Diabetes Mellitus
BS. Nguyễn Hồng Anh
According to the Centers or Disease Control and Prevention
(2020), nearly 27 million adults in the United States have been
diagnosed with diabetes. Another 7.3 million are suspected to
be undiagnosed, and an estimated 88 million have prediabetes.
Reasons or these substantial rates include an aging population,
which is more likely to develop type 2 diabetes; population
growth within minority groups at particular risk or type 2
diabetes; and a dramatic rise in obesity rates. In 2019, almost
three in 10 women were considered obese prior to becoming
pregnant (Driscoll, 2020). Te strong relationship between diabetes and the current obesity epidemic in the United States
underlines the critical need or diet and liestyle interventions
to change the trajectory o both.
TYPES OF DIABETES
In nonpregnant individuals, the type o diabetes is based on its
presumed pathogenesis and its maniestations. Absolute insulin
deciency, which generally is autoimmune in etiology, characterizes type 1 diabetes. In contrast, insulin resistance, relative
insulin deciency, or elevated glucose production characterizes
type 2 diabetes (Table 60-1). Both types are generally preceded
by a period o abnormal glucose homeostasis oten reerred to
as prediabetes. Pancreatic β-cell destruction can begin at any
age, but type 1 diabetes is clinically apparent most oten beore
age 30. ype 2 diabetes usually develops with advancing age
but is increasingly identied in younger obese adolescents.
Etiological overlap in diabetes subtypes is well established and
has led to the proposal o a single classication system centered on β-cell unction along with the concept o individualized treatment strategies (World Health Organization, 2020).
Other orms o diabetes include maturity-onset diabetes of the
young (MODY). Te more common MODY type is in obese
adolescents (ODAY Study Group, 2021). Te less common
orm is an autosomal dominant condition and characterized
by mild diabetes diagnosed in adolescence or young adulthood
(Udler, 2020).
■ Classification During Pregnancy
Diabetes is the most common medical complication o pregnancy. Women can be separated into those diagnosed with
diabetes beore pregnancy—pregestational or overt diabetes, and
those diagnosed during pregnancy—gestational diabetes.
Te proportion o pregnancies complicated by diabetes more
than doubled between 1994 and 2008, ater which rates have
leveled (Deputy, 2018; Jovanovič, 2015). In 2018, 7.6 percent
o pregnant women in this country had some orm o diabetes (Martin, 2019). Prevalence is highest among non-Hispanic
TABLE 60-1. Etiological Classification of Diabetes Mellitus
Type 1: β-Cell destruction, usually absolute insulin deficiency
Immune-mediated
Idiopathic
Type 2: Ranges from predominantly insulin resistance to predominantly an insulin secretory
defect with insulin resistance
Other types
Genetic mutations of β-cell function: MODY 1–6, others
Genetic defects in insulin action
Genetic syndromes: Down, Klinefelter, Turner, others
Diseases of the exocrine pancreas: pancreatitis, cystic fibrosis
Endocrinopathies: Cushing syndrome, pheochromocytoma, others
Drug or chemical induced: glucocorticosteroids, thiazides, β-adrenergic agonists, others
Congenital infections: rubella, cytomegalovirus, coxsackievirus
Gestational diabetes (GDM)
MODY = maturity-onset diabetes of the young.
Adapted from American Diabetes Association, 2020; Powers, 2018
blacks, Mexican-Americans, Puerto Rican-Americans, and Native
Americans (Powers, 2018).
■ White Classification
Until the mid-1990s, the classication system o Priscilla White
(1978) or diabetic pregnant women was the linchpin o management. oday, the White classication is used less oten but
still provides simple, useul inormation on pregnancy risks and
prognosis (Bennett, 2015). Because most currently cited literature also contains data rom these older classications, the one
previously recommended by the American College o Obstetricians and Gynecologists (1986) is shown in Table 60-2.
Te American College o Obstetricians and Gynecologists
(2019a) no longer recommends the White classication. Te
current ocus is whether diabetes antedates pregnancy or is rst
diagnosed during pregnancy. Many now recommend the system
proposed by the American Diabetes Association (Table 60-3).
TABLE 60-1. Etiological Classification of Diabetes Mellitus
Type 1: β-Cell destruction, usually absolute insulin deficiency
Immune-mediated
Idiopathic
Type 2: Ranges from predominantly insulin resistance to predominantly an insulin secretory
defect with insulin resistance
Other types
Genetic mutations of β-cell function: MODY 1–6, others
Genetic defects in insulin action
Genetic syndromes: Down, Klinefelter, Turner, others
Diseases of the exocrine pancreas: pancreatitis, cystic fibrosis
Endocrinopathies: Cushing syndrome, pheochromocytoma, others
Drug or chemical induced: glucocorticosteroids, thiazides, β-adrenergic agonists, others
Congenital infections: rubella, cytomegalovirus, coxsackievirus
Gestational diabetes (GDM)
MODY = maturity-onset diabetes of the young.
Adapted from American Diabetes Association, 2020; Powers, 2018.
TABLE 60-2. Modified White Classification Scheme Used from 1986 Through
1994 for Diabetes Complicating Pregnancy
Plasma Glucose Level
Class Onset Fasting 2-Hour Postprandial Therapy
A1 Gestational <105 mg/dL <120 mg/dL Diet
A2 Gestational >105 mg/dL >120 mg/dL Insulin
Class Age of Onset (yr) Duration (yr) Vascular Disease Therapy
B Over 20 <10 None Insulin
C 10 to 19 10 to 19 None Insulin
D Before 10 >20 Benign retinopathy Insulin
F Any Any Nephropathya Insulin
R Any Any Proliferative retinopathy Insulin
H Any Any Heart Insulin
aWhen diagnosed during pregnancy: proteinuria ≥500 mg/24 hr before
20 weeks’ gestation.
PREGESTATIONAL DIABETES
Considering the previously mentioned high percentage o
undiagnosed diabetes, many women identied with gestational diabetes likely have previously unrecognized type 2
diabetes. Indeed, 5 to 10 percent o women with gestational
diabetes are diagnosed with overt diabetes immediately ater
pregnancy.
■ Diagnosis
Women with high plasma glucose levels, glucosuria, and ketoacidosis present no diagnostic challenge. Women with a random
plasma glucose level >200 mg/dL plus classic signs and symptoms such as polydipsia, polyuria, and unexplained weight loss,
those with a asting glucose level >125 mg/dL, or those with
a rst-trimester glycosylated hemoglobin (HbA1c) level o ≥6.5
percent are considered by the American Diabetes Association
blacks, Mexican-Americans, Puerto Rican-Americans, and Native
Americans (Powers, 2018).
■ White Classification
Until the mid-1990s, the classication system o Priscilla White
(1978) or diabetic pregnant women was the linchpin o management. oday, the White classication is used less oten but
still provides simple, useul inormation on pregnancy risks and
prognosis (Bennett, 2015). Because most currently cited literature also contains data rom these older classications, the one
previously recommended by the American College o Obstetricians and Gynecologists (1986) is shown in Table 60-2.
Te American College o Obstetricians and Gynecologists
(2019a) no longer recommends the White classication. Te
current ocus is whether diabetes antedates pregnancy or is rst
diagnosed during pregnancy. Many now recommend the system
proposed by the American Diabetes Association (Table 60-3).
TABLE 60-1. Etiological Classification of Diabetes Mellitus
Type 1: β-Cell destruction, usually absolute insulin deficiency
Immune-mediated
Idiopathic
Type 2: Ranges from predominantly insulin resistance to predominantly an insulin secretory
defect with insulin resistance
Other types
Genetic mutations of β-cell function: MODY 1–6, others
Genetic defects in insulin action
Genetic syndromes: Down, Klinefelter, Turner, others
Diseases of the exocrine pancreas: pancreatitis, cystic fibrosis
Endocrinopathies: Cushing syndrome, pheochromocytoma, others
Drug or chemical induced: glucocorticosteroids, thiazides, β-adrenergic agonists, others
Congenital infections: rubella, cytomegalovirus, coxsackievirus
Gestational diabetes (GDM)
MODY = maturity-onset diabetes of the young.
Adapted from American Diabetes Association, 2020; Powers, 2018.
TABLE 60-2. Modified White Classification Scheme Used from 1986 Through
1994 for Diabetes Complicating Pregnancy
Plasma Glucose Level
Class Onset Fasting 2-Hour Postprandial Therapy
A1 Gestational <105 mg/dL <120 mg/dL Diet
A2 Gestational >105 mg/dL >120 mg/dL Insulin
Class Age of Onset (yr) Duration (yr) Vascular Disease Therapy
B Over 20 <10 None Insulin
C 10 to 19 10 to 19 None Insulin
D Before 10 >20 Benign retinopathy Insulin
F Any Any Nephropathya Insulin
R Any Any Proliferative retinopathy Insulin
H Any Any Heart Insulin
aWhen diagnosed during pregnancy: proteinuria ≥500 mg/24 hr before
20 weeks’ gestation.1070
Section 12
Medical and Surgical Complications
(2019) and the World Health Organization (2019) to have overt
diabetes rst detected in pregnancy.
Women with only minimal metabolic derangement may be
more dicult to identiy. o diagnose overt diabetes in pregnancy, the International Association o Diabetes and Pregnancy
Study Groups (IADPSG) Consensus Panel (2010) recognizes the
threshold values ound in Table 60-4 or asting or random plasma
glucose and HbA1c levels at prenatal care initiation. Te American
Diabetes Association (2020) and the World Health Organization
(2019) now also consider a plasma glucose level >200 mg/dL
measured 2 hours ater a 75-g oral glucose load to be diagnostic.
No consensus has been reached as to whether such testing should
be universal or limited to those women classied as high risk.
Regardless, a presumed diagnosis o overt diabetes in pregnancy based on these thresholds should be conrmed postpartum. Risk actors or impaired carbohydrate metabolism
in pregnant women include a strong amilial history o diabetes, prior delivery o a large newborn, persistent glucosuria, or
unexplained etal losses.
■ Harm in Pregnancy
With overt diabetes, the embryo, etus, and mother requently
experience serious complications directly attributable to diabetes (Egan, 2020). Many o these complications might be
prevented each year by preconceptional care or improved glycemic control (Peterson, 2015). Using HbA1c values as objective risk quartiles, Finneran and Kieer (2020) reported that
glycemic control throughout pregnancy and a late-pregnancy
HbA1c level <6.5 percent leads to reduced rates o adverse
obstetrical and neonatal outcomes. Te likelihood o successul
outcomes with overt diabetes, however, is not simply related
to glucose control. Te degree o underlying cardiovascular or
renal disease may be more important. Tus, advancing stages
o the White classication, seen in able 60-2, are inversely
related to avorable pregnancy outcomes. Shown in Table 60-5
are data that chronicle the adverse pregnancy outcomes with
overt diabetes, and many are described next (Battarbee, 2020b).
■ Fetal Effects
Spontaneous Abortion
Up to 25 percent o overtly diabetic mothers have an early
miscarriage, and poor glycemic control is an associated actor.
