Diabetes in Pregnancy

Abstract

Pregnancy is usually a joyous event for most women and their families in many cultures. However, in certain situations, this celebratory moment is marred by various maternal complications; chief among them is diabetes mellitus. Over eighty percent of diabetes in pregnancy is attributed to Gestational Diabetes Mellitus (GDM). Also, GDM presents a higher risk of affected mothers developing diabetes later in the future. There is a growing prevalence of GDM which necessitates the need for closer monitoring and more screening of pregnant women. This can be achieved by following set guidelines of countries and public health organisations to ensure safer pregnancies, safer deliveries, and healthier babies.

1. Introduction

Pregnancy is usually a joyous event for most women and their families in many cultures. However, in certain situations, this celebratory moment is marred by various maternal complications; chief among them is diabetes mellitus.

Diabetes mellitus, also known as diabetes, is a metabolic disorder characterised by high blood glucose levels over a long period of time [1]. In pregnant women, it manifests as either gestational diabetes mellitus (GDM) or pre-existing diabetes [2]. Gestational diabetes mellitus (GDM) is defined as glucose intolerance of variable degree that is first discovered during pregnancy [3], while pre-existing diabetes is glucose intolerance existing before pregnancy.

Diabetes in pregnancy is associated with a number of poor outcomes during the pregnancy period, during childbirth, and the immediate postpartum period [2]. Infants of mothers with pre-existing diabetes mellitus also experience double the risk of serious injury at birth, triple the likelihood of caesarean delivery and quadruple the incidence of new-born intensive care unit (NICU) admission [4].

In this chapter, we’ll be exploring the prevalence of diabetes in pregnancy, the body’s adaptation to pregnancy, the pathophysiology of diabetes in pregnancy, associated complications, diagnostic criteria for GDM and PDM, the management of this condition, and recommendations to reduce its prevalence.

1.1 Epidemiology

Statistics show that about 87–90% of diabetes in pregnancy is GDM, whereas 10–13% is pre-existing diabetes [5]. Further data also shows that diabetes complicates 2–45% of pregnancies across the globe, depending on the region, population characteristics, and diagnostic criteria [6, 7, 8].

1.2 How the body adapts to pregnancy

In pregnancy, a woman’s body goes through significant anatomic and physiological changes to provide the support needed to nurture the growing foetus, while still maintaining normal body functions required for survival [9]. Some of these changes are due to hormonal production before conception. These changes then consolidate throughout the period of pregnancy, affecting every system and organ in the woman’s body. For the majority of women who experience uncomplicated pregnancy, these changes are reversed following delivery. It is important to understand the normal physiologic adaptations of the body to pregnancy, so we can recognise when an abnormal occurrence comes into the picture. Although the major system affected by GDM is the endocrine system, it is still important to explore some of the changes in the other systems of the body. This is because hyperglycaemia can affect multiple body systems.

1.2.1 Cardiovascular changes in pregnancy

Beginning in the first trimester, changes are seen in the cardiovascular system, with cardiac output increasing by 20% as early as the eighth week of gestation [10]. This is mediated primarily by peripheral vasodilation which produces a 25–30% fall in systemic vascular resistance. To compensate for this fall, the heart increases the cardiac output to around 40% throughout pregnancy. This is achieved by a mix of increased stroke volume and heart rate. There is also a compensatory increase in plasma volume to about 50%, with a lesser increase in the red blood cell mass, and a fall in platelet count [11]. Some of these changes also lead to a hypercoagulable state in pregnancy.

Some examination findings may include collapsing pulse and murmur which may be erroneously interpreted as pathological.

1.2.2 Renal

There is a 40% fall in systemic vascular resistance by the sixth week of pregnancy which affects the renal vasculature. As a consequence of renal vasodilatation, renal plasma flow and glomerular filtration rate (GFR) both increase, compared to non-pregnant levels, by 40–65% and 50–85%, respectively [12].

1.2.3 Respiratory system

The demand for oxygen increases significantly during pregnancy due to the increased metabolic rate [10].

1.2.4 Endocrine system

Changes occur in the endocrine system across the adrenal and thyroid glands, and also across the metabolic processes of the body. There is a change in how the body metabolises glucose, protein and lipids. More details will be shed specifically on glucose metabolism further down in the chapter.

