REVIEW

A Review of the Pathophysiology and

Management of Diabetes in Pregnancy
Aoife M. Egan, MB, BCh, PhD; Margaret L. Dow, MD; and Adrian Vella, MD

Abstract

Diabetes is a common metabolic complication of pregnancy and affected women fall into two sub-
groups: women with pre-existing diabetes and those with gestational diabetes mellitus (GDM). When
pregnancy is affected by diabetes, both mother and infant are at increased risk for multiple adverse
outcomes. A multidisciplinary approach to care before, during, and after pregnancy is effective in
reducing these risks. The PubMed database was searched for English language studies and guidelines
relating to diabetes in pregnancy. The following search terms were used alone and in combination:
diabetes, pregnancy, gestational diabetes, GDM, prepregnancy, and preconception. A date restriction was
not applied. Results were reviewed by the authors and selected for inclusion based on relevance to the
topic. Additional articles were identified by manually searching reference lists of included articles.
Using data from this search we herein summarize the evidence relating to pathophysiology and
management of diabetes in pregnancy. We discuss areas of controversy including the method and
timing of diagnosis of GDM, and choice of pharmacologic agents to treat hyperglycemia during
pregnancy. Therefore, this review is intended to serve as a practical guide for clinicians who are caring
for women with diabetes and their infants.
ª 2020 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2020;95(12):2734-2746

M
ore than 21 million births are lower rates of congenital malformations
affected by maternal diabetes and stillbirth compared with those with
From the Departments of worldwide each year.1 In 2016 in type 1 diabetes.8 GDM is diabetes diagnosed
Endocrinology (A.M.E., A.V.)
and Obstetrics and Gynecol- the United States, pre-existing (including in the second or third trimester of pregnancy
ogy (M.L.D.), Mayo Clinic, type 1 or 2) and gestational diabetes mellitus in the absence of overt diabetes before gesta-
Rochester, MN.
(GDM) had a prevalence of 0.9% and 6.0%, tion.9 Women with GDM have a 30%
respectively, among women who delivered increased risk of cesarean delivery and a
a live infant.2 Recently, efforts have 50% increased risk of gestational hyperten-
redoubled to diagnose and treat diabetes sion. Their offspring have a 70% increased
earlier in pregnancy.3 Diabetes during preg- risk of prematurity and are 30% more likely
nancy has significant implications for the to be LGA.10 GDM is strongly associated
maternal-fetal dyad. Type 1 diabetes is asso- with future maternal type 2 diabetes11; there
ciated with a two- to five-fold increased risk is increasing evidence that exposure to all
of major complications including congenital forms of diabetes in pregnancy confers a
anomaly, stillbirth, and neonatal death; and higher risk of childhood adiposity, insulin
50% of infants experience complications resistance, and adverse neurodevelopmental
such as prematurity, large for gestational outcomes.11-14
age (LGA), and admission to a neonatal The aim of this review is to provide an
intensive care unit.4-6 Women with type 2 update on the pathophysiology and manage-
diabetes typically have less dramatic changes ment of diabetes in pregnancy.
in glucose metabolism and are less prone to
diabetic ketoacidosis (DKA) and caesarean METHODS
delivery compared with those with type 1 The PubMed database was searched for
diabetes.7,8 However, studies are conflicting English language studies and guidelines
on whether their offspring have similar or relating to diabetes in pregnancy. The

