and diabetes in women, in general, will also contribute to MDG 4 (child survival) and MDG 3 (gender equality).
  
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- – The Global Reproductive Health Strategy endorsed by the World Health Assembly in 2004, calls for strengthening and ensuring access to reproductive health and for reducing maternal morbidity and mortality. Again although specific mention of diabetes is not made, the strategies to improve reproductive health will have to take into account all matters that affect sexual and reproductive health, such as diabetes and GDM.
- – The Political Declaration at the UN HLM in September 2011 and the report of the UN Secretary General to the General Assembly before the UN HLM on NCDs. This report clearly states the need to create linkages between NCDs and Maternal and Child Health Programs. The report also raises concern that the rising prevalence of high blood pressure and GDM is increasing adverse outcomes of pregnancy and maternal health.³
Mainstreaming or integrating diabetes into Sexual and Reproductive Health and Rights Agenda: This is crucial in building and sustaining action—managers and providers of reproductive health services are in an advantageous position to integrate diabetes into their programs. There is need to systematically deliberate on appropriate interventions. A fitting beginning would be making policies for all pregnant women, with priority to high-risk women, to be tested for diabetes and to take the appropriate follow-up actions. In many developing countries where the problem of GDM is significant and requires intervention and health systems are weak, it may call for concerted efforts among international development partners to provide support. To get it right will require strengthening of health systems to further reinforce maternal and child care services at primary care level and integrating elements of NCD prevention and health promotion.⁶⁶
Using information technology: Having saved a mother with GDM with preeclampsia from dying of obstructed labor or postpartum hemorrhage and her large-for-gestational age baby; or a mother with severe malnutrition and anemia and her low-birth-weight baby, what can be done to ensure their future good health and prevent or significantly delay the onset of hypertension or type 2 diabetes? This will require integration of services and cost effective investments in information technology to identify and track high-risk individuals to enlighten, empower, and encourage them to adopt healthy living throughout life as well as empowering local community health workers to support and follow their progress. Enrolling, monitoring, and tracking GDM mothers during and after the pregnancy and their offsprings using information technology may be the most appropriate place to begin this health system transformation.⁶⁸
Operational research: Evidence generation through pilot programs is urgently needed to provide answers to several questions regarding policy formulation, program planning, and implementation.

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Chapter Notes

Hyperglycemia during Pregnancy: Epidemiology and Public Health Relevance1