In one study, those whose HbA1c concentrations were >12
percent or whose preprandial glucose concentrations persisted
above 120 mg/dL had an elevated miscarriage risk (Galindo,
2006). In a large Chinese population-based study, those with a
history o diabetes had an increased risk o miscarriage, and the
risk rose 8 percent or each 20-mg/dL incremental rise in asting glucose (Wei, 2019). In 89 pregnancies in women with the
monogenic orm o MODY, only women with the causative
glucose kinase (GCK) mutation were more likely to miscarry
(Bacon, 2015). Another analysis o 128 GCK-MODY pregnancies showed that the observed miscarriage rate was comparable to the background rate (Dickson, 2019). Tese women
have hyperglycemic variability that can be dicult to control.
Preterm Delivery
Overt diabetes is an undisputed risk actor or preterm birth.
In an analysis o more than 500,000 pregnancies in Ontario,
TABLE 60-3. Proposed Classification System for Diabetes in Pregnancy
Gestational diabetes: diabetes diagnosed during pregnancy that is not clearly overt (type 1 or type 2) diabetes
Type 1 Diabetes:
Diabetes resulting from β-cell destruction, usually leading to
absolute insulin deficiency
a. Without vascular complications
b. With vascular complications (specify which)
Type 2 Diabetes:
Diabetes from inadequate insulin secretion in the face of
increased insulin resistance
a. Without vascular complications
b. With vascular complications (specify which)
Other types of diabetes: genetic in origin, associated with pancreatic disease, drug-induced, or chemically induced
Data from American Diabetes Association, 2017a; Powers, 2018.
TABLE 60-4. Diagnosis of Overt Diabetes in Pregnancya
Measure of Glycemia Threshold
Fasting plasma glucose At least 7.0 mmol/L (126 mg/dL)
Hemoglobin A1c At least 6.5%
Random plasma glucose At least 11.1 mmol/L (200 mg/dL) plus confirmation
aApply to women without known diabetes antedating pregnancy. The decision to perform
blood testing for evaluation of glycemia on all pregnant women or only on women with
characteristics indicating a high risk for diabetes is based on the background frequency of
abnormal glucose metabolism in the population and on local circumstances.
Data from International Association of Diabetes and Pregnancy Study Groups Consensus
Panel, 2010.CHAPTER 60
Diabetes Mellitus 1071
almost 20 percent o women with diabetes were delivered preterm compared with 5.6 percent o women without diabetes,
obesity, or hypertension (Berger, 2020). More than 60 percent were indicated preterm births, that is, due to obstetrical
or medical complications. Notably, more than 37 percent o
women with diabetes and chronic hypertension delivered preterm. In a review o Caliornia births, 19 percent o women
with pregestational diabetes delivered beore 37 weeks’ gestation compared with 9 percent o controls (Yanit, 2012). In a
study rom the United Kingdom, the preterm delivery rate was
42 percent or 8690 type 1 diabetic women and 3 percent or
those with type 2 diabetes (Murphy, 2021).
Malformations
Te incidence o major malormations in etuses o women
with type 1 diabetes approximates 11 percent and is at least
double the rate in etuses o nondiabetic mothers (Jovanovič,
2015). Tis risk is present or all women with pregestational
diabetes, including those with type 2 disease (inker, 2020).
Congenital anomalies constitute almost hal o perinatal deaths
in diabetic pregnancies.
Cardiovascular malormations account or more than hal
o the anomalies, and Table 60-6 lists selected malormations
reported by the National Birth Deects Prevention Study (inker, 2020). In a study o more than 2 million births in Canada, the risk o an isolated cardiac deect was veold higher
in women with type 1 diabetes compared with nondiabetic
mothers (Liu, 2013). Te caudal regression sequence, described
in Chapter 15 (p. 280), is a rare malormation that, according
to the National Birth Deects Prevention Study, is 80 times
more likely in women with pregestational diabetes.
Poorly controlled diabetes, both preconceptionally and
early in pregnancy, is thought to underlie this elevated risk
or major malormation. In one study o mothers with type
1 diabetes, a periconceptional HbA1c <6.5 percent carried a
twoold risk or a etal major cardiac deect, and a HbA1c >9
percent carried a sixold risk (Ludvigsson, 2018). Others cite
similar requencies (Murphy, 2021). Figure 60-1 shows the
association between HbA1c levels and etal congenital malormation rates in a Parkland Hospital cohort o women with
overt diabetes (Martin, 2021).
Te etiological mechanisms that explain this link include
excess production o toxic superoxide radicals, altered cell signaling pathways, upregulation o some genes by hyperglycemia, and
TABLE 60-5. Selected Maternal and Perinatal Outcomes
in Percent in Women with Gestational
and Overt Diabetes Compared with
Nondiabetic Womena
Normal GDM Overt DM
182,464b 10,549b 2993b
Factor (%) (%) (%)
Maternal
Chronic HTN 1.5 5.0 11.5
Renal disease 0.5 0.6 2.7
Gestational HTN 8.0 12.9 22.9
Chorioamnionitis 4.1 4.0 5.2
Cesarean birth 42 59 69
Neonatal
RDS 3.8 4.7 11.0
Ventilation 2.8 3.1 7.0
NICU admit 12.8 19.8 41.9
Macrosomia 7.7 18.1 29.9
Deathc 0.2 0.1 0.4
aUnless specified, all comparisons p <0.001.
bNumber of women in group.
c
p <0.05.
DM = diabetes mellitus; GDM = gestational diabetes mellitus;
HTN = hypertension; NICU = neonatal intensive care unit;
RDS = respiratory distress syndrome.
TABLE 60-6. Selected Congenital Malformations
in Pregnancies Complicated by Overt
Diabetes
Birth Defect OR (95% CI)
Cardiovascular
Fallot tetralogy 5.3 (3.5–8.0)
AV septal defect 10.5 (6.2–17.9)
Aortic coarctation 4.5 (2.8–7.1)
Neural-tube defect
Anencephaly 3.5 (1.9–6.4)
Encephalocoele 5.4 (2.5–11.7)
Hydrocephaly 8.2 (5.0–13.5)
Cleft palate 4.3 (2.9–6.5)
Esophageal 3.4 (1.9–6.1)
Hypospadias 2.8 (1.7–4.8)
Renal 8.1 (3.9–16.9)
Sacral agenesis 80.2 (46.1–139.3)
CI = confidence interval; OR = odds ratio.
FIGURE 60-1 Association between fetal malformation rates and
HbA1c values determined at initiation of prenatal care in 1573 pregnancies in women with pregestational diabetes.1072
Section 12
Medical and Surgical Complications
activation o programmed cell death (Basu, 2018; Reece, 2012).
One review o potential molecular mechanisms suggests that cellular responses to oxidative stress represent possible therapeutic
targets to prevent diabetes-induced embryopathy (Yang, 2015).
Altered Fetal Growth
Diminished etal growth may result rom congenital malormations or rom substrate deprivation due to advanced maternal
vascular disease. Tat said, etal overgrowth is more typical o
pregestational diabetes. Maternal hyperglycemia prompts etal
hyperinsulinemia, and this in turn stimulates excessive somatic
growth. Except or the brain, most etal organs are aected by
the macrosomia that characterizes the etus o diabetic women.
Newborns are described as anthropometrically dierent rom
other large-or-gestational age (LGA) neonates (Catalano,
2003; Durnwald, 2004). Specically, those whose mothers
are diabetic have excessive at deposition on the shoulders and
trunk, which predisposes to shoulder dystocia or etopelvic disproportion (Fig. 60-2).
Te incidence o macrosomia rises signicantly when mean
maternal blood glucose concentrations chronically exceed 130
mg/dL (Hay, 2012). In addition, the overall birthweight distribution o neonates o diabetic mothers is skewed toward consistently heavier birthweights. In one sonographic study, the
macrosomia rates or Nordic women with type 1, type 2, or
gestational diabetes were 35, 28, and 24 percent, respectively
(Hammoud, 2013). Moreover, the abdominal circumerence
grew disproportionately larger in the diabetic groups. Analysis o
head circumerence/abdominal circumerence (HC/AC) ratios
shows that this disproportionate growth occurs mainly in diabetic pregnancies that ultimately yield macrosomic newborns.
Unexplained Fetal Demise
Te risk o etal death is three to our times higher in women
with pregestational diabetes (Gardosi, 2013; Patel, 2015). In
the United Kingdom study o more than 17,000 pregnancies in
women with pregestational diabetes, the stillbirth incidence was
similar in those with type 1 or type 2 diabetes—10.4 versus 13.5
per 1000 live and stillbirths, respectively (Murphy, 2021). Stillbirth without an identiable cause is a phenomenon relatively
limited to pregnancies complicated by overt diabetes. Tese stillbirths are “unexplained” because common actors such as obvious
placental insuciency, placental abruption, etal-growth restriction, or oligohydramnios are not identied. Tese etuses are typically LGA and die beore labor, usually later in the third trimester.
Tese unexplained stillbirths are usually associated with poor
glycemic control. In one study, suboptimal glycemic control was
identied in two thirds o unexplained stillbirths between 1990
and 2000 (Lauenborg, 2003). Fetuses o diabetic mothers also
oten have elevated lactic acid levels. Salvesen and colleagues
(1992, 1993) analyzed etal blood samples and reported that
mean umbilical venous blood pH was lower in diabetic pregnancies and was signicantly related to etal insulin levels. Tese
ndings support a hypothesis that hyperglycemic-mediated
chronic aberrations in oxygen and etal metabolite transport
may underlie these unexplained etal deaths (Pedersen, 1977).
Maternal ketoacidosis also can cause etal death (Bryant,
2017). Moreover, stillbirths rom placental insuciency occur
with increased requency in women with overt diabetes and are
usually associated with severe preeclampsia. In the prior cited
Caliornia study, the etal death risk was sevenold higher in
women with hypertension and pregestational diabetes compared with the threeold increased risk associated with diabetes
alone (Yanit, 2012). Stillbirth rates are also elevated in women
with advanced diabetes and vascular complications.
Hydramnios
Diabetic pregnancies are oten complicated by excess amnionic
fuid. In one sonographic study, 18 percent o 314 pregnancies complicated by pregestational diabetes were ound to have
hydramnios in the third trimester, which was dened as an
amnionic fuid index (AFI) >24 cm. Women with elevated
HbA1c values in the third trimester were more likely to have
hydramnios (Idris, 2010). In a similar study, poor maternal
glucose control was associated with macrosomia and hydramnios (Vink, 2006). A likely—albeit unproven—explanation
is that etal hyperglycemia causes etal polyuria (Chap. 14, p.
256). In a study rom Parkland Hospital, Dashe and coworkers
(2000) ound that the AFI parallels the amnionic fuid glucose
level among women with diabetes.
Neonatal Effects
Beore tests o etal health and maturity became available, delivery beore term was deliberately selected or women with diabetes to avoid unexplained stillbirth. Although this practice has
been largely abandoned, a higher requency o preterm delivery
in women with diabetes persists. One analysis o early-term
delivery (370/7 to 386/7 weeks) showed a 13-percent reduction
in such deliveries in women with diabetes between 2005 and
2011 (Little, 2015). Most indicated deliveries are prompted by
advanced diabetes with superimposed preeclampsia.
