This chapter should be cited as follows:
Lam AYR, Lim W, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.416423

The Continuous Textbook of Women’s Medicine Series – Obstetrics Module

Volume 8

Maternal medical health and disorders in pregnancy

Volume Editor: Dr Kenneth K Chen, Alpert Medical School of Brown University, USA Originating Editor: Professor Sandra Lowe

Chapter

Clinical Management of Diabetes in Pregnancy

First published: August 2021

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By completing 4 multiple-choice questions (randomly selected) after studying this chapter readers can qualify for Continuing Professional Development awards from FIGO plus a Study Completion Certificate from GLOWM
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INTRODUCTION

Diabetes mellitus is one of the most common metabolic conditions affecting pregnancy.^1,2 Diabetes in pregnancy can be categorized into pre-gestational diabetes mellitus (type 1 or type 2), and gestational diabetes mellitus (GDM). It is estimated that diabetes mellitus affects 1 in 6 (16.8%) pregnancies, with 13.6% from pre-gestational diabetes and 86.4% from GDM.³

Diabetes mellitus in pregnancy increases the risk of adverse maternal and neonatal outcomes. With comprehensive multidisciplinary care, as well as preconception counseling for pre-gestational diabetes mellitus, the risk of these complications can be mitigated.

PHYSIOLOGY: GLUCOSE HOMEOSTASIS IN PREGNANCY

During pregnancy, several metabolic adaptations occur to ensure adequate fetal growth and development, and to provide the mother with adequate energy stores for the increased demands of pregnancy.⁴

Glucose is the main energy substrate for the fetus and placenta. Fetal gluconeogenesis is minimal; thus, the fetus is highly reliant on placental supply of glucose from the maternal circulation. Glucose crosses the placenta by facilitated carrier-mediated diffusion through glucose transporter proteins (GLUTs). Maternal glucose concentrations exceeding that of the fetus will drive net glucose transport toward the fetus.⁵

Insulin sensitivity in the mother changes over the course of pregnancy (Figure 1). Early pregnancy is an anabolic state, involving increases in maternal fat stores and insulin sensitivity.⁶ This enables nutrient storage in early pregnancy to meet fetoplacental and maternal requirements during late gestation and lactation. Insulin sensitivity peaks between gestational weeks 9 and 16, resulting in reduced insulin requirements and a higher likelihood of hypoglycemia in insulin-treated women.⁷ Increasing insulin resistance and insulin requirements occur during the remainder of pregnancy, most pronounced in the third trimester.⁸ This is attributed to the effects of placental hormones, including human placental lactogen, progesterone, prolactin, placental growth hormone, and cortisol.⁹ In non-diabetic pregnancy, the increasing insulin resistance is accompanied by compensatory hyperinsulinemia. This compensatory rise in endogenous insulin production does not occur in women with pre-existing diabetes, resulting in greater maternal hyperglycemia, particularly postprandially.

Pregnancy is also a state of “accelerated starvation”, or an exaggerated response to overnight fasting compared to the non-pregnant state. This involves a greater fall in plasma glucose and amino acids, and a more pronounced rise in free fatty acids with enhanced ketogenesis during periods of fasting.⁶

POTENTIAL FETAL, NEONATAL, AND MATERNAL RISKS OF DIABETES IN PREGNANCY

Pre-gestational diabetes is associated with increased risks of adverse fetal, neonatal, and maternal outcomes during pregnancy (Table 1). The risk of adverse fetal and neonatal outcomes correlates largely with the degree of maternal glycemic control.^10,11

The adverse effects of GDM on pregnancy are largely similar, except for the risk of congenital malformations, which is mostly associated with pre-gestational diabetes mellitus. A meta-analysis by Balsells et al. suggested an increased risk of congenital malformations in gestational diabetes, albeit less than pre-gestational diabetes mellitus.¹² A limitation of this study was that potential contributing factors such as maternal age, obesity, and possible pre-conception hyperglycemia could not be ascertained.

These are summarized in Table 2.

PRECONCEPTION CARE

Structured care by a multidisciplinary team should start from the preconception period. Preconception care programs aim to empower women with pre-existing diabetes with knowledge on how to achieve a healthy and successful pregnancy. These programs have been shown to improve pregnancy preparation and reduce adverse pregnancy outcomes in women with T1DM and T2DM.^13,14 They also result in significant healthcare cost savings.^15,16,17

Preconception counseling

The American Diabetes Association recommends that preconception counseling should be part of routine diabetes care for women who have reproductive potential, starting at puberty.¹⁸

Preconception counseling is the responsibility of both primary care physicians and specialists who provide diabetes care. The content of preconception counseling may vary, depending on the patient’s current and future childbearing goals. However, crucial points to address include:

• Potential fetal, neonatal, and maternal risks of diabetes in pregnancy.
• The importance of planning a pregnancy, and the increased risks associated with an unplanned pregnancy.
• How to access preconception care.
• Contraception and family planning.
• What to do should an unexpected pregnancy occur.

Preconception care of women who are actively planning pregnancy

Women who are actively planning a pregnancy should do so in conjunction with a multidisciplinary team comprised of endocrinologists, diabetes nurse educators, and dieticians.