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DIABETES IN PREGNANCY

following search terms were used alone and

in combination: diabetes, pregnancy, gesta- ARTICLE HIGHLIGHTS
tional diabetes, GDM, prepregnancy, and pre- d Annually, maternal diabetes affects more than 21 million births
conception. A date restriction was not
worldwide.
applied. Results were reviewed by the au-
thors and selected for inclusion based on d Women may be categorized into those with pre-existing dia-
relevance to the topic. Additional articles betes (including either type 1 or type 2 diabetes) or those with
were identified by manually searching refer- gestational diabetes mellitus where diabetes develops during,
ence lists of included articles. and is a consequence of, pregnancy.
d Gestational diabetes mellitus is typically diagnosed in the late
PATHOPHYSIOLOGY second trimester of pregnancy and resolves following delivery,
although long-term risk of developing type 2 diabetes is
Normal Maternal Glucose Metabolism
substantial.
Although early pregnancy is a time of rela-
tive insulin sensitivity, this sensitivity d Women of childbearing age with pre-existing diabetes should
decreases sharply in the second and early receive pre-pregnancy care to optimize their medical status
third trimester of pregnancy.15,16 This before conception.
reduces insulin-dependent glucose uptake d During pregnancy, intensive glycemic control and close follow-
in tissues such as muscle and fat and serves up by a multidisciplinary team is essential to ensure the best
as a maternal physiologic adaption to pre-
possible clinical outcomes.
serve carbohydrate for the rapidly growing
fetus.17 In addition, impaired insulin-
mediated suppression of maternal lipolysis
and fat oxidation provides fatty acids as an abnormality of glucose tolerance were hy-
alternative energy source.18 This process is perglycemia before 22 weeks’ gestation and a
likely mediated by a number of factors low first-phase insulin response during an
including an increase in progesterone, estro- intravenous glucose tolerance test.26 The
gen, cortisol, and human placental growth first-phase insulin response to intravenous
hormone.19-21 Typically a two- to three-fold glucose represents an early burst of insulin
increase in insulin production is sufficient release and is followed by a gradually
to meet this challenge, and studies confirm increasing phase of insulin secretion over
an increase in pancreatic fractional beta cell several hours.27 This first-phase response
area in human pregnancy.22 It would appear plays a significant role in maintaining
that insulin secretion increases significantly glucose homeostasis in healthy individuals
by early pregnancy, even before increases and is lost in the early stages of diabetes.28
in insulin resistance.23 In animal models, The degree of insulin resistance in the
lactogenic hormones seem to stimulate this third trimester of pregnancy is not an
process through a direct effect on beta cells; important predictor of abnormal glucose
however, it is uncertain if this is the case in tolerance within 6 months after GDM. This
humans.24,25 suggests a chronic beta cell defect exacer-
bated by pregnancy.15,29,30
GDM. Frequently, the insulin secretory
response is inadequate and hyperglycemia Pre-existing Diabetes. Women with pre-
develops, leading to a diagnosis of GDM in existing diabetes face similar changes in in-
women without pre-existing diabetes. sulin resistance. The ability of the beta cell to
Limited evidence from physiologic studies in compensate is more profoundly impaired in
such women suggests that subtle abnormal- type 2 diabetes and negligible in type 1 dia-
ities of insulin secretion precede pregnancy betes. Although the clinical impact may be
and persist after parturition. In one such insignificant, a pregnancy-induced increase
study of high-risk women with GDM, inde- in C-peptide (suggesting improved beta cell
pendent predictors of a postpartum function) has even been observed in women
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 MAYO CLINIC PROCEEDINGS

with established type 1 diabetes and unde- steal phenomenon” and once established, is
tectable C-peptide levels at baseline.31,32 believed to favor a high glucose flux with
stimulation of fetal triacylglycerol formation
Early Pregnancy Hyperglycemia d Fetal and deposition of excess fetal adipose tissue
Effects even when maternal blood glucose is
Maternal hyperglycemia both peri- normal.40 The Pedersen hypothesis was
conceptually and during the first trimester developed in an era when most cases of hy-
of pregnancy can result in major birth perglycemia in pregnancy were due to type
defects and pregnancy loss.5,33 Whereas 1 diabetes. However, during the past 50
these outcomes typically affect pregnancies years, increases in maternal obesity have
with pre-existing diabetes, in women with changed this landscape, and the metabolic
GDM the risk of malformations increases milieu to which the developing fetus is
with maternal fasting glucose, body mass in- exposed is undoubtedly different in obesity
dex (BMI), and earlier gestational age at (with or without type 2 diabetes).42 For
diagnosis.34 Most commonly these malfor- example, maternal triglyceride levels are
mations affect the cardiac or central nervous 40% to 50% higher in mothers with obesity
system and include transposition of the great and GDM compared with normal-weight
arteries, septal defects, neural tube defects, mothers during pregnancy. Placental lipases
and caudal regression syndrome d the latter can hydrolyze maternal triglycerides to free
of which is almost universally associated fatty acids for fetal-placental availability,
with diabetes in pregnancy.33,35 Oxidative and there is increasing evidence that these
stress has been suggested to play a role in are also important substrates for fetal fat
the development of such complications, but accretion and overgrowth.43
further studies of mechanism are Excessive fetal growth may be expressed
needed.36,37 Although maternal hyperglyce- as macrosomia or LGA. Macrosomia is typi-
mia in the second and third trimester is typi- cally defined as an absolute birthweight of
cally associated with excessive fetal growth, greater than 4000 to 4500 g, whereas LGA
women with pre-existing diabetes may have refers to a birthweight greater than 90th
impaired fetal growth through two mecha- percentile for gestational age. Affected in-
nisms. Maternal microvascular disease con- fants are at risk for asphyxia, perinatal death,
fers a significant risk of intrauterine growth shoulder dystocia with or without birth
restriction, whereas hyperglycemia in the injury, respiratory distress, and hypoglyce-
first trimester may impair placental develop- mia.38 Additional metabolic complications
ment and subsequent fetal growth through that may be present at birth and arise from
poorly understood mechanisms.38,39 maternal hyperglycemia include hypocalce-
mia, hypomagnesemia, polycythemia, and
Fetal Overnutrition hyperbilirubinemia.
Maternal glucose is transferred to the fetus
across the placenta down a concentration Long-Term Offspring Outcomes
gradient determined by both maternal and It is difficult to separate the role of fetal
fetal glucose levels. Maternal hyperglycemia exposure to maternal hyperglycemia from
therefore promotes fetal hyperglycemia and factors such as maternal obesity and envi-
stimulates fetal insulin secretion.40 This pro- ronmental exposures. However, offspring of
cess constitutes the “hyperglycemia-hyperin- mothers with pre-existing diabetes or GDM
sulinemia hypothesis” or the “Pedersen are heavier at birth and at every age with
hypothesis.”41 Taking this process a step an increased risk of type 2 diabetes
further, fetal glucose use increases with fetal compared with those born to mothers
hyperinsulinemia, lowering fetal glucose and without diabetes.38 Epigenetic variation
increasing the transplacental glucose established in utero may explain the link
gradient and rate of glucose transfer. This between the uterine milieu and later disease
is described as the “fetoplacental glucose susceptibility.44 Although a number of
n n
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DIABETES IN PREGNANCY