Although modern neonatal care has reduced neonatal death
rates due to immaturity, neonatal morbidity due to preterm
birth continues to be a serious consequence. In one Neonatal Research Network study o 10,781 extremely preterm neonates, those born to diabetic women treated with insulin prior
FIGURE 60-2 This 6050-g macrosomic neonate was born to a
woman with gestational diabetes.CHAPTER 60
Diabetes Mellitus 1073
to pregnancy were at greater risk or necrotizing enterocolitis
and late-onset sepsis than similarly aged neonates o mothers
without diabetes (Boghossian, 2016).
Respiratory Distress Syndrome
Gestational age rather than overt diabetes is likely the most
signicant actor associated with respiratory distress syndrome
(Chap. 34, p. 615). Indeed, in one analysis o 19,399 verylow-birthweight neonates delivered between 24 and 33 weeks’
gestation, rates o respiratory distress syndrome in newborns o
diabetic mothers were not higher compared with rates in neonates o nondiabetic mothers (Bental, 2011). Diabetes does not
appear to alter the benecial eects o antenatal corticosteroids
to hasten lung maturity (Battarbee, 2020a).
Hypoglycemia and Hypocalcemia
Newborns o a diabetic mother experience a rapid drop in
plasma glucose concentration ater delivery. Tis is attributed
to the hyperplasia o etal β-islet cells that is induced by chronic
maternal hyperglycemia. Low glucose concentrations—dened
as <45 mg/dL—are particularly common in newborns o
women with unstable glucose concentrations during labor (van
Kempen, 2020). Preliminary observations showed that earlyterm etuses exposed to antenatal corticosteroids have a high
rate o hypoglycemia (Gupta, 2020). Frequent blood glucose
measurements in the newborn and active early eeding practices
can mitigate this complication.
Hypocalcemia is dened as a total serum calcium concentration <8 mg/dL in term newborns. Early-onset hypocalcemia
is one o the potential metabolic derangements in neonates o
diabetic mothers. Its cause is unclear. Teories include altered
magnesium–calcium economy, asphyxia, and preterm birth.
In one randomized study, 137 pregnant women with type 1
diabetes were managed with strict versus customary glucose
control (DeMarini, 1994). Almost a third o neonates in the
customary control group developed hypocalcemia compared
with only 18 percent o those in the strict-control group.
Hyperbilirubinemia and Polycythemia
Te pathogenesis o hyperbilirubinemia in neonates o diabetic
mothers is uncertain. A major contributing actor is newborn
polycythemia, which raises the bilirubin load (Chap. 33, p.
606). Polycythemia is thought to be a etal response to relative hypoxia. According to Hay (2012), the sources o this etal
hypoxia are hyperglycemia-mediated elevations in maternal
anity or oxygen and etal oxygen consumption. ogether
with insulin-like growth actors, this hypoxia leads to elevated
etal erythropoietin levels and red cell production.
Cardiomyopathy
Newborns o pregestational and gestational diabetic pregnancies requently have hypertrophic cardiomyopathy. Tis
remodeling can be associated with cardiac dysunction (Aguilera, 2020; Depla, 2021). Huang and coworkers (2013) propose that pathological ventricular hypertrophy in neonates
born to women with diabetes is due to insulin excess. In severe
cases, this cardiomyopathy may lead to obstructive cardiac ailure. In one study, the etuses o 26 women with pregestational
diabetes underwent serial echocardiographic evaluation. In the
rst trimester, etal diastolic dysunction was already evident in
some. In the third trimester, the etal interventricular septum
and right ventricular wall were thicker in etuses o diabetic
mothers (Russell, 2008). Others report similar observations
(Aguilera, 2020). Most aected newborns are asymptomatic
ollowing birth, and hypertrophy usually resolves in the months
ater delivery. Any long-term adverse sequelae remain to be
determined (Depla, 2021).
Long-term Cognitive Development
Intrauterine metabolic conditions are linked to neurodevelopment in ospring. In a study o more than 700,000 Swedish
men, the intelligence quotient o those whose mothers had diabetes during pregnancy averaged 1 to 2 points lower (Fraser,
2014). DeBoer and associates (2005) demonstrated impaired
memory perormance at age 1 year in inants o diabetic mothers. Results rom the Childhood Autism Risks rom Genetics
and the Environment (CHARGE) study indicated that autism
spectrum disorders or developmental delay also were more
common in children o diabetic women (Krakowiak, 2012).
Adane and colleagues (2016) conrmed a consistent relationship between maternal diabetes and diminished cognitive and
language development in studies o younger children but not
older children. Because interpreting eects o the intrauterine
environment on neurodevelopment is conounded by postnatal
actors, the link between maternal diabetes, glycemic control,
and long-term neurocognitive outcome remains unconrmed.
Inheritance
Te risk o developing type 1 diabetes i either parent is aected
is 3 to 5 percent. ype 2 diabetes has a much stronger genetic
component. I both parents have type 2 diabetes, the risk o their
ospring developing it approaches 40 percent (Powers, 2018).
Both types o diabetes develop ater a complex interplay between
genetic predisposition and environmental actors. ype 1 diabetes is prompted by environmental triggers such as inection, diet,
or toxins and is heralded by the appearance o islet-cell autoantibodies in genetically vulnerable people (Pociot, 2016).
■ Maternal Effects
Diabetes and pregnancy can interact to an extent that maternal welare can be jeopardized. With the possible exception o
diabetic retinopathy, however, the long-term course o diabetes
does not appear to be aected by pregnancy.
In one analysis o more than 800,000 pregnancies, the 1125
mothers with type 1 diabetes had greater risks or hypertension and
respiratory complications than nondiabetic gravidas (Jovanovič,
2015). Te 10,126 mothers with type 2 diabetes had an elevated
risk or hypertension, inection, depression, and cardiac or respiratory complications compared with nondiabetic gravidas.
Maternal death is uncommon, but rates in women with
diabetes are still higher than those in unaected gravidas. In
one analysis o 972 women with type 1 diabetes, the maternal
mortality rate was 0.5 percent. Deaths stemmed rom diabetic
ketoacidosis, hypoglycemia, hypertension, and inection (Leinonen, 2001).1074
Section 12
Medical and Surgical Complications
Preeclampsia
Pregnancy-associated hypertension is the complication that
most oten orces preterm delivery in diabetic women. Te incidence o chronic and gestational hypertension—and especially
preeclampsia—is remarkably increased (Chap. 40, p. 690).
In one metaanalysis o 92 studies, women with pregestational
diabetes had a nearly ourold higher pooled relative risk or
preeclampsia (Bartsch, 2016). In the prior cited Caliornia
study, preeclampsia developed three to our times more oten
in women with overt diabetes. Moreover, those diabetics with
coexistent chronic hypertension were almost 12 times more
likely to develop preeclampsia (Yanit, 2012).
Women with type 1 diabetes in more advanced White classes
typically exhibit preexisting vascular complications and nephropathy. Tese women are more likely to develop preeclampsia
(Fig. 60-3). Tis rising risk may be related to oxidative stress,
which plays a key role in the pathogenesis o diabetic complications and preeclampsia. With this in mind, the Diabetes and
Preeclampsia Intervention rial (DAPI) randomly assigned
762 women with type 1 diabetes to antioxidant vitamin C and
E supplementation or placebo in the rst hal o pregnancy
(McCance, 2010). Preeclampsia rates were not improved except
in the ew with a low antioxidant status at baseline.
Preventively, low-dose aspirin prophylaxis is recommended
in women at high risk o preeclampsia, which includes those
with type 1 or type 2 diabetes (Chap. 40, p. 705). An 81-mg
oral daily dose is initiated between 12 and 28 weeks’ gestation
and is continued until delivery (American College o Obstetricians and Gynecologists, 2020a).
Diabetic Nephropathy
Diabetes is the leading cause o end-stage renal disease in
the United States (Chap. 56, p. 1003). Clinically detectable
nephropathy begins with microalbuminuria, recognized as
30 to 300 mg o protein in a 24-hour urine collection specimen. Tis may maniest as early as 5 years ater diabetes onset.
Macroalbuminuria—more than 300 mg in a 24-hour collection specimen—develops in patients destined to have end-stage
renal disease. Hypertension almost invariably develops during
this period, and renal ailure ensues typically in the next 5 to
10 years. Te incidence o overt proteinuria is nearly 30 percent
in individuals with type 1 diabetes and ranges rom 4 to 20
percent in those with type 2 diabetes (Reutens, 2013). Regression is common, presumably rom improved glucose control.
Approximately 5 percent o gravidas with overt diabetes
already have renal involvement (American College o Obstetricians and Gynecologists, 2020c). As many as 40 percent o
these will develop preeclampsia (Vidae, 2008). In addition,
Ambia and associates (2020) reported that the rates o preterm
delivery, preeclampsia, and etal-growth restriction were signi-
cantly higher in diabetic women with proteinuria >300 mg/d
compared with rates in diabetic gravidas whose 24-hour protein
excretion was <300 mg/d.
In general, pregnancy does not appear to worsen diabetic
nephropathy. In one prospective study o 43 women with diabetes, diabetic nephropathy did not progress through 12 months
ater delivery (Young, 2012). Most o these women had only
mild renal impairment. Conversely, pregnant women with
moderate to severe renal impairment may have accelerated progression o their disease (Vidae, 2008). As in women with glomerulopathies, hypertension or substantial proteinuria beore or
during pregnancy is a major predictive actor or ultimate progression to renal ailure in women with diabetic nephropathy.
Diabetic Retinopathy
Retinal vasculopathy is a highly specic complication o both
type 1 and type 2 diabetes. In the United States, diabetic retinopathy is the most important cause o visual impairment in
working-aged adults. Te rst and most common visible lesions
are small microaneurysms ollowed by blot hemorrhages that
orm when erythrocytes escape rom the aneurysms. Tese areas
leak serous fuid that creates hard exudates. Such eatures are
termed background or nonproliferative retinopathy.
With increasingly severe retinopathy, the abnormal vessels
o background eye disease become occluded. Tis leads to retinal ischemia and inarctions that appear as cotton wool exudates.
Tese are considered preproliferative retinopathy. In response to
ischemia, neovascularization begins on the retinal surace and
out into the vitreous cavity. Vision is obscured when these vessels bleed. Laser photocoagulation beore hemorrhage reduces
the rate o visual loss progression and blindness by hal. Te
procedure may be perormed during pregnancy when indicated.
In one study o nearly 500 pregnancies in women with type
1 diabetes, a third had prepregnancy retinopathy and 16 percent o these showed worsening (Bourry, 2021). Almost 25
percent o those without prepregnancy retinopathy developed
disease during pregnancy. Fortunately, development o sightthreatening retinopathy was rare, and only 4 percent o patients
ollowed postpartum had progression o disease.