1.3 Pathophysiology of diabetes

Diabetes Mellitus develops majorly as a result of either defective insulin secretion from the beta cells of the pancreas or a defect in the insulin-sensitive cells which reduces the body’s response to the available insulin [1]. A dysfunction in any of these two processes leads to abnormally high glucose levels.

1.3.1 Glucose regulation in a healthy adult

The human body utilises glucose as an immediate source of energy. The optimal level of glucose for proper body functioning is usually about 70–100 mg/dL [13]. Any value below or above this range constitutes a problem. Although the body can utilise other fuels, like protein and fat, as a source of energy, the breakdown of these alternative fuels creates ketoacids which makes the body acidic. This can lead to metabolic acidosis—which is a non-optimal state [14].

Regulation of glucose in the blood is largely carried out by the endocrine hormones in the pancreas via a process of continuous negative feedback loop. The main hormones involved in this process are insulin, glucagon, somatostatin and amylin. Insulin, formed in the beta cells of the pancreas, is the main hormone in this process and it lowers blood glucose levels. Conversely, Glucagon increases blood glucose levels. Somatostatin, produced by the pancreas’s delta cells, helps balance insulin and glucagon levels, while the Delta cells of the pancreas help to balance the levels of insulin and glucagon. Amylin is the hormone that induces the feeling of fullness following a meal, thus preventing overeating.

For glucose to be utilised by the body, it is transported at a cellular level through the body tissues. This transportation is regulated by insulin which aids the diffusion rate of glucose into cells. After glucose enters the cell, it is converted to glucose-6-phosphate which can either be used immediately or be stored as glycogen.

1.3.2 Glucose regulation during pregnancy

As earlier explained, during a healthy pregnancy, a woman’s body undergoes various physiological changes to meet the demands of the growing foetus in her womb. The adaptive change that is important for glucose metabolism occurs in the metabolic systems. During this period the insulin sensitivity of the woman’s body varies to meet the requirements of pregnancy. In the early phase of gestation, insulin sensitivity is increased thus promoting the uptake of glucose into storage for the later part of pregnancy. As gestation progresses, there is a surge of several hormones including placental hormones, oestrogen, cortisol, placental growth hormone, placental lactogen, progesterone and leptin. This surge leads to a state of insulin resistance which elevates blood glucose levels. This insulin-resistant state leads to the endogenous production of glucose via the breakdown of protein and fats, further increasing the level of blood glucose. The glucose is transported to the foetus via the placenta to aid growth in-utero.

Some evidence shows that the maternal body compensates for this state of resistance through hypertrophy and hyperplasia of pancreatic beta-cells to produce more insulin. Placental hormones are important in this process as the maternal state of insulin sensitivity is reversed after a few days following the foetus and placenta delivery. Gestational Diabetes often occurs when there is an imbalance in this process.

1.4 Presentation and diagnostic criteria

Diabetes in pregnancy often presents with similar symptoms as diabetes in the rest of the population. These symptoms include increased thirst, increased urination, and increased appetite. However, these symptoms may either be absent in pregnancy or falsely attributed to pregnancy symptoms thus the diagnosis may be overlooked. Typically, diabetes in pregnancy goes undiagnosed until blood glucose is checked at antenatal visits.

It is important to note that pregnant women who are categorised as ‘low-risk’ do not require glucose testing. However, this category is limited to women who meet all the following criteria:

• Age lesser than 25 years.

• Normal weight before pregnancy.

• Member of an ethnic group with a low prevalence of GDM.

• No known history of diabetes in first-degree relatives.

• No personal history of abnormal glucose tolerance.

• No personal history of poor obstetric outcomes.

1.4.1 Risk factors for DM

There are certain factors that predispose pregnant women to a higher risk of GDM. Some of these include [15]:

1. Obesity, particularly severe obesity.

2. First-degree relatives living with type 2 DM.

3. Medical history of GDM, or delivery history of large for gestational age (LGA) infant.

4. Polycystic ovarian syndrome (PCOS).

5. Recurrent glycosuria positive result.

It should be noted that screening for GDM usually occurs between weeks 24–28—second or third trimester—of the gestational period. As such, high levels of glucose seen in the first trimester are often grouped as pre-pregnancy diabetes.