offspring methylation variants appear to be with pre-existing diabetes before and during
independently associated with GDM and pregnancy can reduce the risk of major
type 2 diabetes, these observations have not adverse outcomes including congenital mal-
led to the development of biomarkers to pre- formations and stillbirths.4,33
dict which children are most at risk of meta-
bolic disease.44,45 Another emerging concern
MANAGEMENT
is the potentially negative effect of maternal
diabetes on offspring cognitive development, Preconception Care
but reports have been conflicting and causal Pre-Existing Diabetes. Preconception coun-
pathways are unclear.46 Type 1 diabetes risk seling should form part of every consultation
is increased in offspring with maternal or for women of reproductive age with diabetes.
paternal diabetes of any type, and appears Long-acting, reversible forms of contracep-
even higher with paternal diabetes.47 tion such as intrauterine devices or
implantable progestin are highly effective
Impact of Treatment on Outcomes and should be recommended until preg-
GDM. In the case of GDM, two randomized nancy is desired.51 For women who are
controlled trials confirm that treating actively contemplating pregnancy, targeted
women from 24- to 28-wk gestation im- pre-pregnancy care delivered by a multidis-
proves pregnancy outcomes. In the Austra- ciplinary team on a 1- to 2-month basis is
lian Carbohydrate Intolerance Study in both clinically and cost effective
Pregnant Women study, 490 women with (Table 1).52,53 An A1c target of less than or
GDM were assigned to an intervention arm equal to 6.5% is associated with the lowest
that involved dietary advice, glucose moni- risk of congenital anomalies,54 and a goal
toring, and insulin therapy as required and A1c of less than 6.0% is recommended.55
510 women were assigned to routine care. However, this is not always achievable due
There was a reduction in the primary to issues such as hypoglycemia, and women
outcome of serious perinatal complications should be encouraged that any improvement
(including death, shoulder dystocia, bone in HbA1c will improve their chances of a
fracture, and nerve palsy) when GDM was positive pregnancy outcome. Hypoglycemia
treated.48 Landon et al49 randomized women management should be reviewed and
with mild GDM to either nutritional coun- glucagon prescribed if insulin is used. Pre-
seling and diet therapy along with insulin if conception visits should include baseline
needed (treatment group) or usual prenatal laboratory investigations (including thyroid
care (control group). They found that more function) and assistance with smoking
intensive care of women with mild GDM cessation if indicated. Folic acid should be
reduced the risk of secondary outcomes prescribed and continued until 12-wk
including fetal overgrowth, shoulder gestation. Advisory groups vary on the sug-
dystocia, caesarean delivery, and hyperten- gested dose of folic acid. A minimum of 400
sive disorders. There was no effect on the mg per day is advised55,56; however, higher
primary outcome, a composite of stillbirth or doses of up to 5 mg per day have also been
perinatal death and neonatal complications recommended based on a theoretical benefit
including hyperbilirubinemia, hypoglyce- of reducing the increased risk of neural tube
mia, hyperinsulinemia, and birth trauma.49 defects associated with pre-existing
Other retrospective data show increased diabetes.57,58
risks of neonatal hypoglycemia and intensive Potentially teratogenic medications such
care admission in women with suboptimal as angiotensin-converting enzyme inhibitors,
glucose control.50 angiotensin receptor blockers, and statins
should be discontinued.59 Women must be
Pre-Existing Diabetes. There is a large body screened for diabetes complications. Diabetic
of evidence indicating that a structured, retinopathy has the potential to worsen dur-
evidence-based approach to care of women ing pregnancy particularly if there is a rapid
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 MAYO CLINIC PROCEEDINGS