Another group o investigators evaluated 80 women with
type 2 diabetes and identied retinopathy, mostly mild, in 14
percent during early pregnancy (Rasmussen, 2010). Progression was identied in 14 percent.
Other risk actors that have been associated with progression o retinopathy include hypertension, higher levels o insulinlike growth actor 1, placental growth actor, and macular
edema identied in early pregnancy (Huang, 2015; Vestgaard,
2010). Te American Academy o Ophthalmology (2019)
15
B
(n=164)
Diabetic class C
(n=129)
Preeclampsia incidence
(percent)
D
(n=172)
F
(n=26)
Total
(n=491)
30
45
60
Swedena
United Statesb
FIGURE 60-3 Incidence of preeclampsia in 491 women with type
1 diabetes stratefied by diabetic class in Sweden and the United
States. (Data from Hansona, 1993; Sibaib, 2000.)CHAPTER 60
Diabetes Mellitus 1075
recommends that pregnant women with overt diabetes should
be oered retinal assessment ater the rst prenatal visit. Subsequent eye examinations depend on severity o retinopathy
and level o glucose control. Currently, most agree that laser
photocoagulation and good glycemic control during pregnancy
minimize the potential or deleterious eects o pregnancy.
Ironically, “acute” rigorous metabolic control during pregnancy has been linked to acute worsening o retinopathy. In a
study o 201 women with retinopathy, almost 30 percent su-
ered eye disease progression during pregnancy despite intensive
glucose control (McElvy, 2001). Tat said, Wang and coworkers (1993) observed that although retinopathy worsened during the critical months o rigorous glucose control, long-term
progression o eye disease actually slowed.
Diabetic Neuropathy
Peripheral, symmetrical sensorimotor diabetic neuropathy is
uncommon in pregnant women. However, one orm o this,
diabetic gastropathy, can be troublesome during pregnancy. It
causes nausea and vomiting, nutritional problems, and dicult
glucose control. Aected women are advised that this complication is associated with a high risk o morbidity and poor
perinatal outcome (Kitzmiller, 2008). reatment with metoclopramide and dopamine D2 receptor antagonists is sometimes successul. Gastric neurostimulators have shown success
during pregnancy (Fuglsang, 2015). reatment o hyperemesis
gravidarum can be challenging, and we routinely provide insulin initially by continuous inusion or diabetic women who are
admitted with this condition (Chap. 57, p. 1015).
Diabetic Ketoacidosis
Tis serious complication develops in approximately 1 percent o
diabetic pregnancies and is most oten encountered in women with
type 1 diabetes (Ehrmann, 2020). It is increasingly being reported
in women with type 2 or even those with gestational diabetes (Bryant, 2017; Sibai, 2014). Diabetic ketoacidosis (DKA) may develop
with hyperemesis gravidarum, inection, insulin noncompliance,
insulin pump ailures, β-mimetic drugs given or tocolysis, and
corticosteroids given to induce etal lung maturation. DKA results
rom an insulin deciency combined with an excess in counter-regulatory hormones such as glucagon. Tis leads to gluconeogenesis
and ketone body ormation. Te ketone body β-hydroxybutyrate
is synthesized at a much greater rate than acetoacetate, which is
preerentially detected by commonly used ketosis-detection methods. Tus, serum or plasma assays or β-hydroxybutyrate more
accurately refect true ketone body levels.
Te maternal mortality rate with DKA is <1 percent, but
perinatal mortality rates associated with a single episode o DKA
may reach 35 percent (Bryant, 2017; Guntupalli, 2015). Noncompliance is a prominent actor, and this and DKA were historically considered prognostically bad signs in pregnancy (Pedersen,
1974). Importantly, pregnant women usually develop DKA at
lower blood glucose thresholds than when nonpregnant. In a
study rom Parkland Hospital, the mean glucose level or pregnant
women with DKA was 380 mg/dL, and the mean HbA1C value
was 10 percent (Bryant, 2017). Euglycemic ketoacidosis during
pregnancy also is possible but is rare (Sibai, 2014; Smati, 2020).
One management protocol or diabetic ketoacidosis is shown
in Table 60-7. An important cornerstone o management is
TABLE 60-7. Management of Diabetic Ketoacidosis During Pregnancy
Laboratory Assessment
Obtain arterial blood gases to document degree of acidosis present; measure glucose,
creatinine, ketones, and electrolyte levels at 1- to 2-hour intervals
Insulin
Low-dose, intravenous
Loading dose: 0.2–0.4 U/kg
Maintenance: 2–10 U/hr
Fluids
Isotonic sodium chloride for 3L, then 0.45% saline
Total replacement in first 12 hours of 4–6 L
1 L in first hour
500–1000 mL/hr for 2–4 hours
250 mL/hr until 80 percent replaced
Glucose
Begin 5-percent dextrose in 0.45% saline when glucose plasma level reaches 250 mg/dL
(14 mmol/L)
Potassium
If initially normal or reduced, an infusion rate up to 15–20 mEq/hr may be required; if
elevated, wait until levels decrease into the normal range, then add to intravenous
solution in a concentration of 20–30 mEq/L
Bicarbonate
Add one ampule (44 mEq) to 1 L of 0.45 normal saline if serum pH is <7.1
Data from Bryant, 2017; Powers, 2018; Sibai, 2014.1076
Section 12
Medical and Surgical Complications
vigorous rehydration with crystalloid solutions o normal saline
or Ringer lactate.
Infections
Te rates o many inections are higher in diabetic pregnant
women. Common ones include candidal vulvovaginitis, bacterial urinary and respiratory tract inections, and puerperal pelvic sepsis. However, in one study o more than 1250 diabetic
gravidas screened beore 16 weeks’ gestation, rates o bacterial
vaginosis or vaginal colonization with Candida or Trichomonas
species were not increased (Marschalek, 2016).
In one population-based study o almost 200,000 pregnancies,
the risk o asymptomatic bacteriuria in women with diabetes was
increased twoold (Sheiner, 2009). Another study ound positive
urine culture results in 25 percent o diabetic women (Alvarez,
2010). In a 2-year analysis o pyelonephritis in pregnant women
at Parkland Hospital, 5 percent with diabetes developed pyelonephritis compared with 1.3 percent without diabetes (Hill, 2005).
Rates o urinary tract inections can be minimized by screening
and eradicating asymptomatic bacteriuria (Chap. 56, p. 995).
Last, Johnston and colleagues (2017) reported that 16.5 percent o women with pregestational diabetes had postoperative
wound complications ollowing cesarean delivery. Prevention
options are described in Chapter 30 (p. 550).
■ Preconceptional Care
Because o the close relationship between pregnancy complications and maternal glycemic control, eorts to achieve glucose
targets are typically more aggressive during pregnancy. Unortunately, nearly hal o pregnancies in the United States are
unplanned, and diabetic women requently begin pregnancy
with suboptimal glucose control (Finer, 2016; Kim, 2005).
Management preerably should begin beore pregnancy and
then include specic goals during each trimester.
o minimize early pregnancy loss and congenital malormations, the National Preconception Health and Healthcare Initiative Clinical Workgroup established values or optimal glycemic
control beore conception (Frayne, 2016). Tis was dened as a
HbA1c level <6.5 percent in women with pregestational diabetes. Te American Diabetes Association (2017b) has also dened
optimal preconceptional glucose control in those using insulin.
Refective values are sel-monitored preprandial glucose levels
o 70 to 100 mg/dL, peak 2-hour postprandial values o 100 to
120 mg/dL, and mean daily glucose concentrations <110 mg/dL.
In one prospective population-based study o 933 pregnant
women with type 1 diabetes, the risk o congenital malormations was not demonstrably higher with HbA1c levels <6.9 percent compared with the risk in more than 70,000 nondiabetic
gravidas (Jensen, 2010). However, a substantial ourold greater
risk or malormations was ound or HbA1c levels >10 percent
(see Fig. 60-1). Another study ound ewer adverse outcomes
with improved HbA1c values rom conception to midpregnancy
(Davidson, 2020).
I indicated, evaluation and treatment or diabetic complications such as retinopathy or nephropathy should be instituted
beore pregnancy. Last, olate, 400 μg/d orally, is given periconceptionally and during early pregnancy to decrease the risk
o neural-tube deects (Egan, 2020).
■ Firsttrimester Care
Careul monitoring o glucose control is essential. For this reason, we routinely hospitalize women with overt diabetes during early pregnancy to initiate an individualized glucose control
program and provide education. Tis also aords an opportunity to assess the extent o diabetic vascular complications
and precisely establish gestational age. Te checklist provided
by the Society or Maternal-Fetal Medicine (2020) is helpul.
Some initial evaluations done at Parkland Hospital include
assessment o 24-hour urine protein excretion and serum creatinine level, retinal examination, and echocardiogram i chronic
hypertension is comorbid.
First-trimester screening or aneuploidy may include measurement o maternal serum pregnancy-associated plasma protein A (PAPP-A), β-human chorionic gonadotropin (hCG),
and ultrasound measurement o etal nuchal translucency
(Chap. 17, p. 333). Noninvasive prenatal testing with cell-ree
DNA also is suitable. Although initially thought not to be di-
erent in women with pregestational diabetes, one analysis o
more than 100 insulin-treated women identied reductions
in median PAPP-A and β-hCG levels compared with gravidas without diabetes (Gurram, 2014). Not surprisingly, they
detected no dierence in nuchal translucency measurements.
When calculating aneuploidy risks in women with diabetes,
these dierences should be considered.
■ Insulin Treatment
Te gravida with overt diabetes is best treated with insulin.
Although oral hypoglycemic agents have been used successully
or gestational diabetes (p. 1083), these agents are not currently recommended or overt diabetes, despite some controversy (American College o Obstetricians and Gynecologists,
2020c). In an international, placebo-controlled trial including
502 insulin-treated women with type 2 diabetes, adjunctive
metormin therapy was associated with improved glycemic
control, reduced maternal weight gain, lower cesarean delivery
rate, and less neonatal adiposity (Feig, 2020). Importantly, the
proportion o small-or-gestational age newborns was higher in
the insulin plus metormin group, but the rate o composite
serious neonatal outcomes was not increased compared with
those receiving insulin plus placebo.
Maternal glycemic control can usually be achieved with multiple daily insulin injections and adjustment o dietary intake.
Table 60-8 lists the action proles o common short- and longacting insulins (Powers, 2018). Subcutaneous insulin inusion
by a calibrated pump does not yield better pregnancy outcomes
compared with multiple daily injections. However, an inusion pump is a sae alternative in appropriately selected patients
(Farrar, 2016). With the advent o sensor-augmented insulin pumps and closed-loop insulin delivery systems, improved
glycemic control with either manual or computer-generated
insulin adjustments based on continuous glucose monitoring is now possible (Bergenstal, 2021; Stewart, 2016). In one
study o insulin pump use in women with type 1 diabetes, total
daily insulin doses declined in the rst trimester but later rose
more than threeold. Postprandial glucose elevations prompted
most o the required daily-dose increases (Roeder, 2012). I aCHAPTER 60
Diabetes Mellitus 1077
continuous-inusion insulin pump is elected, initiation prepregnancy may help avoid hypoglycemia and ketoacidosis risks associated with the device's learning curve (Sibai, 2014).