1.4.2 Risk factors for GDM

Pregnant women in this category are at a higher risk of developing GDM [15]:

1. Factors with the pregnant woman:

   • 35 years old or older;

   • overweight or obese prior to pregnancy;

   • personal history of impaired glucose tolerance;

   • Polycystic Ovarian Syndrome (PCOS)

2. A family history of diabetes

3. Abnormal pregnancy and/or delivery history:

   • unexplained foetal death, stillbirth or miscarriage;

   • foetal macrosomia;

   • foetal malformations;

   • polyhydramnios;

   • Gestational Diabetes Mellitus (GDM)

4. Conditions in present pregnancy:

   • large for gestational age;

   • polyhydramnios;

   • recurrent vulvovaginal candidiasis

1.4.3 Diagnostic criteria

Normal blood glucose levels range from 70 mg/dL (3.9 mmol/L) to 100 mg/dL (5.6 mmol/L). When the fasting blood glucose (FBG) is between 100 and 125 mg/dL (5.6–6.9 mmol/L), changes in lifestyle and monitoring glycaemia are recommended [13]. However, when the fasting blood glucose is 126 mg/dL (7 mmol/L) or higher on two separate occasions, a diagnosis of diabetes mellitus is made. The diagnostic standard cut-off point for diagnosing GDM is the 50-g Glucose Challenge Test with ≥7.8 mmol/L (140 mg/dl) as the cut-off point [15].

1.4.3.1 Diagnosis of pregnancy complicated by DM

Diagnosis for pregnancy complicated by DM can be diagnosed when any of these conditions exist [15]:

1. Glycosylated haemoglobin A1c (GHbA1c) ≥6.5%);

2. FPG ≥7.0 mmol/L (126 mg/dl);

3. 2-hour OGTT≥11.1 mmol/L (200 mg/dl);

4. Classic signs of hyperglycaemia or hyperglycaemic crises symptoms, meanwhile random plasma glucose ≥11.1 mmol/L (200 mg/dl)

1.4.3.2 Diagnostic standard for GDM

The Oral Glucose Tolerance Test (OGTT) is the gold standard for diagnosing GDM. The procedure involves eating a balanced diet containing at least 150 g of carbohydrates per day for 3 days prior to the test, which is followed by a period of fasting (no ingestion of any food) for 8 to 14 hours before the test.

The first blood sample is taken by 9 a.m. for measurement of the fasting blood glucose. After that, the patient is given a drink of 75-g glucose load (75-g glucose dissolved in 300 ml of water, consumed within 5 minutes). Following the ingestion of the glucose solution, blood samples are taken at 1 and 2-hour intervals to measure the blood glucose levels post-ingestion. During the waiting period, smoking, eating, or drinking any other fluids is prohibited.

1.4.3.3 Diagnostic approaches***

The American College of Obstetricians and Gynaecologists recommends a two-step procedure for diagnosing GDM [3, 15]. If after 1 hour the blood glucose level is more than 7.8 mmol/L (140 mg/dL), a 100 g dose of glucose is given. The diagnosis of gestational diabetes is thus defined by a blood glucose level meeting or exceeding the cut-off values of at least two intervals:

• Before glucose intake (fasting): 5.3 mmol/L (95 mg/dL).

• 1 hour post-consumption of glucose solution: 10.0 mmol/L (180 mg/dL).

• 2 hours post-consumption of glucose solution: 8.6 mmol/L (155 mg/dL).

• 3 hours post-consumption of glucose solution: 7.8 mmol/L (140 mg/dL).

One-step approach: a diagnostic 75-g OGTT is performed at the 24th–28th week of gestation without the prior 50-g GCT screening. The one-step approach can be applied to high-risk pregnant women with GDM, or pregnant women not previously diagnosed with overt diabetes in well-conditioned medical institutions.

Two-step approach: measure FPG (step 1). If FPG ≥5.1 mmol/L, GDM can be diagnosed; if 4.4 mmol/L ≤ FPG <5.1 mmol/L, diagnostic 75-g OGTT (step 2) is followed to diagnose GDM. Or perform an initial screening by measuring the plasma or serum glucose concentration after a 50-g GCT (step 1) and perform a diagnostic OGTT (step 2) on that subset of women exceeding the glucose threshold value on the GCT. If 50-g GCT ≥11.1 mmol/L, FPG is performed to diagnose GDM; if the FPG value is normal, 75-g OGTT should be performed as soon as possible.