and normal serum creatinine; but complica-

TABLE 1. Components of Prepregnancy Care for
tions including pre-eclampsia and preterm
Women With Established Diabetesa
delivery are more common.61 Although
Discuss
fertility declines significantly as kidney dis-
Timeline for pregnancy
ease progresses, pregnancy is still possible.62
Contraceptive options
Positive ways to reduce risk of adverse outcomes However, for women with end-stage renal
Complete baseline laboratory studies including
disease, deferral of pregnancy until after kid-
HbA1c
ney transplantation may be appropriate.
Creatinine Renal function is closely linked with blood
Thyroid-stimulating hormone pressure, which must be monitored closely
Urine albumin-creatinine ratio during pregnancy. Tight blood pressure con-
Stop/replace medications with possible teratogenic trol before and during pregnancy is associ-
effects including ated with improved outcomes.63 Nifedipine
Hypoglycemic agents other than metformin and and labetolol are commonly used agents. a-
insulin Methyldopa is also a reasonable choice but
Statins is commonly associated with postural dizzi-
ACE inhibitors and ARBs
ness,64 and requires less convenient frequent
Initiate prenatal vitamins which should include
dosing. A reasonable blood pressure goal in
Folic acid (up to 5 mg/d) women with diabetes and chronic hyperten-
1000 mg elemental calcium
sion is less than 135/85 mmHg.56 An electro-
600 IU vitamin D
cardiogram is suggested for all women55 and
Review
further screening for coronary artery disease
HbA1c target of <6.5%
should be considered in those who are at
Blood pressure (<135/85 mm Hg)
Hypoglycemia management (if indicated) high risk d for example, due to advanced
Nutritionist referral and weight optimization
maternal age, pre-existing hypertension,
Screening for complications including
chronic kidney disease, tobacco use, or a
family history of premature coronary artery
Retinal assessment
Electrocardiogram disease.51 Although all women with diabetes
Evaluation for coronary artery disease if indicated should meet with a dietician before preg-
a
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin
nancy, this is particularly important for
receptor blocker. women with overweight or obesity who
should be offered advice on ways to lose
weight before pregnancy.51,59

improvement in glycemic control.60 An

ophthalmologist with expertise in diabetic
retinopathy should perform a comprehen- TABLE 2. Risk Factors for GDMa
sive eye exam and any necessary treatment Overweight or obese BMI
before pregnancy. A baseline creatinine, esti- GDM in a prior pregnancy
mated glomerular filtration rate and urine Family history of diabetes
albumin:creatinine ratio are an important in- Non-European ethnicity
dications of pre-pregnancy renal function Polycystic ovarian syndrome
and can play critical roles in determining Increasing age
timing of delivery in women with even Physical inactivity
mild underlying renal compromise. Multiple pregnancy
Nephrology referral should be considered if Previous delivery of a macrosomic baby
serum creatinine is abnormal or if total pro- Previous stillbirth
tein excretion exceeds 2 g/d.59 Pregnancy a
BMI ¼ body mass index; GDM ¼ gestational diabetes
does not result in worsening of kidney func- mellitus.
tion in women with diabetic nephropathy