Monitoring
Sel-monitoring o capillary glucose levels using a glucometer is recommended because this involves the woman in her
own care (Dong, 2020). Te American Diabetes Association
(2017b) recommends asting and postprandial glucose monitoring, and Table 60-9 lists glucose goals recommended in
pregnancy. Currently not standard care, one study showed that
longitudinal HbA1c values could be used or risk stratication
(Finneran, 2020). Advances in noninvasive glucose monitoring
will undoubtedly render intermittent capillary glucose monitoring obsolete. Subcutaneous continuous glucose monitoring devices have shown that pregnant women with diabetes
experience signicant periods o daytime hyperglycemia and
nocturnal hypoglycemia that are undetected by traditional
monitoring (Combs, 2012). Such glucose monitoring systems,
coupled with a continuous insulin pump, oer the potential o
an “articial pancreas” to avoid hypo- or hyperglycemia during
pregnancy (Bergenstal, 2021).
Diet
Nutritional planning includes appropriate weight gain through
carbohydrate and caloric modications based on height, weight,
and degree o glucose intolerance (American Diabetes Association, 2017b; Egan, 2020). Te mix o carbohydrate, protein,
and at is adjusted to meet the metabolic goals and individual
patient preerences. A minimum o 175 g/d o carbohydrates
ideally is provided. In one analysis o more than 200 obese
pregnant women with glucose intolerance, a lower carbohydrate intake, particularly late in pregnancy, was associated with
lower at mass in ospring at birth (Renault, 2015). Allotted carbohydrates are distributed throughout the day in three
small- to moderate-sized meals and two to our snacks. Weight
loss is not recommended, but modest caloric restriction may be
appropriate or overweight or obese women. An ideal dietary
composition is 55 percent carbohydrate, 20 percent protein,
and 25 percent at, o which <10 percent is saturated at.
Hypoglycemia
Diabetic control can be unstable in the rst hal o pregnancy,
and the incidence o hypoglycemia peaks during the rst trimester. One study ound hypoglycemic events—blood glucose
values <40 mg/dL—in 37 o 60 women with type 1 diabetes.
A ourth o these were considered severe because the women
were unable to treat their own symptoms and required assistance rom another person (Chen, 2007). Caution is recommended when attempting to achieve euglycemia in women with
recurrent episodes of hypoglycemia.
From one Cochrane database review, loose glycemic control,
dened as asting glucose values >120 mg/dL, was associated
with greater risks or preeclampsia, cesarean delivery, and birthweight >90th percentile compared with women with tight or
moderate control (Middleton, 2016). With very tight control,
dened by asting values <90 mg/dL, no obvious benets were
gained, but the number o cases o hypoglycemia increased.
■ Secondtrimester Care
Maternal serum alpha-etoprotein determination at 16 to 20
weeks’ gestation is used in association with targeted sonographic
examination to detect neural-tube deects and other anomalies (Chap. 17, p. 338). Tese serum levels may be lower in
diabetic pregnancies, and interpretation is altered accordingly.
Because the incidence o congenital cardiac anomalies shown
in able 60-6 is increased veold in mothers with diabetes,
etal echocardiography is an important part o second-trimester
sonographic evaluation (Society or Maternal-Fetal Medicine,
2020). Dashe and coworkers (2009) cautioned that detection
o etal anomalies in obese diabetic women is more dicult
than in similarly sized women without diabetes.
Regarding second-trimester glucose control, normoglycemia
with sel-monitoring continues to be the goal. Ater the rst
trimester's glucose instability, a stable period ensues. Tis is
then ollowed by higher insulin requirements. Tese stem rom
the enhanced peripheral resistance to insulin that is related to
pregnancy and is described in Chapter 4 (p. 57).
Although most women with pregestational diabetes require
a higher total daily insulin dose with advancing gestational age,
a small proportion will experience a reduction in their daily
dose later in pregnancy. Te signicance o this drop remains
uncertain. One Australian study evaluated women with alling
TABLE 60-8. Action Profiles of Commonly Used Insulins
Insulin Type Onset Peak (hr) Duration (hr)
Short-acting (SC)
Lispro <15 min 0.5–1.5 2–4
Glulisine
Aspart
<15 min
<15 min
0.5–1.5
0.5–1.5
2–4
2–4
Regular (SC) 30–60 min 2–3 3–6
Regular inhaled 30–60 min 2–3 3
Long-acting (SC)
Degludec 1–9 hr — <12
Detemir 1–4 hr Minimala 12–24
Glargine 1–4 hr Minimala 20–24
NPH 1–4 hr 4–10 10–16
aMinimal peak activity.
NPH = neutral protamine Hagedorn; SC = subcutaneous.
TABLE 60-9. Self-Monitored Capillary Blood Glucose
Goals
Specimen Level (mg/dL)
Fasting ≤95
Premeal ≤100
1-hr postprandial ≤140
2-hr postprandial ≤120
0200–0600 ≥60
Mean (average) 100
Hemoglobin A1c ≤6%1078
Section 12
Medical and Surgical Complications
insulin requirements (FIR), dened as a ≥15 percent drop
in the peak total daily insulin dose ater 20 weeks’ gestation
(Padmanabhan, 2017). In 158 women with type 1 and type 2
diabetes and FIR, the risk or a composite o adverse outcomes
indicative o placental insuciency was ourold greater than in
those without FIR. Te composite primary outcome included
preeclampsia, etal-growth disorders, delivery beore 30 weeks’
gestation, placental abruption, and etal death beore 20 weeks.
FIR was more common in women with type 1 diabetes.
■ Thirdtrimester Care and Delivery
During the past several decades, the threat o late-pregnancy stillbirth in women with diabetes prompted recommendations or
various etal surveillance programs beginning in the third trimester. Such protocols include etal movement counting, periodic
etal heart rate monitoring, intermittent biophysical prole evaluation, and contraction stress testing (Chap. 20, p. 384). None o
these techniques has been subjected to prospective randomized
clinical trials, and their primary value seems related to their low
alse-negative rates. Te American College o Obstetricians and
Gynecologists (2020c, 2021) suggests initiating such testing at 32
to 34 weeks’ gestation. With reassuring testing and no other complications, delivery is anticipated between 390/7 and 396/7 weeks.
At Parkland Hospital, women with diabetes are seen in a specialized Maternal–Fetal Medicine clinic every 2 weeks. During
these visits, glycemic control records are evaluated, and insulin
doses are adjusted. Women are routinely instructed to perorm
etal kick counts beginning early in the third trimester. At 34
weeks’ gestation, admission to our High-Risk Pregnancy Unit is
oered to all insulin-treated women. Approximately hal o these
women choose admission. While in the hospital, they continue
daily etal movement counts and undergo etal heart rate monitoring three times a week. With no other complications, delivery
at Parkland is typically planned or 38 weeks.
At the University o Alabama at Birmingham, weekly antenatal testing is initiated no later than 34 weeks’ gestation.
wice-weekly testing is reserved or those with poorly controlled diabetes or supervening medical or obstetrical complications. Delivery is planned or 39 weeks’ gestation in those
with good glycemic control and reassuring antenatal testing.
Earlier delivery is planned or those with poor glycemic control
or signicant comorbidities.
For vaginal delivery, labor induction may be attempted
when the etus is not excessively large and the cervix is considered avorable (Chap. 26, p. 486). Cesarean delivery at or near
term has requently been used to avoid the traumatic birth o
a large etus in a woman with diabetes. In women with more
advanced diabetes, especially those with vascular disease, the
reduced likelihood o successul labor induction remote rom
term has also contributed to an increased cesarean delivery rate.
In an analysis o pregnancy outcomes o diabetic women rom
University o Alabama at Birmingham according to the White
classication, the rates o cesarean delivery and preeclampsia
escalated with White class (Bennett, 2015). In another study, a
HbA1c level >6.4 percent at delivery was independently associated with urgent cesarean delivery (Miailhe, 2013). Tis suggests
that tighter glycemic control during the third trimester might
reduce late etal compromise and cesarean delivery or etal indications. Many o these women have undergone prior cesarean
delivery. Somewhat related to this, the cesarean delivery rate or
women with overt diabetes has remained at approximately 80
percent or the past 40 years at Parkland Hospital.
Reducing or withholding the dose o long-acting insulin on
the day o delivery is recommended. Regular insulin should be
used to meet most or all o the insulin needs o the mother during this time, because insulin requirements typically drop markedly ater delivery. During labor, continuous insulin inusion by
calibrated intravenous pump is most satisactory (Table 60-10).
Te woman should be adequately hydrated intravenously and
given glucose in sucient amounts to maintain euglycemia.
Capillary or plasma glucose levels are checked hourly during
active labor, and regular insulin is administered accordingly.
■ Puerperium
Oten, many diabetic women may require virtually no insulin
or the rst 24 hours or more postpartum. Subsequently, insulin
requirements may fuctuate markedly during the next ew days.
Inection must be promptly detected and treated. When appropriate, oral agents can be restarted. For type 2 diabetic women
who will be transitioned to oral agents, this can be done on
postoperative day 1.
Counseling in the puerperium should include a discussion
o birth control. Eective contraception is especially important
in women with overt diabetes to allow optimal glucose control
beore subsequent conception (Chap. 38, p. 664).
GESTATIONAL DIABETES
In the United States in 2016, almost 6 percent o pregnancies
were complicated by gestational diabetes (Deputy, 2018). Worldwide, its prevalence diers according to race, ethnicity, age, and
body composition and by screening and diagnostic criteria. As
discussed in the ollowing sections, several persisting controversies pertain to the diagnosis and treatment o gestational diabetes.
TABLE 60-10. Insulin Management for Labor Induction or Scheduled Cesarean Delivery
Give evening dose insulin.
Withhold morning dose.
Infuse intravenous normal saline at 100–125 mL/hr.
Regular insulin is infused at 1–1.25 units/hr if glucose levels >100 mg/dL.
Measure glucose levels hourly.
With active labor or if glucose levels are >70 mg/dL, change from intravenous saline to 5% dextrose given at 100–150 mL/hr
with a target glucose level of ∼100mg/dL.CHAPTER 60
Diabetes Mellitus 1079
Te word gestational implies that diabetes is induced by pregnancy—ostensibly because o exaggerated physiological changes
in glucose metabolism (Chap. 4, p. 57). Gestational diabetes
is dened as carbohydrate intolerance o variable severity with
its onset or rst recognition during pregnancy (American College o Obstetricians and Gynecologists, 2019a). Tis denition applies whether or not insulin is used or treatment and
undoubtedly includes some women with previously unrecognized overt diabetes.
Te term gestational diabetes aims to communicate the need
or enhanced surveillance during pregnancy and to stimulate urther testing postpartum. Te most important perinatal correlate
is excessive etal growth, which may result in both maternal and
etal birth trauma. Te likelihood o etal death with appropriately treated gestational diabetes is not dierent rom that in the
general population. More than hal o women with gestational
diabetes ultimately develop overt diabetes in the ensuing 20 years.