Glycemic control

Stringent glycemic control is crucial before withdrawing reliable contraception, as periconception maternal hyperglycemia is associated with a higher risk of spontaneous abortion and congenital malformations.^19,20 Periconception glycemic control has been reported as an independent predictor of congenital malformation (adjusted odds ratio [aOR] 1.3 [95% CI 1.2, 1.4] per 1% [11 mmol/mol] linear increase in HbA1c above 6.3% [45 mmol/mol]).¹⁹ The risk of spontaneous abortion in women with diabetes mellitus can be up to double that of non-diabetic women.^10,21 This risk appears to be reversed with optimal glycemic control.²²

Therefore, the goal is to minimize fetal exposure to maternal hyperglycemia during the crucial period of fetal organogenesis, which occurs prior to 7 weeks' gestation and often before a woman first discovers that she is pregnant.²³ Most International bodies (see Table 3) recommend a preconception HbA1c target of <48 mmol/mol or <6.5%, as this is associated with risk of congenital anomalies equivalent to the non-diabetic population.^18,19,24 There is little evidence regarding capillary blood glucose (CBG) or interstitial fluid glucose derived from continuous glucose monitoring (CGM) targets in women who are planning pregnancy. Despite the absence of such evidence, various International bodies have published their recommendations for such targets. The 2015 NICE guidelines recommend that women with T1DM and T2DM who are planning pregnancy aim for the same CBG targets as recommended for all people with T1DM.²⁵ These are CBG levels of 5–7 mmol/l upon waking, 4–7 mmol/l before meals at other times of the day, and 5–9 mmol/l at least 90 min post-meal.²⁶ The use of real-time CGM during preconception period did not yield significant pregnancy outcome benefits.²⁷ Currently, CGM has not been recommended in routine preconception care.

Medication optimization

Optimization of glucose-lowering medications

Women with T2DM on treatment with oral glucose-lowering agents who are planning to become pregnant should be counseled on the safety of these medications in pregnancy. The two main oral glucose-lowering agents used in pregnancy are metformin and glibenclamide (glyburide). ADA recommends converting oral agents to insulin therapy as a preferred management strategy.¹⁸ NICE recommends that metformin may continue to be used as an adjunct or alternative to insulin, when the potential benefits of improved glycemia outweighs the risk of harm. NICE also recommends ceasing all other blood glucose-lowering agents.³⁰ Diabetes Canada recommends continuing metformin and/or glibenclamide if glycemic control is optimal until pregnancy is achieved, while those on other agents should be switched to insulin therapy.²⁸

Insulin-treated women with diabetes seeking to conceive should be treated with multiple daily insulin injections (MDIIs) or continuous subcutaneous insulin infusion (CSII), as these regimens are more likely than premixed insulin therapy to achieve target blood glucose levels during the preconception period and during pregnancy. MDII therapy involves the use of intermediate- or long-acting basal insulin to inhibit hepatic glucose production and lipolysis throughout the day, and mealtime short- or rapid-acting insulin to cover dietary carbohydrate intake. CSII therapy involves the continuous infusion of rapid-acting insulin by an insulin pump. Changes to insulin regimens should be made in advance of withdrawing contraceptive measures.²⁹

Insulin

In view of transfer of glucose and gluconeogenic substrates to the fetus, women with T1DM have a two–threefold higher propensity for hypoglycemia, and a reduction in insulin requirements by approximately 10–20% in the first trimester.^31,32 From the second trimester, insulin requirements increase, plateauing at 36–37 weeks' gestation.³² Peak insulin requirements may be up to twice that pre-pregnancy.³² Immediately postpartum, diabetogenic pregnancy hormones are cleared rapidly, with swift recovery of insulin sensitivity. The dosage of glucose lowering medications must therefore be reduced postpartum. In the initial few postpartum days, insulin requirements are approximately half of that needed at the time of delivery.¹⁸

Table 4 describes the time-action profiles of various insulin preparations in non-pregnant populations. There may be large inter- and intra-individual variability in the onset, peak, and duration of action of the various types of insulin.

Human insulins

Prior to the development of analog insulins, human insulins were the only formulations available for use in pregnancy. Soluble (regular) insulin is a quick-acting human insulin formulation, which has a slower onset and a longer duration of action than endogenous insulin. This confers an increased risk of undesirable postprandial hypoglycemia.³⁴ Neutral protamine Hagedorn (NPH) insulin is an intermediate-acting human insulin formulation, which has a duration of action of 16–18 h and must be administered twice a day to provide adequate 24-h basal insulin cover. NPH insulin also has a peak at 4–10 h post-injection, which may confer higher risks of hypoglycemia in the fasted state.³³

Insulin analogs

Rapid-acting insulin analogs include lispro, aspart, and glulisine. These can be used as mealtime insulin in MDII therapy, or in an insulin pump. Rapid-acting insulin analogs have faster onset of action, earlier time to peak, and shorter duration of action than regular insulin, mimicking endogenous insulin physiology more closely. This allows rapid-acting insulin analogs to provide superior control of postprandial hyperglycemia and reduce risks of hypoglycemia in the late post-meal period. Superior control of postprandial hyperglycemia is crucial, as the postprandial glucose level after the first trimester is the most important contributor to the risk of macrosomia.³⁷ Compared to regular insulin, lispro and aspart use in women with pre-gestational DM was associated with similar obstetric, fetal, and neonatal outcomes.^{38,39,40,41,42} Lispro and aspart have been approved by the European Medicines Agency for use in pregnancy, and are FDA category B. There has been no published data on the use of glulisine in pregnancy, and it is not FDA approved for use in pregnancy.

Long-acting insulin analogs include detemir and glargine. They are “peakless” and have a longer duration of action compared to NPH insulin. The efficacy and safety of detemir has been established in a multinational randomized controlled trial involving pregnant women with T1DM.^43,44 Detemir has demonstrated lower fasting glucose levels, similar hypoglycemia rates and perinatal outcomes, and noninferior glycemic control compared to NPH.^41,43 Detemir has been approved for use by the European Medicines Agency for use in pregnancy, and is FDA category B. Some women may require twice-daily dosing of detemir, due to inter-individual variability in the duration of action.

Glargine has a higher receptor affinity for the type 1 insulin-like growth factor receptor. This has led to theoretical concerns about undesirable effects of glargine on mitogenicity, fetal growth, and diabetic retinopathy.^33,45 Limited data on the glargine use in women with pre-gestational DM suggest comparable maternal, fetal, and neonatal outcomes compared with other basal insulins.^46,47,48 Insulin glargine does not carry an FDA classification consistent with current labeling.