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DIABETES IN PREGNANCY

TABLE 3. Options for GDM Screening and Diagnosisa,b

No. abnormal Oral glucose
Criteria values required load, g Glucose cut-offs, mg/dL (mmol/L)
Two-step strategy
Non- fasting glucose challenge test 1 50 130, 135, or 140 (7.2, 7.5, or 7.8)
Followed by either of the options below
1. Carpenter and Coustan 2c 100 Fasting 95 (5.3)
1-h 180 (10.0)
2-h 155 (8.6)
3-h 140 (7.8)
2. NDDG 2c 100 Fasting  105 (5.8)
1-h 190 (10.6)
2-h 165 (9.2)
3-h 145 (8.0)
One-step strategy
2010 IADPSG / 2013 WHO 1 75 Fasting 92 (5.1)
1-h 180 (10.0)
2-h 153 (8.5)
a
GDM ¼ gestational diabetes mellitus; IADPSG ¼ International Association of the Diabetes and Pregnancy Study Groups; NDDG ¼
National Diabetes Data Group.
b
From the American Diabetes Association.9
c
ACOG notes that one elevated value may be used for diagnosis.

GDM. As the majority of women have at 140 mg/dL with resultant implications for
least one risk factor for GDM (Table 2) and sensitivity and specificity. Women whose
50% of pregnancies are unplanned, deliv- glucose levels meet or exceed the pre-
ering effective GDM prevention specified threshold then undergo a 100-
interventions pre-pregnancy is chal- gram, 3-hour diagnostic test and GDM is
lenging.65,66 Many studies, including a diagnosed in the setting of two or more
recent large Finnish study and a meta- abnormal values.9
analysis, have shown the efficacy of inter- The International Association of the Dia-
vention when patients seek care before betes and Pregnancy Study Groups recom-
pregnancy, thus this remains a potent target mend a one-step process with a 2-hour, 75-
for improving care.67,68 gram oral glucose tolerance test (OGTT)
and diagnostic cutoffs based on outcomes
Diagnosis of GDM from the Hyperglycemia and Adverse Preg-
There is a general consensus that women nancy Outcome Study.70,71 The cutoff points
with risk factors for type 2 diabetes should chosen convey an odds ratio of at least 1.75
have testing for undiagnosed diabetes using for outcomes including LGA, neonatal
standard diagnostic criteria at their initial C-peptide greater than 90th percentile, and
prenatal visit.9,69 neonatal body fat percentage greater than
Standard GDM screening is recommen- 90th percentile compared with women with
ded at 24- to 28-weeks' gestation and a num- mean glucose levels at 24 to 28 weeks in
ber of options are available (Table 3). The the study. Neonatal risks appeared to be lin-
most common approach in the United States early related to the degree of maternal dys-
is to screen all women with a non-fasting, glycemia. Nonetheless, with older data
50-gram glucose challenge followed by a 1- suggesting overall low frequency of neonatal
hour venous glucose test. Thresholds for risks, there has been a reluctance to intro-
the 1-hour glucose value vary from 130 to duce these guidelines at many institutions

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 MAYO CLINIC PROCEEDINGS

TABLE 4. IOM Guidelines for Gestational Weight Gain During Pregnancya,b

Recommended Recommended mean weight gain:
Pre-gestational BMI category BMI, kg/m2 total weight gain, kg trimesters 2 and 3, mean kg/wk (range)
Underweight <18.5 12.5-18.0 0.51 (0.44-0.58)
Normal weight 18.5-24.9 11.5-16.0 0.42 (0.35-0.50)
Overweight 25.0-29.9 7.0-11.5 0.28 (0.23-0.33)
Obese 30.0 5.0-9.0 0.22 (0.17-0.27)
a
BMI ¼ body mass index; IOM ¼ Institute of Medicine.
b
Adapted from The National Academies Press78 with permission.