Moreover, mounting evidence implicates long-range complications that include obesity and diabetes in their ospring.
■ Screening and Diagnosis
Despite almost 50 years o research, there is still no agreement
on the optimal screening method or gestational diabetes. Te
diculty in achieving consensus is underscored by the controversy ollowing publication o the single-step approach shown
in Table 60-11, which assesses the glucose values ollowing a
75-g oral glucose load. Tis strategy is espoused by the International Association o Diabetes and Pregnancy Study Groups
Consensus Panel (2010) and was greatly infuenced by results
o the Hypoglycemia and Pregnancy Outcomes (HAPO) study,
described subsequently. Although the American Diabetes Association (2019) supports this new scheme, the American College o Obstetricians and Gynecologists (2019a) continues to
recommend a two-step approach to screen and then diagnose
gestational diabetes. Similarly, the National Institutes o Health
(NIH) Consensus Development Conerence in 2013 concluded
that evidence is insucient to adopt a one-step approach.
Te recommended two-step approach begins with either
universal or risk-based selective screening using a 50-g, 1-hour
oral glucose challenge test. Participants in the Fith International
Workshop Conerences on Gestational Diabetes endorsed use o
selective screening criteria shown in Table 60-12 (Metzger, 1998).
TABLE 60-11. Threshold Values for Diagnosis of
Gestational Diabetes with 75-g OGTT
Plasma
Glucose
Glucose Concentration
Thresholda
Above Threshold
(%)
mmol/L mg/dL Cumulative
Fasting 5.1 92 8.3
1-hr OGTT 10.0 180 14.0
2-hr OGTT 8.5 153 16.1b
aOne or more of these values from a 75-g OGTT must be
equaled or exceeded for the diagnosis of gestational diabetes.
bIn addition, 1.7% of participants in the initial cohort were
unblinded because of fasting plasma glucose levels
>5.8 mmol/L (105 mg/dL) or 2-hr OGTT values
>11.1 mmol/L (200 mg/dL), bringing the total to 17.8%.
OGTT = oral glucose tolerance test.
TABLE 60-12. Risk-Based Recommended Screening Strategy for Detecting GDMa
GDM risk assessment: should be ascertained at the first prenatal visit
Low Risk: Blood glucose testing not routinely required if all the following are present:
Member of an ethnic group with a low prevalence of GDM
No known diabetes in first-degree relatives
Age <25 years
Weight normal before pregnancy
Weight normal at birth
No history of abnormal glucose metabolism
No history of poor obstetrical outcome
Average Risk: Perform blood glucose testing at 24 to 28 weeks using either:
Two-step procedure: 50-g oral glucose challenge test (GCT), followed by a
diagnostic 100-g OGTT for those meeting the threshold value in the GCT
One-step procedure: diagnostic 100-g OGTT performed on all subjects
High Risk: Perform blood glucose testing as soon as feasible, using the procedures
described above, if one or more of these are present:
Severe obesity
Strong family history of type 2 diabetes
Previous history of GDM, impaired glucose metabolism, or glucosuria
If GDM is not diagnosed, blood glucose testing should be repeated at 24 to 28
weeks’ gestation or at any time symptoms or signs suggest hyperglycemia
aCriteria of the Fifth International Workshop-Conference on Gestational Diabetes.
GDM = gestational diabetes mellitus; OGTT = oral glucose tolerance test.1080
Section 12
Medical and Surgical Complications
Conversely, the American College o Obstetricians and Gynecologists (2019a) recommends universal screening o pregnant
women with a protocol that provides a 50-g oral glucose load and
that is ollowed in 1 hour by a laboratory-based blood glucose test.
It is suggested that attempts to identiy the minority o women
who should not be screened would add unnecessary complexity.
Screening should be perormed between 24 and 28 weeks’ gestation in those women not known to have glucose intolerance earlier in pregnancy. Tis 50-g screening test is ollowed by a diagnostic
100-g, 3-hour oral glucose tolerance test (OGTT) i screening results
meet or exceed a predetermined plasma glucose concentration.
For the 50-g screening test, the plasma glucose level is measured 1 hour ater a 50-g oral glucose load without regard to
the time o day or time o last meal. In an earlier review, the
pooled sensitivity or a threshold o 140 mg/dL ranged rom 74
to 83 percent depending on 100-g thresholds used or diagnosis
(van Leeuwen, 2012). Sensitivity estimates or a 50-g screen
threshold o 135 mg/dL improved only slightly to 78 to 85 percent, but specicity dropped rom a range o 72 to 85 percent
or 140 mg/dL to 65 to 81 percent. Using a threshold o 130
mg/dL marginally improves sensitivity with a urther decline in
specicity (Donovan, 2013). In the absence o clear evidence
supporting one cuto value over another, the American College
o Obstetricians and Gynecologists (2019a) sanctions using any
one o these three 50-g screen thresholds. At Parkland Hospital,
we continue to use 140 mg/dL as the screening threshold to
prompt the 100-g test. Te threshold used at the University o
Alabama at Birmingham is 135 mg/dL.
Justication or screening and treatment o women with gestational diabetes was strengthened by a randomized treatment
trial in 1000 women (Crowther, 2005). Women diagnosed
with gestational diabetes ater a 75-g OG and assigned
to receive dietary advice with blood glucose monitoring plus
insulin therapy were compared with a cohort assigned to usual
prenatal care. Te ormer group had a signicantly lower risk
o a composite perinatal adverse outcome that included death,
shoulder dystocia, bone racture, and nerve palsy. Macrosomia
dened by birthweight ≥4000 g complicated 10 percent o
deliveries in the intervention group compared with 21 percent
in the routine prenatal care group. Cesarean delivery rates were
almost identical in the two study groups.
Slightly dierent results were reported by the Maternal–Fetal
Medicine Units Network randomized trial o 958 women identied with mild gestational diabetes using a two-step screening
and diagnosis approach (Landon, 2009). Tey reported no di-
erences in rates o composite morbidity that included stillbirth,
birth trauma, and neonatal hypoglycemia, hyperinsulinemia,
and hyperbilirubinemia. Secondary analyses did demonstrate a
50-percent reduction in macrosomia, ewer cesarean deliveries,
and a signicant decrease in shoulder dystocia rate—1.5 versus
4 percent—in treated versus routine care groups.
Based largely on these two landmark studies, the U.S. Preventive Services ask Force (2021) recommends universal
screening in low-risk women ater 24 weeks’ gestation. However, the ask Force concluded that evidence is insucient to
assess the balance o benets versus harms o screening beore
24 weeks. Earlier screening in obese women did not result in
better outcomes (Harper, 2020).
Te optimal OG to identiy gestational diabetes also is
debated. Proposed criteria or interpretation o the diagnostic 100-g OG are shown in Table 60-13. Criteria or the
75-g OG are shown in able 60-11. A secondary analysis o the Maternal-Fetal Medicine Units Network treatment
trial showed that women diagnosed with either the National
Diabetes Data Group (NDDG) or the Carpenter-Coustan
criteria beneted rom treatment (Harper, 2016). However,
the number needed to treat to prevent a shoulder dystocia
was higher or the Carpenter-Coustan criteria. Others report
similar observations (Ghaari, 2020). At Parkland Hospital,
we use the NDDG criteria or diagnosis, whereas CarpenterCoustan criteria are preerred at the University o Alabama at
Birmingham.
Controversies of Screening and Diagnosis
Te HAPO study was a 7-year international epidemiological
study o 23,325 pregnant women at 15 centers in nine countries analyzing the association o various levels o glucose intolerance during the third trimester with adverse perinatal outcomes
(HAPO Study Cooperative Research Group, 2008). Blood glucose levels were stratied into seven categories (Fig. 60-4). Tese
values were then correlated with rates or birthweight >90th
percentile, primary cesarean delivery, neonatal hypoglycemia,
and cord serum C-peptide levels >90th percentile. Cord serum
C-peptide is secreted in equimolar concentrations with insulin
and refects etal β-islet cell unction. Findings generally supported the supposition that increasing plasma glucose levels
were associated with increasing adverse outcomes.
The International Association of Diabetes and
Pregnancy Study Group
Tis workshop conerence in 2008 concerned the diagnosis and
classication o gestational diabetes. Ater reviewing the results
o the HAPO study, a panel developed recommendations or the
diagnosis and classication o hyperglycemia during pregnancy.
TABLE 60-13. Diagnosis of Gestational Diabetes Mellitus
Using Threshold Glucose Values from
100-g Oral Glucose Tolerance Testa,b
NDDGc Carpenter–Coustand
Time (mg/dL) (mmol/L) (mg/dL) (mmol/L)
Fasting 105 5.8 95 5.3
1-hr 190 10.6 180 10.0
2-hr 165 9.2 155 8.6
3-hr 145 8.0 140 7.8
aThe test should be performed when the patient is fasting.
bTwo or more of the venous plasma glucose concentrations listed are met or exceeded for a positive diagnosis.
cSerum glucose level.
dSerum or plasma glucose level.
NDDG = National Diabetes Data Group.
Data from American College of Obstetricians and
Gynecologists, 2019a; American Diabetes Association,
2019; Ferrara, 2002.CHAPTER 60
Diabetes Mellitus 1081
Tis panel allowed or the diagnosis o overt diabetes during
pregnancy as shown in able 60-4. It also recommended a
single-step approach to the diagnosis o gestational diabetes
using the 75-g, 2-hour OG and thresholds derived using an
arbitrary 1.75 odds ratio o outcomes such as LGA birthweight
and cord serum C-peptide levels >90th percentile. Only one
o these thresholds, shown in able 60-11, would need to be
met or exceeded to make the diagnosis o gestational diabetes.
During their deliberations, the IADPSG estimated that
implementation o these recommendations would raise the
prevalence o gestational diabetes in the United States to 17.8
percent! Said another way, using this approach, the number o
women with mild gestational diabetes would increase almost
threeold with no evidence o treatment benet (Cundy, 2012).
Feldman and coworkers (2016) evaluated the implementation o the IADPSG paradigm in a beore-ater analysis that
included more than 6000 women. Compared with a two-step
approach, the new strategy was associated with a signicant
rise in gestational diabetes diagnosis rates but not with reduced
macrosomia rates. Remarkably, they identied a higher primary cesarean delivery rate associated with adoption o the
IADPSG recommendations. Te American Diabetes Association (2013, 2019) initially recommended adopting this new
approach, based on benets inerred rom trials in women identied using a two-step approach described earlier. However, it
now concludes that data also support a two-step strategy.
NIH Consensus Development Conference
Prompted by these disparate recommendations, the NIH Consensus Development Conerence on Diagnosing Gestational
Diabetes Mellitus (2013) was convened. Te panel ound
insucient evidence to adopt the one-step diagnostic process
proposed by the IADPSG and recommended continuation o the two-step
approach. Te Consensus Conerence
panel did also suggest that urther studies resolving the benecial uncertainties
associated with the one-step approach
could warrant revision o their conclusions.