Newer insulin analogs

Glargine U-300 is a concentrated form of glargine, containing 300 units/ml instead of 100 units/ml. Insulin degludec is an ultra-long-acting insulin with a duration of action exceeding 42 h. They are both not currently approved for use in pregnancy.^49,50,51

Fiasp is a rapid-acting insulin analog containing insulin aspart with the addition of vitamin B3 and L-Arginine to hasten absorption. There are no available data with Fiasp in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.⁵²

Metformin

The recommendation by various international groups for the use of oral glucose lowering agents in pregnancy vary considerably.⁵³ Some international groups have expressed extreme reluctance regarding the use of metformin, such as ADA and ACOG,^18,54 whilst others include metformin as an option particularly for gestational diabetes, such as CDA, NICE, SMFM, HKCOG.^55,28,30,56

Metformin alone is not considered adequate treatment for women with pre-existing T2DM in pregnancy as they are unlikely to achieve adequate glycemic control. Up to 43% of women primarily treated with metformin during pregnancy required supplementary insulin therapy to achieve optimal glycemic control.^57,58,59

NICE recommends that women with T2DM may use metformin as an adjunct or alternative to insulin in the preconception period and during pregnancy, when the likely benefits from improved blood glucose outweigh the potential for harm.²⁵

Metformin crosses the placenta readily and metformin levels in the fetal circulation have been reported to be half or the same as the maternal metformin levels.^60,61 Despite metformin crossing the placenta, there is reassuring data regarding the short-term safety of metformin use in both early and late pregnancy. Several meta-analyzes showed no evidence of an increased risk for major malformations and adverse neonatal outcomes with first-trimester metformin use.^62,63,64

However, there is limited long-term follow-up information, especially concerning metformin use in pregnancies complicated by pre-existing diabetes although good data on pediatric follow up has been published from its use for gestational diabetes.⁶⁵ At age 7, 290 children from the Australian cohort were assessed and there were no differences in offspring measures. Two years later, 99 children all from the New Zealand cohort were reviewed. Of note, their mothers had a higher BMI at enrolment than those randomized to insulin (35.4 versus 32.0, p = 0.08)). These children were larger by measures of weight, arm, and waist circumferences, waist: height (p <0.05), body mass index, triceps skin fold (p: 0.05), DEXA fat mass and lean mass (p: 0.07).⁵⁶ Body fat percentage was similar by DEXA and bioimpedence. Visceral adipose tissue and liver fat were similar by magnetic resonance imaging (MRI). Metabolic markers including HbA1c, fasting glucose, fasting lipids, adiponectin, and leptin were all similar.

Further data regarding the long-term impact of these small but statistical differences in body composition is awaited along with the results of newer trials including the offspring from the EMPOWaR and MOP trials may shed more light as these studies compared metformin with placebo rather than insulin. The MiTy Kids' trial will assess the children of mothers with type 2 diabetes receiving metformin in addition to insulin.^66,67,68

Cessation/substitution of potentially teratogenic medications

Women should be reviewed with a plan to cease potentially teratogenic or fetotoxic medications either in advance of conception to allow substitution with more appropriate medications or as early as possible after confirmation of pregnancy. These include ACE inhibitors (ACE-I), angiotensin receptor blockers (ARB), and statins (see below).^69,70

Folic acid supplementation

Folate requirements increase to 600 ug/day during pregnancy. Women with diabetes who are planning a pregnancy should receive folic acid supplements to reduce the risk of neural tube defects.^71,72 Supplementation should be started at least 1 month prior to conception, as neural-tube development begins as early as the third week after conception.⁷³ Although not evidence based, a higher dose (5 mg/day) is sometimes recommended for women with diabetes and should be given until week 12 of gestation, after which the dose may be reduced to 0.4 to 1.0 mg/day.^25,29

Screening and management of diabetes-related complications

Management of diabetic retinopathy: preconception, antenatal, and postpartum care

preconception

Women should undergo retinal examination prior to conception to accurately determine the presence and severity of diabetic retinopathy (DR).¹⁸ Ophthalmologist referral should be made if severe non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), or diabetic macular edema is detected at screening. Women should be counseled about the risks of worsening retinopathy during pregnancy and up to 1 year postpartum, especially if retinopathy is severe.^74,75,76,77 Overall, 10 to 26% of women without retinopathy may develop background retinopathy changes during pregnancy. However, these are generally mild, do not require intervention, and usually regress postpartum.^74,77,78,79 If the degree of pre-existing retinopathy warrants therapy, The Endocrine Society recommends deferring conception until the retinopathy has been treated and stabilized.²⁹

Antenatal and postpartum

Dilated eye examinations should occur ideally before pregnancy or in the first trimester. Patients should be monitored every trimester and for 1 year postpartum as indicated by the degree of retinopathy.¹⁸ As hypertension and poor glycemic control are modifiable risk factors for DR progression, these should be optimized. Rapid improvement of hyperglycemia is associated with potential worsening of pre-existing diabetic retinopathy. The postulated mechanisms include (i) reduced blood flow or increased ischemia, and (ii) elevated insulin-like growth factor 1 (IGF-1) secondary to improved glycemia. IGF-1 levels are also elevated due to the pregnancy state.⁸⁰ Despite this, retinopathy should not delay blood glucose optimization in women with a high HbA1c in early pregnancy.⁸¹

Pan-retinal laser photocoagulation may be used safely and effectively for treatment of PDR during pregnancy.⁸² Anti-VEGF medications (Ranibizumab, Aflibercept and Bevacizumab) are used for treatment of DME in non-pregnant patients. These agents have been assigned FDA pregnancy category C, as animal studies have shown evidence of embryo-fetal toxicity, but there are no controlled data in human pregnancy and a risk–benefit approach should be taken regarding their use.⁸³

Management of diabetic nephropathy: preconception, antenatal, and postpartum care