due to the expectation of higher rates of motivated patients can struggle to achieve
GDM and resultant demands on resources these goals, particularly in the setting of
in the setting of a lack of perceived improve- type 1 diabetes and/or hypoglycemia. In
ment in outcomes. this scenario, individualized, less-stringent
There are differing opinions on how and targets are acceptable. One should bear in
when to diagnose diabetes in early preg- mind that in type 2 diabetes, the contribu-
nancy. The American College of Obstetri- tion of fasting glucose (versus postprandial)
cians and Gynecologists (ACOG) accepts to the HbA1c level becomes greater as con-
the 24-week criteria applied to a 100-gram trol declines, increasing up to 70% in those
OGTT in early pregnancy, but there are with an HbA1c greater than 10.0%.76 Fasting
few data to support this practice.69 Whereas glucose elevations (as opposed to postpran-
accelerated fetal growth may occur before dial elevations) are also more predictive of
24- to 28-weeks' gestation in women with fetal macrosomia.77 This information can
GDM,72 early elevations in glucose levels be useful when adjusting insulin regimens.
are often no longer present by the time of
routine OGTT.73 This makes identification Gestational Weight Gain and Diet
of at-risk women challenging. Given this dif- In women with and without diabetes, exces-
ficulty, there is an impetus to discover alter- sive gestational weight gain is associated
nate diagnostic markers for hyperglycemia in with poorer pregnancy outcome. The Insti-
early pregnancy.74 tute of Medicine guidelines for gestational
weight gain are based on pre-pregnancy
Glycemic Goals During Pregnancy BMI and are outlined in Table 4.78 Close
The American Diabetes Association and attention to food intake is necessary during
ACOG recommend similar glucose targets pregnancy to avoid excessive gestational
for women with pre-existing diabetes and weight gain while ensuring strict glycemic
GDM as follows: fasting glucose less than control.51 The dietary reference intakes for
or equal to 95mg/dL, 1 hour after eating pregnant women should be followed and
less than or equal to 140 mg/dL, and 2 hours they recommend a minimum of 175 grams
after eating less than or equal to 120 mg/ of carbohydrates, 71 grams of protein, and
dL.55,56,69 HbA1c levels naturally decrease 28 grams of fiber.56 In practice, many pro-
during pregnancy due to increased red blood viders follow Endocrine Society guidance
cell turnover and may not fully capture tran- that advises limiting carbohydrates to 35%
sient glycemic excursions, which can drive to 45% total calories and distributing
macrosomia.56,75 Therefore, whereas a first- throughout three meals and up to four
trimester HbA1c of less than 6.0% is associ- snacks throughout the day.57 Sugars and
ated with the lowest rates of adverse fetal refined carbohydrates should be eliminated
outcomes, it should be considered a second- with ideal carbohydrate sources including
ary measure of glycemic control later in fresh vegetables, some fruits, and whole
pregnancy.54,56 Unfortunately, even highly grains.79 Approximately 80% of women
n n
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DIABETES IN PREGNANCY

with GDM can reach their glycemic goals diabetes is controversial. Metformin, a
with diet and lifestyle modifications alone.10 biguanide and glyburide (glibenclamide), a
sulphonylurea have been studied and used
Pharmacotherapy with good effect during pregnancy.84,85
Insulin. In women with type 1 diabetes, Metformin transfers to the fetus with high
multiple daily injection and continuous sub- fetal-to-maternal ratios. Although it was
cutaneous insulin infusion regimens (also previously thought that glyburide did not
known as insulin pump therapy) are both transfer in significant quantities, more recent
effective during pregnancy.59 There is data suggest that it can increase expression
insufficient evidence to recommend one of glucose transporter 1 in the placenta and
mode of insulin delivery over another, and promote fetal overgrowth.74 In women with
there is need for trials evaluating modern GDM, glyburide is associated with higher
pumps which integrate with glucose sensors birth weights and neonatal hypoglycemia
and have features such as low glucose sus- compared with insulin, and metformin
pend.80 The currently available hybrid resulted in less gestational weight gain but
closed loop system (Medtronic MiniMed LGA at delivery.86 Patients with GDM on
670G insulin pump) is not appropriate for glyburide are less likely to require a transi-
use in automode during pregnancy as its tion to insulin than those on metformin.85
algorithm targets a glucose of 120 mg/dL, Small groups of children exposed to met-
which is above the recommended fasting formin in utero have been followed for up to
goal.81 The Continuous Glucose Monitoring 9 years; although there was similar total and
in Pregnant Women With Type 1 Diabetes abdominal body fat percent and metabolic
(CONCEPTT) trial found that pregnant variables, metformin-exposed children were
women who used continuous glucose larger than nonexposed children by several
monitoring (CGM) (with or without pump measures including weight and waist
therapy) had a lower incidence of LGA in- circumference.87 There are no long-term
fants (odds ratio, 0.51; 95% CI, 0.28 to 0.9, studies of children exposed to glyburide.
P¼.0210) and fewer incidences of neonatal Other members of the sulfonylurea class
hypoglycemia (0.45; 95% CI,0.22 to 0.89, of medications along with thiazolidine-
P¼.0250).82 It is anticipated that these diones, glucagon-like peptide 1 receptor ago-
findings will translate into increased use of nists, dipeptidyl peptidase-4 inhibitors, and
CGM technology during pregnancy. At the sodium glucose-cotransporter 2 inhibitors
moment, there is no evidence for use of are not recommended for use during preg-
technology such as insulin pumps or CGM nancy or pregnancy planning.
in women with type 2 or gestational
diabetes. Approach to Management of Hyper-
Aspart and lispro are safe and effective glycemia. During pregnancy, intensification
options for rapid acting insulin during preg- of therapy should occur within 1 to 2 weeks
nancy. Isophane insulin (neutral protamine if glycemic targets are not met (>15% to
Hagedorn) was traditionally used as a 20% of readings above goal). Insulin is recom-
longer-acting insulin; however, insulin ana- mended for women with pre-existing dia-
logues are increasingly used. Detemir, for betes, as alternative agents will be ineffective
example, has been studied during pregnancy in the case of type 1 diabetes and unable to
in a randomized controlled trial83; and there counteract the significant increases in insulin
is extensive clinical experience with glargine resistance associated with type 2 diabetes.
during pregnancy. Newer insulin analogues Guidelines differ in the case of GDM treat-
have not been studied. ment. For example, the American Diabetes
Association considers insulin to be first-line
Noninsulin Agents. The use of oral hypogly- therapy for women with GDM but does not
cemic agents during pregnancy to treat pre- favor metformin or glyburide if an alternative
existing type 2 diabetes or gestational is required.56 ACOG recommends insulin as