A recent trial compared the IADPSG
single-step approach to the more traditional two-step approach in almost
24,000 women (Hillier, 2021). Consistent with the IADPSG prediction, the
incidence o gestational diabetes was
16.5 percent in those who underwent
single-step testing compared with 8.5
percent in women assigned to two-step
testing. However, incidences o hypertensive disorders o pregnancy, primary
cesarean delivery, LGA newborns,
and/or a perinatal composite outcome
including measures o birth trauma and
perinatal death were not materially di-
erent between testing groups. Tus,
this large and pragmatic trial does not
show maternal or perinatal benet and
thus does not justiy the increased patient and healthcare costs
o broadening the diagnosis o gestational diabetes using the
proposed single-step approach (Casey, 2021).
■ Maternal and Fetal Effects
Adverse consequences o gestational diabetes dier rom those
o pregestational diabetes (see able 60-5). Similar to women
with overt diabetes, adverse maternal eects associated with
gestational diabetes include a higher requency o hypertension
and cesarean delivery.
Unlike women with overt diabetes, women with gestational
diabetes do not appear to have etuses with substantially higher
rates o anomalies than the general obstetrical population (American College o Obstetricians and Gynecologists, 2019a; Sheeld,
2002). In a study o more than 1 million women rom the Swedish
Medical Birth Registry, major malormation rates were marginally
elevated in etuses o gestational diabetics compared with those o
nondiabetic controls—2.3 versus 1.8 percent (Fadl, 2010).
From this Registry, the stillbirth rate was not higher. Additionally, the stillbirth rate was not increased in an analysis o
more than 800,000 pregnancies rom 2005 through 2011
(Jovanovič, 2015). Tat said, women with elevated asting glucose levels have elevated rates o unexplained stillbirths similar
to those o women with overt diabetes. Tis increasing risk with
progressive maternal hyperglycemia emphasizes the importance
o identiying women with evidence o preexisting diabetes
early in pregnancy (see able 60-4).
Fetal Macrosomia
Te primary eect attributed to gestational diabetes is excessive
etal size that is variably dened and discussed in Chapter 47
30
LGA frequency (percent)
20
25
15
10
5
Glucose levels
Fasting
2 hour
1 hour ≥212
≥178
≥100
158–177
194–211
95–99
140–157
172–193
90–94
126–139
156–171
85–89
109–125
133–155
80–84
91–108
106–132
75–79
≤90
≤105
≤75
FIGURE 60-4 Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. The frequency of newborn birthweight ≥90th percentile for gestational age plotted against glucose levels fasting and at 1- and 2-hr intervals following a 75-g oral glucose load. LGA =
large for gestational age. (Reproduced with permission from HAPO Study Cooperative
Research Group, Metzger BE, Lowe LP, et al: Hyperglycemia and adverse pregnancy outcomes, N Engl J Med. 2008 May 8;358(19):1991–2002.)1082
Section 12
Medical and Surgical Complications
(p. 832). Te perinatal goal is to avoid dicult delivery rom
macrosomia and concomitant birth trauma associated with
shoulder dystocia. In one analysis o more than 80,000 vaginal
births in Chinese women, the calculated risk or shoulder dystocia in newborns weighing ≥4200 g was 76-old greater than
the risk in those weighing <3500 g (Cheng, 2013). However,
the odds ratio or shoulder dystocia in women with diabetes
was <2. Said another way, although gestational diabetes is
certainly a risk actor, it accounts or only a small number o
pregnancies complicated by shoulder dystocia.
One study identied shoulder dystocia in approximately
4 percent o women with mild gestational diabetes compared with <1 percent o women with a 50-g glucose screen
result <120 mg/dL (Landon, 2011). Te excessive shoulder
and trunk at that commonly characterizes the macrosomic
newborn o a diabetic mother predisposes such neonates to
shoulder dystocia or cesarean delivery (Durnwald, 2004;
McFarland, 2000). However, one prospective study o etal
adipose measurements demonstrated no dierences between
measurements in 630 ospring o women with gestational
diabetes and 142 without diabetes (Buhling, 2012). Te
authors attributed this negative nding to successul treatment o gestational diabetes.
Insulin-like growth factors also infuence etal growth. Tese
proinsulin-like polypeptides are produced by virtually all etal
organs and are potent stimulators o cell dierentiation and
division. Although not a current clinical tool, one study ound
that maternal insulin-like growth actor 1 levels strongly correlated with birthweight (Luo, 2012). Te HAPO Study Cooperative Research Group (2008) also ound dramatic elevations
in cord serum C-peptide levels associated with rising maternal glucose levels ollowing a 75-g OG. C-peptide levels
>90th percentile were ound in almost a third o newborns
in the highest glucose categories. Other actors implicated in
macrosomia include epidermal growth actor, broblast growth
actor, platelet-derived growth actor, leptin, and adiponectin
(Grissa, 2010; Loukovaara, 2004; Mazaki-ovi, 2005).
Maternal body mass index (BMI) is an independent and
more substantial risk actor or etal macrosomia than is glucose
intolerance (Ehrenberg, 2004; Mission, 2013). In a secondary
analysis o women with either untreated mild gestational diabetes or normal glucose tolerance testing results, higher BMI
levels were associated with rising birthweight, regardless o glucose levels (Stuebe, 2012). Another analysis ound that gestational diabetes, compared with obesity or gestational weight
gain, contributed the least to the population-attributable raction o LGA neonates (Kim, 2014). Te highest raction o
LGA neonates was attributable to maternal obesity plus excessive gestational weight gain. Similarly, Egan and colleagues
(2014) ound that excessive gestational weight gain is common
in women with gestational diabetes and coners an additive risk
or etal macrosomia.
Weight distribution also seems to play a role because the risk
o gestational diabetes is greater with maternal truncal obesity.
One cohort study ound that increased maternal abdominal
subcutaneous at thickness at 18 to 22 weeks’ gestation correlated with BMI and was a better predictor o gestational diabetes (Suresh, 2012).
Neonatal Hypoglycemia
Hyperinsulinemia may provoke severe neonatal hypoglycemia
within minutes o birth, but only three ourths o these episodes occur in the rst 6 hours (Harris, 2012). Te denition
o neonatal hypoglycemia is debated, and recommended clinical
thresholds range rom 35 to 45 mg/dL. One NIH workshop
conerence on the topic supported a threshold o 35 mg/dL in
term newborns but cautioned that this practice is not strictly
evidence based (Hay, 2009). reating neonates with glucose levels <47 mg/dL did not improve outcomes compared with treating those with glucose levels <36 mg/dL (van Kempen, 2020).
Newborns described by the HAPO Study Cooperative
Research Group (2008) had an incidence o clinical neonatal
hypoglycemia that rose with increasing maternal OG result
values dened in Figure 60-4. Te requency varied rom 1 to 2
percent, but it was as high as 4.6 percent in women with asting
glucose levels ≥100 mg/dL. Similarly, an analysis o more than
3000 Korean women who underwent a 50-g OG ound that
neonates born to women with a screening result ≥200 mg/dL
were 84 times more likely to have hypoglycemia than those
born to women with a result <140 mg/dL (Cho, 2016). Te
risk o neonatal hypoglycemia correlates with umbilical cord
C-peptide levels. Te risk also rises with birthweight, independent o a maternal diabetes diagnosis (Mitanchez, 2014).
■ Management
Women with gestational diabetes can be divided into two
unctional classes using asting glucose levels. Pharmacological
methods are usually recommended i diet modication does
not consistently maintain the asting plasma glucose levels <95
mg/dL or the 2-hour postprandial plasma glucose <120 mg/dL
(American College o Obstetricians and Gynecologists, 2019a).
Whether pharmacological treatment should be used in women
with lesser degrees o asting hyperglycemia is unclear. No controlled trials have been done to identiy ideal glucose targets
or etal risk prevention. On the other hand, the HAPO Study
Cooperative Research Group (2008) did demonstrate increased
etal risk at glucose levels below the threshold used or diagnosis o diabetes. Te Fith International Workshop Conerence
recommended that asting capillary glucose levels be kept ≤95
mg/dL (Metzger, 2007).
In their systematic review, Hartling and associates (2013)
concluded that treating gestational diabetes resulted in signi-
cantly lower incidences o preeclampsia, shoulder dystocia, and
macrosomia. For example, the calculated risk ratio was 0.50 or
delivering a newborn >4000 g ater treatment. Tese investigators caution that the attributed risk or these outcomes is low,
especially when glucose values are only moderately elevated.
Tey were unable to demonstrate an eect on neonatal hypoglycemia or on uture metabolic outcomes in the ospring.
Diabetic Diet
Nutritional instructions generally include a carbohydrate-controlled diet sucient to maintain normoglycemia and avoid ketosis. On average, this includes a caloric intake o 30 to 35 kcal/
kg/d. In one study, 152 women with gestational diabetes were
randomly assigned to a 40- or a 55-percent daily carbohydrateCHAPTER 60
Diabetes Mellitus 1083
diet, and no dierences in insulin levels and pregnancy outcomes
were ound (Moreno-Castilla, 2013). Te American College o
Obstetricians and Gynecologists (2019a) suggests that carbohydrate intake be limited to 33 to 40 percent o the total daily calories. Te remaining calories are apportioned to give 20 percent as
protein and 40 percent as at.
Te most appropriate dietary approach or women with gestational diabetes has not been established. One metaanalysis
o trials o low-glycemic-index diets ound that diets higher in
complex carbohydrates and dietary ber reduced the risk o
macrosomia and likelihood o insulin use in women with gestational diabetes (Wei, 2016). However, there clearly are limits
to what can be accomplished with various dietary approaches
alone. Most and Langer (2012) ound that insulin was eective in reducing the risk o excessive birthweight in ospring o
obese women with gestational diabetes. Casey and colleagues
(2015b) also ound that dietary treatment alone or morbidly
obese women with mild gestational diabetes did not reduce
neonatal at mass or LGA birthweights.
Exercise
Few trials have evaluated exercise specically or women with
gestational diabetes. Te American College o Obstetricians
and Gynecologists (2020b) recommends regular physical activity that incorporates aerobic and strength-conditioning exercise
during pregnancy and extends this to women with gestational
diabetes. wo recent metaanalyses demonstrate that structured exercise programs during pregnancy diminish weight
gain during pregnancy and even reduce the risk o developing
gestational diabetes (Russo, 2015; Sanabria-Martinez, 2015).
Exercise during pregnancy in women with gestational diabetes
also lowers glucose levels (Jovanovic-Peterson, 1989).
Glucose Monitoring
Hawkins and associates (2008) compared outcomes in 315
women with diet-treated gestational diabetes who used personal
glucose monitors against those o 615 gestational diabetics who
were also diet-treated but who underwent intermittent asting
glucose evaluation during weekly obstetrical visits. Women
using daily blood-glucose sel-monitoring had signicantly
ewer macrosomic newborns. Tey also gained less weight ater
diagnosis than women evaluated during clinic visits only. Tese
ndings support the common practice o blood-glucose sel-
monitoring or women with diet-treated gestational diabetes.