A diagnosis of diabetic nephropathy (DN) is made based on the presence of albuminuria and/or reduced estimated glomerular filtration ratio (eGFR) in the absence of other primary causes of kidney damage.⁸⁴ It is important to note that during pregnancy, renal hyperfiltration results in underestimation of eGFR, hence one should use creatinine level to monitor progression of nephropathy.^85,86

Preconception

Women planning a pregnancy should undergo screening for DN with measurement of serum creatinine and evaluation of albuminuria with a spot urine albumin-to-creatinine ratio or a 24-h urinary protein measurement. Women who are found to have DN preconception should be counseled that pregnancies complicated by DN are associated with increased rates of cesarean delivery, pre-eclampsia, preterm delivery, IUGR and perinatal mortality. However, with improved antenatal care, women in developed countries with diabetic nephropathy largely achieve successful pregnancy outcomes. In one retrospective cohort study, the perinatal mortality rate was 3%, comparable to patients with DM but no renal involvement.⁸⁷

Women with moderate-to-severe renal insufficiency with serum creatinine ≥124 umol/l (1.4 mg/dl) have significant risks of accelerated DN progression in pregnancy, which may not be reversible.⁸⁸ Women with a serum creatinine ≥120 umol/l, urine ACR >30 mg/mmol or eGFR <45 ml/min should see a nephrologist before discontinuation of contraception. In women with more advanced renal dysfunction, pregnancy may lead to permanent worsening of renal function and accelerate progression to end stage renal failure. These women need specialist counseling as dialysis or transplant may be required prior to, or even during, pregnancy.

Blockade of the renin-angiotensin-aldosterone system (RAAS) with either an ACE-i or ARB is recommended in non-pregnant patients to decrease proteinuria and slow the progression of diabetic nephropathy.^89,90 Use of these agents during pregnancy is not recommended.

Evidence of ACE-I and ARB-associated teratogenicity for first-trimester exposures is conflicting. In contrast, there is unequivocal associated fetal renin angiotensin aldosterone blockade for second- and third-trimester exposures, that may result in renal failure oligohydramnios, intrauterine growth retardation (IUGR), and death.^69,91

In women with significant proteinuria who are planning to conceive, stopping RAAS blockade may cause worsening proteinuria and more rapid decline in renal function, especially as successfully conceiving may take an indeterminate period.

Therefore, the risks and benefits of conceiving while taking these agents must be carefully deliberated with the patient, preferably by a nephrologist.^{70,92,93,94,95} Enalapril and captopril are considered compatible with breastfeeding by the American Academy of Pediatrics, and may be restarted after delivery.⁹⁶

Antenatal and postpartum

Blood pressure control using agents which are safe in pregnancy is crucial for the management of DN during pregnancy. Blood pressure-lowering therapy should be started if blood pressure consistently exceeds 135/85 mmHg. Blood pressure targets should not range lower than 120/80 mmHg, as lower targets may impair fetal growth.¹⁸ Prospective studies in pregnant women with T1DM treated to blood pressure <135/85 mmHg and urinary albumin excretion <300 mg/24 h showed a reduction in pre-eclampsia and preterm delivery.^97,98 Safe and effective antihypertensive agents, which can be substituted for ACE inhibitors and angiotensin receptor blockers while actively planning or during pregnancy, include methyldopa, nifedipine, labetalol, diltiazem, prazosin, and clonidine.^18,29

There is no guidance on the schedule of care for women with CKD, however, their renal function and obstetrics progress should be monitored regularly antenatally and in the postpartum period. One suggested approach is to monitor serum creatinine and urine albumin/creatinine ratio at least 4 weekly, and at least 2 weekly beginning at 32 weeks' gestation.⁹⁹

Cardiovascular disease

Although ischemic heart disease is rarely encountered in pregnancy, it is a major cause of maternal morbidity and mortality.¹⁰⁰ Women who have symptoms of, or documented ischemic heart disease should be referred to a cardiologist prior to withdrawal of contraception. Pregnancy is contraindicated in severe cardiac disease.¹⁰¹

Assessment for and management of co-existing medical conditions

Hypertension

Due to vasodilation in normal pregnancy, blood pressure decreases early in pregnancy, nadirs mid-gestation, and continues to rise until delivery. Previously, the early drop in diastolic blood pressure was reported to range between 10 and 15 mmHg. A recent study seemed to suggest a much less profound drop of between 0 and 2 mmHg from 12 weeks' gestation to nadir at around 19 weeks' gestation, with a subsequent increase of between 8 and 10 mmHg to delivery.¹⁰²

Hypertensive disorders in pregnancy are common in women with diabetes, with an overall incidence of 45% in T1DM and 40% in T2DM. T1DM is more often associated with pre-eclampsia, while T2DM is more often associated with chronic hypertension.¹⁰³

Most guidelines recommend a blood pressure target of <135/85 mmHg for women with pre-existing diabetes.^{21,30,54,104,105} Blood pressures lower than 120/80 mmHg should be avoided.

Hyperlipidemia

Women with pre-existing diabetes may have concomitant metabolic syndrome and dyslipidemia. Several hormonally mediated changes in lipid metabolism occur in pregnancy: very low-density lipoprotein cholesterol (VLDL) cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C) increase, with peak levels occurring at term. High-density lipoprotein cholesterol (HDL-C) rises by mid-gestation and declines at term.¹⁰⁶

Statins are not recommended for use during pregnancy. It is unlikely that withdrawing statins for the limited duration of conception, pregnancy, and breastfeeding will have significant long-term adverse health outcomes.^18,29

Women who have significant hypertriglyceridemia should receive dietary counseling to achieve a low-fat diet with less than 20% of calories from fat. Omega-3 fatty acids (3–4 g per day) lower TG levels and prevent essential fatty acid deficiency, which may otherwise result from a fat-restricted diet.¹⁰⁶ Routine use of fibrates and niacin during pregnancy is not recommended.²⁹