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 MAYO CLINIC PROCEEDINGS

first-line therapy with metformin (or rarely prompt growth evaluation. Starting at 32-
glibenclamide) to be used as a reasonable weeks' gestation, it is reasonable to initiate
alternative,69 and the Society for Maternal once- or twice-weekly monitoring such as
Fetal Medicine states that metformin or in- the nonstress test, biophysical profile, or
sulin are reasonable first-line pharmacologic modified biophysical profile.55 This may be
therapies.88 Until such time that further in- started earlier or the frequency increased on
formation is available, treatment must be an individual basis.
considered on a case-by-case basis taking into Women with well-controlled diabetes
account the degree of hyperglycemia, health and reassuring fetal testing may be managed
care and financial resources, and patient expectantly to between 39 0/7 weeks and 39
preference. 6/7 weeks of gestation, but women with
diabetes-related complications, poor glyce-
Aspirin. Women with pre-existing diabetes mic control, or prior stillbirth should be
are at increased risk of pre-eclampsia,89 and considered for delivery between 36 0/7 and
in accordance with the US Preventive Ser- 38 6/7 weeks of gestation.55
vices Task Forces,90 low-dose aspirin (81 mg During labor, women should have
per day) is recommended after 12-weeks' continuous electronic fetal monitoring.
gestation.55,56 Because of the abnormal adiposity of neo-
nates of diabetic mothers, prophylactic
DKA During Pregnancy cesarean delivery may be recommended if
DKA in a pregnant woman is a life- the estimated fetal weight exceeds 4500
threatening emergency caused by an abso- grams.55
lute or relative deficiency in insulin. Preg-
nancy is a ketogenic state, and DKA may GDM. Women with GDM who are poorly
occur even at normal blood glucose levels.56 controlled or require pharmacologic inter-
Although women with type 1 diabetes are at vention should undergo fetal surveillance
greatest risk, DKA may occur in pregnancy similar to women with pre-existing dia-
with any type of diabetes. If there is a suspi- betes. Women whose hyperglycemia is
cion or diagnosis of DKA during pregnancy, controlled with lifestyle interventions alone
it should be treated as an emergency with should not be delivered before 39-weeks'
immediate specialist review.58 In the past, gestation and do not require induction at
fetal mortality rates of up to 35% have later gestational ages unless otherwise indi-
been reported with DKA, but this has cated. In those who are well-controlled but
decreased in recent years with improved requiring pharmacologic intervention,
diagnosis and management.55 delivery is recommended between 39 0/7
weeks and 39 6/7 weeks of gestation. Finally,
Fetal Monitoring and Delivery Planning in women who are poorly controlled, de-
Pre-existing Diabetes. Most women will livery between 37 0/7 weeks and 38 6/7
undergo an ultrasound in early pregnancy weeks may be justified. Although there is
to show viability. A detailed fetal anatomy less evidence to support such a strategy in
scan should occur at 18- to 20-weeks' women with GDM, cesarean delivery may be
gestation and certain women may undergo recommended if the estimated fetal weight is
fetal echocardiography, particularly if first- at least 4500 grams.69
trimester glycemic control is not at goal or All women with complications will
there is suspicion of a cardiac defect.55 Ul- benefit from anesthesiology consultation in
trasound is commonly used to assess fetal the third trimester of pregnancy to review
growth in the third trimester but there are the birth plan and analgesic options. If ste-
no recommendations on frequency. Given roids are required to accelerate fetal lung
the risk of macrosomia, a greater fundal maturation, an increased insulin require-
height, excessive maternal weight gain, and ment over the following 3 to 5 days is antic-
persistent poor glucose control should ipated and increased glucose monitoring is
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DIABETES IN PREGNANCY