Postprandial surveillance or gestational diabetes is superior
to preprandial surveillance (DeVeciana, 1995). Te American
College o Obstetricians and Gynecologists (2019a) and the
American Diabetes Association (2019) recommend glucose
assessment our times daily. Te rst check is perormed asting, and the remainder are done 1 or 2 hours ater each meal.
At Parkland Hospital in women with diet-treated gestational
diabetes, changing to postprandial monitoring signicantly
reduced weekly maternal weight gain (0.45 lb) compared with
preprandial monitoring (0.63 lb).
Insulin Treatment
Historically, insulin has been considered standard therapy in
women with gestational diabetes when target glucose levels
cannot be consistently achieved through nutrition and exercise.
Insulin does not cross the placenta, and tight glycemic control
can usually be achieved. Insulin therapy is typically added i
asting levels persist above 95 mg/dL in women with gestational
diabetes. Te American College o Obstetricians and Gynecologists (2019a) also recommends that insulin be considered in
women with 1-hour postprandial levels that persistently exceed
140 mg/dL or those with 2-hour levels >120 mg/dL. Importantly, all o these thresholds are extrapolated rom recommendations or managing women with overt diabetes.
Te starting insulin dose is typically 0.7 to 1.0 U/kg/d and is
given in divided doses (American College o Obstetricians and
Gynecologists, 2019a). A combination o intermediate-acting
and short-acting insulin may be used, and dose adjustments are
based on glucose levels at particular times o the day.
At Parkland Hospital, the starting daily dose is divided so
that two thirds is given in the morning beore breakast and
one third in the evening beore dinner. In the morning dose,
one third is regular insulin and two thirds are NPH (neutral
protamine Hagedorn) insulin. For the evening dose, one hal is
regular insulin and the other hal is NPH. Insulin instruction
or these women is accomplished either in a specialized outpatient clinic or during a short hospital stay.
At the University o Alabama at Birmingham, a basal-bolus
approach using insulin glargine with rapid-acting insulin at
each meal is preerred. Ater calculating an initial insulin dose,
hal is given as long-acting glargine at bedtime, and the other
hal is administered as rapid-acting insulin split into three doses
given beore breakast, lunch, and dinner. As shown in able
60-8, when using insulin analogues such as insulin aspart and
insulin lispro, the more rapid onset o action must be considered during postprandial glucose management.
Oral Hypoglycemic Agents
Insulin is the preerred rst-line agent or persistent hyperglycemia in women with gestational diabetes (American College
o Obstetricians and Gynecologists, 2019a; American Diabetes
Association, 2017b). Both organizations acknowledge that several studies support the saety and ecacy o either metormin
(Glucophage) or glyburide (Micronase), which is also called
glibenclamide (Feig, 2020; Langer, 2000; Nicholson, 2009).
Balsells and coworkers (2015) completed a metaanalyses o trials that compared both agents with insulin or with each other.
In the seven trials comparing glyburide with insulin, glyburide
was associated with higher birthweight, more macrosomia, and
more requent neonatal hypoglycemia. In the six trials comparing metormin with insulin, metormin was associated with
less maternal weight gain, more preterm birth, and less severe
neonatal hypoglycemia. Women requiring insulin initiation or
insulin addition were considered to have ailed treatment. On
average, such ailures occurred in 6 percent o women treated
with glyburide and 34 percent o those treated with metormin.
In the two studies directly comparing oral hypoglycemic agents,
however, treatment ailure rates o both agents were equivalent.
Moreover, reminiscent o ndings rom the trial o adjunctive metormin therapy in women with type 2 diabetes previously described, metormin treatment was associated with less
maternal weight gain, lower birthweight, and less macrosomia.1084
Section 12
Medical and Surgical Complications
Conversely, in a randomized trial o glyburide treatment as an
adjunct to diet therapy in 395 women with mild gestational diabetes, Casey and colleagues (2015a) did not identiy any signi-
cant improvements in pregnancy outcomes in women treated
with adjunctive glyburide.
Concerns have also emerged regarding potential adverse
outcomes among women treated with glyburide. First, glyburide crosses the placenta and reaches concentrations in the
etus that are more than two thirds o maternal levels (Caritis,
2013). In a study o more than 9000 women with gestational
diabetes treated with either insulin or glyburide, a signicant
rise in rates o neonatal intensive care unit admission, respiratory distress, and neonatal hypoglycemia was associated with
glyburide use (Castillo, 2015).
Similarly, metormin reaches etal serum concentrations
nearly equal to maternal levels. However, in one study o 751
women with gestational diabetes who were randomly assigned
to metormin or insulin treatment, short-term perinatal adverse
events such as neonatal hypoglycemia, respiratory distress syndrome, phototherapy, or birth trauma did not dier between
groups (Rowan, 2008; 2011). Te at distribution in children
exposed to metormin showed a tendency toward a more avorable pattern. From a smaller randomized metormin trial, at 18
months, ospring exposed as etuses to metormin were slightly
heavier. However, markers o early motor or language development did not dier compared with those in ospring exposed
as etuses to insulin (Ijäs, 2015).
Te Food and Drug Administration has not approved glyburide or metormin use or treatment o gestational diabetes.
Te American College o Obstetricians and Gynecologists
(2019a) recognizes both as reasonable choices or second-line
glycemic control in women with gestational diabetes. Because
long-term outcomes have not been ully studied, the College
recommends disclosure o the limitations in current saety data.
■ Obstetrical Management
In general, or women with gestational diabetes who do not require
insulin, early delivery or other interventions are seldom required.
Tere is no consensus regarding the value or timing o antepartum
etal testing. It is typically reserved or women with pregestational
diabetes because o the greater stillbirth risk. Te American College
o Obstetricians and Gynecologists (2019a, 2020c) endorses etal
surveillance in women with gestational diabetes and poor glycemic
control. At Parkland Hospital, women with gestational diabetes
are routinely instructed to perorm daily etal kick counts in the
third trimester. As previously discussed, insulin-treated women are
oered inpatient admission ater 34 weeks’ gestation. Approximately hal o these women accept admission, and antepartum
etal monitoring is perormed three times each week.
Women with gestational diabetes and adequate glycemic
control are managed expectantly. Elective labor induction to
prevent shoulder dystocia compared with spontaneous labor
remains controversial. In the truncated GINEXMAL randomized trial o 425 women with gestational diabetes, outcomes o
labor induction between 38 and 39 weeks’ were compared with
expectant management until 41 weeks’ gestation (Alberico,
2017). Although underpowered, this trial demonstrated no
clinically meaningul dierence in the cesarean delivery rate
between the induction and expectantly managed groups—12.6
versus 11.8 percent. However, with early labor induction, neonatal hyperbilirubinemia rates were signicantly higher, and
there was a nonsignicant threeold greater shoulder dystocia
rate. In a cohort study o 8392 women with gestational diabetes, routine delivery at 38 or 39 weeks’ gestation was associated
with a lower rate o cesarean delivery but with an elevated rate
o neonatal intensive care unit admission (Melamed, 2016).
Te American College o Obstetricians and Gynecologists
(2019a) recommends that routine labor induction in women
with diet-treated gestational diabetes should not occur beore
39 weeks’ gestation. As mentioned previously, at Parkland
Hospital, those treated with insulin are delivered at 38 weeks’
gestation. At the University o Alabama at Birmingham, delivery is carried out ater 39 weeks.
Elective cesarean delivery to avoid brachial plexus injuries
in overgrown etuses is another issue. Te American College o
Obstetricians and Gynecologists (2019b) concludes that data are
insucient to determine whether women with gestational diabetes
whose etuses have a sonographically estimated weight ≥4500 g
should undergo cesarean delivery to avoid risk o birth trauma.
In one systematic review, Garabedian and associates (2010) estimated that as many as 588 cesarean deliveries in women with
gestational diabetes and an estimated etal weight o ≥4500 g
would be necessary to avoid one case o permanent brachial
plexus palsy. In one analysis o 903 women with gestational diabetes, sonographic estimates o etal weight within 1 month o
delivery typically overdiagnosed etuses as being LGA. Only 22
percent o women estimated to have an LGA etus actually delivered an overgrown newborn (Scires, 2015). Still, the American
College o Obstetricians and Gynecologists (2020b) acknowledges that prophylactic cesarean delivery may be considered in
diabetic women with an estimated etal weight ≥4500 g.
■ Postpartum Evaluation
Recommendations or postpartum evaluation are based on the
50- to 75-percent likelihood that women with gestational diabetes will develop overt diabetes within 15 to 25 years (American
Diabetes Association, 2019). Te Fith International Workshop
Conerence on Gestational Diabetes recommended that women
diagnosed with gestational diabetes undergo postpartum evaluation with a 75-g OG (Metzger, 2007). Tese recommendations and the classication scheme o the American Diabetes
Association are shown in Table 60-14. However, one study o
insurance claim data rom 2000 to 2013 showed that only 24
percent o women with a pregnancy complicated by gestational
diabetes underwent postpartum screening within a year. Less than
hal o those underwent a 75-g OG (Eggleston, 2016). Te
American College o Obstetricians and Gynecologists (2019a)
recommends either a asting glucose assessment or a 75-g, 2-hour
OG at 4 to 12 weeks postpartum or the diagnosis o overt
diabetes. Te American Diabetes Association (2019) recommends
testing every 1 to 3 years in women with a history o gestational
diabetes but normal postpartum glucose screening.
Women with a history o gestational diabetes are also at risk
or cardiovascular complications associated with dyslipidemia,CHAPTER 60
Diabetes Mellitus 1085
hypertension, and abdominal obesity—the metabolic syndrome
(Chap. 51, p. 903). In a study o 47,909 parous women, the
nearly 5000 women with prior gestational diabetes were 2.6
times more likely to be hospitalized or cardiovascular morbidity
(Kessous, 2013). Another study evaluated 483 women between 5
and 10 years ater being diagnosed with mild gestational diabetes
(Varner, 2017). Investigators ound no increased risk or developing metabolic syndrome associated with additional pregnancies.
However, risk or subsequent diabetes rose almost ourold i gestational diabetes complicated at least one subsequent pregnancy.
■ Recurrent Gestational Diabetes
In one large metaanalysis, the pooled gestational diabetes recurrence rate was 48 percent. Te same investigative group identi-
ed elevated maternal BMI, insulin use, etal macrosomia, and
weight gain between pregnancies as additional risk actors or
gestational diabetes recurrence (Schwartz, 2015, 2016).
Liestyle behavioral changes that include weight control and
exercise between pregnancies would seem likely to prevent gestational diabetes recurrence. However, women randomized to
an exercise program that started beore 14 weeks’ gestation in
a subsequent pregnancy did not have a lower recurrence rate
(Guel, 2016). Conversely, Ehrlich and coworkers (2011)
ound that prepregnancy loss o at least two BMI units was
associated with a lower subsequent risk o gestational diabetes
in women who were overweight or obese in the rst pregnancy.
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