Thyroid disorders

Autoimmune thyroid disease such as Hashimoto thyroiditis and Graves’ disease occur more frequently in women with T1DM. Women with T1DM desiring pregnancy should have their serum TSH measured before withdrawing contraception. Thyroid peroxidase antibodies (TPOAb) should be measured if not done previously. Women with T1DM are also more prone to postpartum thyroid dysfunction, with an incidence of 25%.¹⁰⁷ They should be screened for postpartum thyroiditis with serum TSH measurements at 3 and 6 months postpartum.²⁹

Weight management and nutrition

Obesity is common in patients with T2DM, and increasingly prevalent in patients with T1DM.¹⁰⁸Being overweight and obese are independent risk factors for poor perinatal outcomes. Women with a body mass index (BMI) ≥27 kg/m² desiring pregnancy should be given advice on weight loss prior to conception.⁸¹

ANTENATAL CARE

Antenatal care of pre-existing diabetes in pregnancy

Glycemic targets and monitoring

Women are more insulin sensitive in the first trimester, but become increasingly insulin resistant in the second and third trimesters.¹⁰⁹ Summarized data from 11 studies evaluating third-trimester glucose levels of non-diabetic pregnant women suggests that the average fasting glucose is 3.9 ± 0.4 mmol/l, 1-h postprandial glucose is 5.3–6.8 mmol/l and 2-h postprandial glucose is 4.9–6.1 mmol/l.¹¹⁰

Currently, there are no adequately powered randomized controlled trials evaluating the impact of different glycemic targets for diabetes in pregnancy. Targets recommended by various guidelines are summarized in Table 5. Most of these targets are extrapolated from studies evaluating normoglycemia in pregnancy, and pre-gestational and gestational DM.^{111,112,113,114}

Glycated hemoglobin (HbA1c)

In the non-pregnant state, glycated hemoglobin (HbA1c) reflects average blood glucose concentrations during the preceding 12 weeks.¹¹⁶ In pregnancy, HbA1c values tend to be lower due to increased red cell turnover.¹¹⁷ HbA1c may therefore be monitored more frequently during pregnancy, for example once every 4 weeks.¹¹⁸ HbA1c does not reveal the degree of glycemic variability, or postprandial hyperglycemia, which drives macrosomia.¹¹⁹ Therefore, self-monitoring of blood glucose is the primary method of glucose monitoring in pregnancy.¹⁸

Elevated first-trimester HbA1c is associated with poor outcomes such as stillbirth, spontaneous abortion, and congenital abnormalities (see Figure 2).^24,120,121 Elevated third-trimester HbA1c is associated with macrosomia, preterm delivery, and pre-eclampsia.^122,123 Most guidelines suggest a HbA1c target of <6.0–6.5%.^{21,30,54,104,105} While striving for these tight targets, avoidance of hypoglycemia remains important due to associated risks of low birth weight, in addition to the usual risks of hypoglycemia.¹¹⁹

Capillary blood glucose monitoring

Frequent self-monitoring of blood glucose (SMBG) is required for intensification of DM treatment in pregnancy. Postprandial glucose is superior to preprandial glucose as a predictor of fetal macrosomia.^112,123,124

SMBG should be performed preprandial, postprandial (1 or 2 h after the start of a meal), and at bedtime.^{21,30,54,104,115} The timing of postprandial glucose checks should ideally capture peak postprandial glucose levels. A study utilizing continuous glucose monitoring demonstrated that the average peak postprandial glucose level occurs 90 min after a meal, with significant variation between individuals.¹²⁵ Multiple factors influence this, such as variable gastric emptying, meal timings, glycemic index, or macronutrient content of meals.^126,127,128

Newer methods of blood glucose monitoring

The need for frequent fingerpricks for capillary blood glucose (CBG) monitoring is cumbersome and painful. Newer methods of glucose monitoring involve measurement of the interstitial fluid glucose by continuous blood glucose monitoring (CGM) and flash glucose monitoring systems.¹²⁹ However, these technologies are more costly and not all have been validated for use in pregnancy.

CGM devices measure interstitial glucose at 5–10 s intervals, providing about 288 values per day.¹²⁹ There are two types of CGM: real-time and retrospective CGM. Glucose sensors for CGM devices typically last for a week. At least two CBG readings per day are required for sensor calibration. CGM may identify glucose excursions, which go undetected by CBG testing.^125,130,131

CONCEPTT (Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes Trial) was a randomized controlled trial of real-time CGM in addition to CBG monitoring, versus CBG monitoring alone for pregnant women with T1DM. CGM use resulted in small improvements in HbA1c, greater time-in-target, fewer hypoglycemic episodes, and better neonatal outcomes.²⁷ Patients benefit from CGM when it is used continuously rather than intermittently.^132,133,134 In women with type 1 diabetes, higher mean glucose levels, higher glucose variability and less time in target range were associated with an increased risk of LGA and neonatal composite outcomes.¹³⁵

The Abbott Freestyle Libre flash glucose monitoring system (flash-GMS) similarly measures interstitial fluid glucose. A reader or smartphone is used to scan a glucose sensor worn on the back of the arm. There is no need for calibration with CBG readings, and the sensor lasts for up to 14 days.^136,137 Flash-GMS is not approved for use in pregnancy in most countries.^138,139 One study compared the accuracy of flash-GMS to CBG monitoring and found the mean absolute difference to be acceptable at 11.8%.^21,140 A more recent study revealed concerns regarding accuracy of flash-GMS in pregnancy, with readings tending to be lower than CBG readings, which may result in divergent treatment decisions.²¹ There are no available randomized controlled trials to validate the use of flash-GMS in pregnancy.

The ADA recommended that CGM should not be used as a replacement for CBG monitoring but rather as a supplementary modality of glycemic monitoring.¹⁸ The use of flash-GMS in pregnancy is not currently advocated by any guideline.