The cut-off points of glucose values of 75-g OGTT: 0 h, 5.1 mmol/L; 1 hour, 10.0 mmol/L; 2 hours, 8.5 mmol/L. The diagnosis of GDM can then be made when any one value is met or exceeded.

1.5 Complications of diabetes in pregnancy

Diabetes in pregnancy is associated with a number of complications in the mother and unborn foetus [16]. These complications can also extend beyond the duration of pregnancy. These complications can be divided into maternal complications and foetal complications.

1.5.1 Maternal complications

1.5.1.1 Miscarriage

Statistics show that women with PDM have a 9–14% rate of miscarriage [16]. Available data further suggests that there is a strong association between the degree of glycaemic control before pregnancy and the rate at which miscarriage occurs in women with PDM. In cases of more long-standing disease (>10 years) with poor control, the miscarriage rates can reach as high as 44%. Thankfully, the miscarriage rate normalises when glycaemic control is optimal.

1.5.1.2 Progression to chronic diabetes mellitus

In ideal conditions, GDM resolves after birth with glucose levels reverting to normal without further treatment. However, studies also show that women with GDM have a 16-year cumulative incidence of diabetes (60%) following the initial diabetic episode in pregnancy [17].

1.5.1.3 Predisposition to other complications of pregnancy

DM in pregnancy increases the risk of the mother developing other pregnancy complications such as pregnancy-induced hypertension, premature rupture of membranes, haemorrhage in the antepartum or postpartum period, and other possible complications [18]. Compared with women who do not have GDM, women with GDM have a higher risk of delivery by caesarean section.

1.5.2 Foetal complications

1.5.2.1 Premature delivery

Babies of mothers with GDM are at a higher risk of being born before the estimated due date, leading to premature delivery [19, 20].

1.5.2.2 Problems at delivery

These babies are also more likely to have several problems at birth ranging from macrosomia, small for date, foetal distress, hypoglycaemia, shoulder dystocia, birth asphyxia among others [19, 20, 21].

1.5.2.3 Birth defects

There is also a higher likelihood of such babies being born with birth defects and also having a higher risk of congenital heart diseases compared to the rest of the population [21].

1.5.2.4 Obesity and DM in future

The effects of being born to a mother with GDM can very well linger beyond infancy and childhood, predisposing the individual to a risk of obesity and DM later in life.

2. Social determinants and effects of gestational diabetes outcomes

DM as a leading cause of NCD morbidity and mortality, especially in the vulnerable state of pregnancy has varying effects on the mother and developing child. Furthermore, as one of the most common metabolic disorders in pregnancy, its effects transcend into different aspects of maternal and neonatal health and wellbeing, including the public health space.

Some of these effects on mothers’ health and physical wellbeing are hyperglycaemia, possible preeclampsia, high-risk delivery of a macrosomic baby; and if unmanaged, altered sensorium, eclampsia, obstetric problems and possible mortality. Likewise, different health complications of diabetes worsened by pregnancy include diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, and diabetes-induced heart disease, i.e., cardiomyopathy, heart failure, ischemic heart disease and coronary heart disease. Some of these effects and complications are irreversible and take a strain on the financial and mental well-being of the pregnant woman and family involved. These complications can increase the direct or indirect cost of adequate care—with more time spent in the health care facility—which might have a poor prognosis among LSE women in rural areas, also worsening the maternal morbidity and mortality indices [21, 22].

Effects on foetal growth in-utero such as intrauterine growth retardation, and malformation of developing organs and systems in babies (also referred to as diabetic embryopathy), usually occurring in the first and second trimester, can lead to anxiety, depression and different types of miscarriage for the pregnant women. These foetal malformations are mostly found in the central nervous and cardiovascular systems, and sometimes with craniofacial defects. Common examples are Microcephaly, Meningomyelocele, Tetralogy of Fallot, persistent truncus arteriosus, Hypoplastic left or right heart syndrome, septal defects (Atrioventricular), Microphthalmia, Cleft lip/palate, Hemifacial microsomia and other neural tube defects [21].