advised. In women with diabetes treated should be started once diet has resumed.55
with insulin, the additional insulin is often Frequent glucose monitoring is essential to
administered intravenously with infusion reduce the risk of severe hypoglycemia.
rates adjusted hourly, typically targeting a Women with GDM should discontinue all
glucose level of 70 to 126 mg/dL.59 glucose-lowering medications following de-
livery, but postpartum glucose testing (capil-
Labor and Delivery lary or venous) should occur before
Maternal hyperglycemia during labor and discharge from hospital to exclude persistent
delivery is associated with neonatal hypogly- diabetes.58
cemia and fetal distress.59 Women with dia-
betes who required pharmacologic Postpartum Care
intervention during pregnancy are generally Breastfeeding is encouraged as it facilitates
managed with an intravenous insulin infu- postpartum weight loss and is likely associ-
sion and hourly glucose testing. With ated with lower future risk of obesity and
respect to the intrapartum glycemic target, diabetes in offspring.92 Women who are
there is no randomized trial evidence to sup- breastfeeding and receiving insulin
port a specific goal; however, most local pol- frequently require additional carbohydrate
icies specify a range that falls between 70 snacks and lower insulin doses to prevent
and 126 mg/dL. If the appropriate expertise hypoglycemia. Based on extensive clinical
is available, women can continue to use their experience, metformin is deemed to be safe
personal insulin pumps during this time.91 while breastfeeding, but there are insuffi-
Women with GDM who were diet- cient data to recommend other glucose-
controlled during pregnancy should also lowering agents except insulin.
have glucose monitoring during labor with At the 6-week postpartum follow-up,
initiation of insulin if glucose levels are women should be counseled on the impor-
above 100 to 126 mg/dL.55,58 tance of planning future pregnancies. Long
On delivery, a neonatologist should re- acting reversible contraception is ideal in
view the infant, and delivery units should this setting and may be used while breast-
have the expertise to provide advanced feeding; however, the risk of an unplanned
neonatal care if required. Unless there is spe- pregnancy will likely outweigh the risk of
cific concern, neonates should remain with any contraceptive option.51,56
their mother and feeding should take place Women with GDM should have an
as soon as possible.59 Two to 4 hours post- OGTT at 4 to 12 weeks' postpartum to rule
delivery, neonatal blood glucose testing out undiagnosed pre-existing diabetes.
should occur to exclude neonatal hypoglyce- HbA1c is not reliable, as it will be affected
mia. Clinical signs such as severe irritability by changes during the recent pregnancy.
or seizure-like activity should prompt earlier Rates of attendance at postpartum glucose
evaluation.59 Measures such as tube feeding testing are reported to be as low as 5%, but
or intravenous dextrose are generally making verbal and written contact with indi-
reserved for when the capillary glucose is vidual women can increase recall rates to
less than 36 mg/dL despite feeding. Addi- 75%.93 Women with GDM require lifelong
tional tests for polycythemia, hyperbilirubi- assessment of their glucose status and other
nemia, and electrolyte abnormalities should cardiovascular risks as GDM is a strong risk
be considered based on clinical evaluation.58 factor for progression to type 2 diabetes,
Because of a rapid increase in insulin stroke, and heart disease.94 Testing may
sensitivity following placental delivery, take the form of HbA1c, fasting plasma
women with pre-existing diabetes typically glucose, or a 75-g OGTT (using non-
require a dramatic reduction in insulin doses pregnant thresholds) and should take place
postpartum. ACOG recommends one-third every 1 to 3 years depending on the presence
to one-half of the pre-delivery doses of of additional risk factors for type 2 dia-
long- and short-acting insulin d the latter betes.56 A total of 52.2% the Hyperglycemia
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 MAYO CLINIC PROCEEDINGS

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