Adjuvant therapies for women with diabetes in pregnancy

Aspirin for pre-eclampsia prevention

Pre-eclampsia is a multisystem disorder of pregnancy, usually defined as hypertension and proteinuria diagnosed after 20 weeks' gestation. Women with pre-existing DM have an increased risk of pre-eclampsia, further increased in those with longer histories of DM and vascular complications.^141,142

Low-dose aspirin (80–150 mg) reduces the risk of pre-eclampsia when initiated before 16 weeks' gestation and taken throughout pregnancy.¹⁴³ Efficacy likely increases with increasing aspirin dosages, and when aspirin is taken at night.^144,145,146 However, the optimal aspirin dose is unclear.

Lifestyle management and medical nutrition therapy

Medical nutrition therapy

Nutrition therapy is the cornerstone of DM management. All individuals with DM in pregnancy should be referred to a registered dietitian for individualized medical nutritional therapy. The goals are to provide enough nutrients for mother and fetus, achieve optimal weight gain, and maintain ideal glycemic control.

There is no optimal diet for diabetes in pregnancy. The Institute of Medicine (IOM) has suggested a rough macronutrient distribution for all populations: 40–60% carbohydrates, 30% protein, and 10% fats. Carbohydrate is the primary nutrient affecting maternal glucose levels. The minimum carbohydrate requirements increase in pregnancy from 130 g/day to 175 g/day.¹⁴⁷

Carbohydrate requirements should be individualized based on weight-gain targets, insulin doses, glucose readings, and patient preference. Individuals should choose carbohydrates that have low glycemic index to improve postprandial glycemic control.¹⁴⁸

Dietary calcium and iodine should be increased due to increased pregnancy requirements.

Weight management

Overweight or obese women who experience pregnancy weight gain greater than IOM recommendations have more adverse outcomes, including increased macrosomia, LGA, and higher rates of cesarean deliveries.^149,150

Although not specific to women with pre-gestational diabetes, IOM guidelines recommend weight gain in pregnancy based on a woman’s pre-pregnancy weight or BMI (Table 6).

Weight loss is not recommended during pregnancy because of potential adverse fetal outcomes. All weight-loss efforts in women who are overweight or obese should take place prior to conception.

Diabetic ketoacidosis in pregnancy

Diabetic ketoacidosis (DKA) in pregnancy is associated with 4–15% maternal and 10–35% neonatal mortality.^21,152,153 Due to constant transplacental transfer of glucose and nutrients, DKA in pregnancy may present atypically with euglycemic DKA.¹⁵⁴

Physiological changes in pregnancy makes one more susceptible to DKA. Firstly, in pregnancy, fat breakdown, ketosis, and protein catabolism occur quicker. Secondly, there is reduced buffering capacity in view of increased alveolar minute ventilation, with resultant compensatory increase in renal excretion of bicarbonate. Lastly, the presence of diabetogenic hormones such as human placental lactogen, free cortisol, prolactin, and progesterone, results in increased insulin resistance.¹⁵⁵ The usual precipitants for DKA are intercurrent illness, hyperemesis, non-compliance, and medications such as β2-agonists and steroids, which may be given for tocolysis and for fetal lung maturation.

Management of DKA in pregnancy is like that in non-pregnant individuals, involving rapid stabilization of maternal biochemistry with aggressive intravenous hydration, intravenous insulin infusion and close monitoring for fetal distress. All maternity units caring for women with diabetes should have protocols available for management of this rare but life-threatening complication. Admission to a high-dependency setting capable of monitoring both mother and fetus is essential. Non-reassuring fetal heart rate tracings are common, but resolve quickly with treatment of DKA.¹⁵⁶ Therefore, emergency delivery should rarely be required.

There are no long-term studies on the outcomes of offspring born to mothers with higher levels of serum ketones. However, there are some concerns about neurocognitive and behavioral detrimental effects. One study analyzed children who were born to women who had high blood ketones and fatty acids during the third trimester and found that they had lower scores of behavioral and intellectual developments at age 2 and 5 years.^157,158

Gestational diabetes

See chapter on screening and pathophysiology

Management of gestational diabetes (GDM) begins with glucose monitoring and modifications to diet and exercise. Pharmacologic treatment should be initiated when target glucose levels cannot be achieved through diet modifications and exercise. Recommended glucose targets for patients with gestational diabetes remain controversial and a range of targets have been recommended but never tested prospectively. These are summarized in Table 7.

The various international groups vary considerably regarding recommended pharmacotherapy in gestational diabetes mellitus.⁵³ Some international guidelines suggested insulin as first line pharmacotherapy should lifestyle modifications fail to achieve optimal glycemic control.^18,104,160 Others recommended a trial of oral glucose lowering agents (e.g., metformin, glibenclamide), with subsequent addition of insulin therapy if oral glucose-lowering agents are insufficient to achieve satisfactory glycemia.^29,30 These oral agents are known to cross the placenta, and fail to provide adequate glycemic control in a substantial proportion of women with GDM.^161,162,163 In the MIG trial, up to 50% of women on metformin therapy required supplementary insulin later in pregnancy.¹⁶⁴ Similarly, glibenclamide appeared to have a failure rate of 20%, with these women requiring insulin therapy.¹⁶⁵

Compared to women with normoglycemic pregnancies, women with GDM have a higher risk of developing T2DM. There is heterogeneity in the relative risks quoted by various studies, which could be attributed by variables such as ethnicity, BMI, family history of DM, and age. A systemic analysis and meta-analysis by Bellamy et al. suggested an at least sevenfold increased risk of T2DM for women with GDM (RR 7.43, 95% CI 4.79–11.51).¹⁶⁶ In view of this increased risk, all women with GDM should undergo a 75-g, 2-hour OGTT at 4–12 weeks' postpartum, and repeat testing every 1–3 years thereafter if this is normal.¹⁸

Risk assessment/antenatal screening

Pregnancies complicated by pre-existing or GDM should be managed as high-risk pregnancies. These women do not represent a homogenous group. The following categories are at particular risk:

• Long duration of pre-existing T1DM or T2DM
• Advanced maternal age
• Very young mothers and adolescents
• Obesity
• Women with DM complications
• Co-existing medical conditions (e.g., hypertension)
• T1DM with frequent hypoglycemia
• Women with a poor obstetric history
• Smokers
• Poor compliance and frequent failure to attend

All women with pre-existing DM should be offered a first-trimester scan for accurate dating. Diabetes adversely affects the screening performance of second-trimester maternal serum screening test for fetal chromosomal anomalies. Therefore, mothers with DM should commence antenatal care early, and undergo the first trimester combined screening test using fetal nuchal translucency measurements and maternal biochemistry.