Other effects surrounding delivery or occurring postnatally are preterm delivery, prematurity, low birth weight, other perinatal morbidities, neurodevelopmental abnormalities causing mental and psychomotor disabilities such as increased chances of Attention Deficit Hyperactivity Disorder (ADHD), gross and fine motor anomalies, learning difficulties (especially in speech and language), Autism Spectrum Disorder with possible brain damage, as well as perinatal mortality in the delivered neonates. The underlying metabolic processes that result in these effects could be associated with maternal hyperglycaemia causing increased oxidative stress, hypoxia, apoptosis, and epigenetic or metabolic changes in developing foetuses [21].

The socio-economic, health-economic, and psychosocial cost of these outcomes on the new mother, caregivers, healthcare professionals, family, society, and the entire population at large, is significantly wide and demanding with features of reduced productivity and preventable resource allocation for more judicious use. These also contribute to neonatal or under 5 morbidity and mortality figures. However, other cumulative factors that contribute to the actualization of these effects and their progress into complications for both mother and child vary from genetics to diet, or nutrition (especially breastfeeding infants for positive effect and development), compliance and environmental exposure [21].

3. Management

Management of GDM and PDM involves a variety of procedures. To start with, regular monitoring is important. Prevention and a combination of medication and lifestyle intervention have proven to obliterate or slow down the maternal and neonatal effects or complications of diabetes in pregnancy. During antenatal care in pregnancy; regular clinical checks on glycaemic control and other associated morbidities such as hypertension, preventive measures including dietary counselling, physical activity for adequate weight control, early identification of risk for complications from diabetes and constant communication with the pregnant woman on her current health state and the foetus are important [21, 23].

In most cases, the therapeutic management of GDM is with insulin therapy as oral hypoglycemic agents have not been proven to be safe due to concerns about potential teratogenicity and transport of glucose across the placenta [24, 25].

3.1 Monitoring

• Maternal metabolic surveillance should be directed at detecting hyperglycaemia severe enough to increase risks to the foetus. Daily self-monitoring of blood glucose (SMBG) appears superior to intermittent office monitoring of plasma glucose [26]. However, this will be initiated for those with a high risk of GDM or those already diagnosed with GDM.

• Glucose is found in the urine of over half of pregnant women, as such routine urine glucose checks may not be useful in GDM [27]. Any positive urine test result should be followed up with a blood glucose test.

• For women treated with insulin, limited evidence indicates that postprandial monitoring is superior to pre-prandial monitoring [28]. However, the success of either approach depends on the glycaemic targets that are set and achieved.

• Maternal surveillance should include blood pressure and urine protein monitoring to detect hypertensive disorders.

• Increased surveillance for pregnancies at risk for foetal demise is appropriate.

• The initiation, frequency, and specific techniques used to assess foetal well-being will depend on the cumulative risk the foetus bears from GDM and any other medical/obstetric conditions present.

• Early assessment for asymmetric foetal growth by ultrasonography, may aid in identifying foetuses that can benefit from maternal insulin therapy [29].

Likewise, for curative measures and at delivery, strict glycaemic surveillance and control with appropriate medications, monitored labour management and are the keystone of perinatal care for expectant mothers with diabetes, while new treatments/remedies for/that would benefit mother and child and prevent effects or complication of this state are continuously being worked on in the clinical and social settings [20].

3.2 Recommendations

In line with a globally or regionally accepted management for diabetes in pregnancy—a multidisciplinary team approach, multilevel healthcare system/setting, local policies and standardised clinical practice guidelines should be made available for continuation of care for both mother and child, especially in the postpartum period, to reduce the effect and complications of diabetes in pregnancy.

This is important because most available guidelines are made for the advanced or global north setting, majorly excluding point-of-contact care guidelines (asides from screening and referral) for basic primary or community-based healthcare centres, where most pregnant women first present or have their deliveries in the developing or global south countries. Likewise, more research work needs to be carried out on the social determinants of DM outcomes in mothers and babies, as it pertains to different localities and socio-economic classes across the globe.

4. Conclusion

GDM and PDM are important complications which can affect the pregnancy of different women. To ensure the appropriate management and delivery of a healthy child by a healthy mother, it is important to adequately screen high-risk mothers and implements the appropriate management strategies per guidelines.

Acknowledgments

The authors would like to thank the academic society that has done extensive work on investigating diabetes in pregnancy.

Conflict of interest

The authors declare no conflicts of interest.