Symptoms and signs of pre-eclampsia should be sought at every visit after 20 weeks given the higher risk of those with both GDM and pre-existing DM (Table 8). Those with pre-existing hypertension, nephropathy, and a previous history of pre-eclampsia are at particular risk.

For women with pre-existing DM, a detailed fetal anomaly scan at 18–20 weeks and a detailed fetal echocardiography at 20 weeks should be performed.³⁰ Serial growth scans are performed thereafter in the third trimester. For both GDM and pre-existing DM, routine antenatal growth scans are performed at 28, 32, and 36 weeks to detect excessive fetal growth.²⁵

Subsequent serial ultrasonography is targeted towards surveillance of fetal growth, specifically macrosomia and polyhydramnios. Biometry should be charted as abdominal circumference correlates with birth weight. In a study evaluating T1DM women, fetal abdominal circumference measurements exceeding the 90th percentile at 30–33 weeks' gestation has a 88% sensitivity and 83% specificity for the prediction of birth weight greater than the 90th centile.¹⁷⁶ Ultrasound-guided management has been suggested with commencement of insulin in women with GDM if the fetal AC is >70th centile.^165,177 A meta-analysis showed an increased need for insulin (ten women with GDM needing insulin to prevent one newborn with an abnormal birthweight).¹⁷⁸ Conversely, another study had shown that a higher maternal glucose threshold to start insulin therapy may be permissible if the fetal abdominal circumference was <70th percentile, allowing more women to avoid insulin.¹⁷⁹

Shoulder dystocia/perinatal trauma

Birth injuries and brachial plexus injuries are rarely associated with GDM, even if it is untreated. The results are discordant and the risk seems to be mainly associated with macrosomia.¹⁸⁰

The NICE diabetes' guideline recommends that pregnant women with diabetes who have a normally grown fetus should be offered elective birth through induction of labor, or by elective cesarean section if indicated, after 38 completed weeks.²⁵

Elective cesarean section should be considered to reduce the potential morbidity for pregnancies complicated by pre-existing or gestational diabetes, regardless of treatment, with an estimated fetal weight of greater than 4.5 kg.¹⁸¹

Studies involving the largest number of vaginal deliveries (34,800 to 267,228) report incidences of shoulder dystocia between 0.58% and 0.70%. Infants of diabetic mothers have a two- to fourfold increased risk of shoulder dystocia compared with infants of the same birth weight born to non-diabetic mothers.¹⁸²

The incidence of brachial plexus injury is 1–2/1000 births. Most recover spontaneously or with physiotherapy.¹⁸² All birth units looking after diabetic pregnancies should be trained in the recognition and prompt team management of shoulder dystocia.

Timing and mode of delivery

The timing and mode of delivery of mothers with DM on insulin should be individualized. Where possible this should jointly involve the multidisciplinary team and the mother, taking into account maternal factors including glycemic control, the presence of other pregnancy complications, past obstetric history and fetal factors including size. Following the well-publicized Montgomery versus Lanarkshire case, which involved a severe case of shoulder dystocia in a diabetic mother resulting in significant permanent neonatal injury, the mother’s views and concerns, which are of material importance to her, should be taken on board in the decision making.¹⁸³ Women should be advised about the risks of macrosomia with potential risks of difficult labor requiring emergency cesarean section, and risks of shoulder dystocia with risks of birth injuries.

Two arguments have been advanced for the delivery of an infant of a diabetic mother 1 or 2 weeks before term. One is the avoidance of unexpected fetal death. The second is the avoidance of fetal trauma associated with vaginal delivery of a large infant of a diabetic mother.

The timing of 38 completed weeks' gestation in the presence of good glycemic control is therefore a compromise between the competing risks of respiratory distress syndrome in the newborn delivered earlier against the risk of fetal demise if the pregnancy continues. Older studies suggested an increased still birth rate in women with GDM, but newer studies using contemporary screening and management approaches have not confirmed this.¹⁸⁴ The absolute risk of stillbirth and infant death in GDM was found to be very equal or even lower than non-diabetic controls, possibly because of closer antenatal monitoring.¹⁸⁵ NICE recommends delivery after 38 completed weeks in diabetes in pregnancy.²⁵

However, if DM is poorly controlled or affects the fetus, it is not recommended that the pregnancy exceed 38 completed weeks' gestation, and consideration be given to earlier delivery on a case-by-case basis. One study randomized women with a suspected macrosomic fetus to induction of labor between 37 and 39 weeks, or expectant management up to 41 weeks. It demonstrated that IOL was associated with better rates of spontaneous vaginal births (RR 1.14, 95% Cl 1.01–1.29), reduced rates of shoulder dystocia (RR 0.32, 95% Cl 0.12–0.85).¹⁸⁶

Generally, cesarean sections (CSs) should be recommended on the basis of obstetric indications. Where the timing has been decided, and in the absence of any indication for cesarean section, induction of labor would be performed with an aim towards achieving vaginal delivery.

Estimating the birth weight at which CSs should be recommended to prevent shoulder dystocia and perinatal trauma is debatable. The RCOG suggests that elective CSs should be considered to reduce the potential morbidity for pregnancies complicated by both pre-existing and gestational diabetes, regardless of treatment, when the estimated fetal weight exceeds 4.5 kg.¹⁸²

MANAGEMENT DURING LABOR AND DELIVERY

Management of labor

Several considerations are necessary for a woman with diabetes prior to admission for delivery. Delivery is best performed in a facility which has a 24-h anesthesia service, a special care baby unit/Neonatal Intensive Care Unit, and staff who are trained in the care of women with DM and their infants.

Latent phase

The woman would be allowed a normal diet and encouraged to ambulate.

Active phase

For both the mother and the fetus, labor is a stress test: the mother has lower insulin requirements because of increased calorie consumption and reduced intake. The fetus must cope with the intermittent hypoxia produced by contractions and unpredictable glucose levels.

Fetal monitoring during labor

NICE suggests continuous electronic fetal monitoring in pregnancies with diabetes.²⁵

Second/third stage of labor

The combination of fetal macrosomia, prolonged labor, and mid-cavity delivery carries a high risk of shoulder dystocia, especially if vacuum-assisted delivery is carried out.¹⁸⁷ Any decision for instrumental delivery performed for a prolonged second stage needs careful consideration, and perhaps as a trial in theater, especially if the labor has been induced and the first stage prolonged.

Analgesia and anesthesia

The obstetric anesthetist is a vital member of the multidisciplinary team.¹⁸⁸ Timely communication is important and the relevant considerations would include:

• If the diabetes is pre-existing or gestational
• The presence of co-existing diabetes' complications
• The degree of glycemic control
• The presence of obstetric complications (e.g., pre-eclampsia)
• Drugs administered

NICE suggests that women with diabetes and comorbidities such as obesity or autonomic neuropathy should be offered an anesthetic assessment in the third trimester.²⁵ If general anesthesia is used, blood glucose should be monitored regularly (every 30 min) from induction of general anesthesia until after the baby is born and the woman is fully conscious. For intravenous pre-hydration before operative anesthesia, a balanced electrolyte solution (0.9% saline) is used rather than a dextrose solution to avoid a large glucose load, which reduces umbilical cord pH and can cause neonatal hypoglycemia.^189,190

Management of preterm labor

Preterm delivery

Two studies have specifically analyzed the risk of spontaneous premature birth in gestational diabetic mothers.^191,192 In a cohort study of more than 46,000 pregnancies (after exclusion of women with pre-gestational diabetes), the risk of spontaneous preterm delivery increased with the level of maternal blood glucose, independently of any perinatal complications associated with prematurity. The RR was 1.42 (1.15–1.77) for GDM pregnancies.¹⁹³ In a study by Ostlund et al., premature delivery before 37 weeks was more common in women with GDM (11.4% versus 5.4%, p = 0.005) and was one of the main reasons for NICU admission. After adjustment for other prematurity-related risk factors (hypertension, pre-eclampsia, maternal BMI), hyperglycemia was a risk factor for premature birth <37 weeks (OR = 2.0 [1.0–3.9]).¹⁹⁴

Tocolytics

The oxytocin receptor antagonist (Atosiban) and calcium channel blockers (Nifedipine) can be used without any specific precautions. However, beta2-agonists have an unfavorable risk: benefit ratio as they cause hyperglycemia.

Corticosteroids

Prenatal corticosteroids, when clearly indicated, should not be avoided solely because of their potential to cause hyperglycemia. Women in whom antenatal corticosteroids are indicated may require hospitalization for closer monitoring of their glucose profile in anticipation of increased insulin requirements. In one study of steroids given to mothers with T1DM, it was noted that the insulin requirement increased by 20% on day 1 and 4, and by 40% on day 2 and 3, with a return to pre-existing requirements by day 6 and 7.¹⁹⁵

There is no benefit in the late administration of corticosteroids (i.e., delivery close to 37 weeks) to mothers with DM, in view of the risks of hyperglycemia.¹⁹⁶

Peripartum glycemic control

The main goal of good peripartum glycemic control is to minimize the incidence of neonatal hypoglycemia, which is thought to be due to fetal hyperinsulinism induced by maternal hyperglycemia. The target peripartum blood glucose level is between 4 and 7 mmol/l.^18,25,104 This can be achieved by means of intravenous regular insulin infusion and dextrose drip, with hourly capillary blood glucose monitoring and infusion rate adjustments.^197,198

Women receiving insulin pump therapy can continue to use their insulin pump in labor, if they are physically capable of doing so. They usually require suspension of the basal insulin during active labor, and may resume their pre-pregnancy pump settings postpartum.¹⁸

POSTPARTUM CARE

Lactation

Women with plans to breastfeed should be educated about the benefits of breastfeeding for the baby, and for their own metabolic health.¹⁹⁹ Medications that are safe for breastfeeding should be prescribed.

Pharmacotherapy

Breastfeeding lowers blood glucose levels. Women may require further insulin dose reductions, or a carbohydrate snack prior to breastfeeding to avoid hypoglycemia.

Women with T1DM may generally resume their pre-pregnancy insulin doses. Women with T2DM may continue metformin therapy, as it is excreted only minimally in breast milk. Glyburide and glipizide are undetectable in breast milk, and may also be used during breastfeeding.²⁰⁰ Limited information is available for other sulphonylureas, other oral glucose-lowering medications and GLP-1 receptor analogs, and their use is not recommended during lactation. If additional glucose-lowering is required, insulin may be added.

Contraception

Contraception is an often overlooked yet extremely crucial element of management. It should be discussed with the patient before she is discharged postnatally, particularly if the woman is at risk of non-attendance at the postnatal clinic, in which case postpartum contraception is desirable. Important considerations include the presence of diabetes' complications, breastfeeding, smoking, age, and plans for future fertility. Contraception is often necessary for effective pre-pregnancy care and optimization of glycemic control before a planned pregnancy. The WHO has issued excellent guidelines regarding contraceptive use.²⁰¹

SUMMARY

While several challenges are present in the management of pregnancies with diabetes, the combined efforts of the multidisciplinary team and the woman living with diabetes can make the experience of pregnancy and motherhood a successful and joyous one.

PRACTICE RECOMMENDATIONS

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