CONTENTS

Contents ................................................................................................................. 1
Figure Contents ....................................................................................................... 2
Table Contents ......................................................................................................... 3
Chapter I : Introduction ........................................................................................... 4
Chapter II :
2.1. Diagnosis........................................................................................................... 5
2.2. Impact in Pregnancy ......................................................................................... 5
2.2.1. Fetal Effects ............................................................................................ 6
2.2.2 Maternal Effects ....................................................................................... 14
2.3. Managemen of Diabetes Militus ....................................................................... 21
Reference ................................................................................................................. 28

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 FIGURE CONTENTS

FIGURE 57-2. The Frequency of Major Congenital Malformation 9

FIGURE 57-3. Macrosomic infant 10

FIGURE 57-7. Retinal Photographs from a 30 year-old Diabetic Woman... 17

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 TABLE CONTENTS

TABLE 57-4. Diagnosis of Overt Diabetes 6

TABLE 57-5. Pregnancy Outcomes of Births 7

TABLE 57-6. Congenital Anomalies of 91 Women with Diabetes... 8

TABLE 57-7. Protocol Recommended of Diabetic Ketoacidosis During Pregnancy ... 20

TABLE 57-8. Action Profiles of Commonly Used Insulins.. 22

TABLE 57-9. Self-Monitored Capillary Blood Glucose Goals. 23

TABLE 57-10. Insulin Management During Labor and Delivery. 26

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 CHAPTER I

INTRODUCTION

The increasing prevalence of type 2 diabetes in general, and in younger people in

particular, has led to an increasing number of afected pregnancies (Ferrara, 2007). In Los
Angeles County, Baraban and coworkers (2008) reported that the age-adjusted prevalence
tripled from 14.5 cases per 1000 women in 1991 to 47.9 cases per 1000 in 2003. us, the number
of pregnant women with diabetes that was undiagnosed before pregnancy is increasing. Many
women found to have gestational diabetes are likely to have type 2 diabetes that has previously
gone undiagnosed (Feig, 2002). In fact, 5 to 10 percent of women with gestational diabetes are
found to have diabetes immediately after pregnancy.

Women with gestational diabetes can be divided into two functional classes using
fasting glucose levels. Pharmacological methods are usually recommended if diet modi cation
does not consistently maintain the fasting plasma glucose levels < 95 mg/dL or the 2-hour
postprandial plasma glucose < 120 mg/dL (American College of Obstetricians and
Gynecologists, 2013).

Whether pharmacological treatment should be used in women with lesser degrees of

fasting hyper- glycemia 105 mg/dL or less before dietary intervention is unclear. ere have been
no controlled trials to identify ideal glucose targets for fetal risk prevention. On the other hand,
the HAPO study (2008) did demonstrate increased fetal risk at glucose levels below the
threshold used for diagnosis of diabetes. The Fifth International Workshop Conference

recommended that fasting capillary glucose levels be kept 95 mg/dL (Metzger, 2007).

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 CHAPTER II

DISCUSSION

2.1 DIAGNOSIS

Women with high plasma glucose levels, glucosuria, and keto- acidosis present no
problem in diagnosis. Similarly, women with a random plasma glucose level 200 mg/dL
plus classic signs and symptoms such as polydipsia, polyuria, and unex- plained weight loss or
those with a fasting glucose level exceeding 125 mg/dL are considered by the ADA (2012) to
have overt diabetes. Women with only minimal metabolic derangement may be more di cult to
identify. To diagnose overt diabetes in pregnancy, the International Association of Diabetes
and Pregnancy Study Groups (IADPSG) Consensus Panel (2010) recommends threshold
values for fasting or random plasma glucose and glycosylated hemoglobin (A1c) levels at
prenatal care initiation (Table 57-4). There was no consensus on whether such testing should
be universal or limited to those women classi ed as high risk. Regardless, the tentative diagnosis
of overt diabetes during pregnancy based on these thresholds should be confirmed postpartum.
Risk factors for impaired carbohydrate metabolism in pregnant women include a strong
familial history of diabetes, prior delivery of a large newborn, persistent glucosuria, or
unexplained fetal losses.

Table 57-4. Diagnosis of Overt Diabetes is Pregnancy (Modified from International

Association of Diabetes and Pregnancy Study Groups Consensus Panel, 2010)

5
2.2. IMPACT ON PREGNANCY

With pregestational or overt diabetes, the embryo, fetus, and mother frequently
experience serious complications directly attributable to diabetes. The likelihood of successful
outcomes with overt diabetes is related somewhat to the degree of glycemic control, but more
importantly, to the degree of underlying cardiovascular or renal disease. us, advanc- ing stages
of the White classi cation, seen in Table 57-2, are inversely related to favorable pregnancy
outcomes. As an example shown in Table 57-5, data from Yang and associates (2006)
chronicles the deleterious pregnancy outcomes of overt diabetes. These maternal and fetal
complications are described in the following sections.

TABLE 57-5. Pregnancy Outcomes of Births (Nova Scocia from 1988 to 2002)

2.2.1. FETAL EFFECTS

2.2.1.1. Spotaneous Abortion

Several studies have shown that early miscarriage is associated with poor glycemic
control. In 215 women with type 1 diabetes enrolled for prenatal care before 9 weeks gestation,
24 percent had an early pregnancy loss (Rosenn, 1994). Only those whose initial
glycohemoglobin A1c concentrations were 12 percent or whose preprandial glucose
concentrations were persistently 120 mg/dL were at increased risk. In another analysis of
127 Spanish women with pregestational diabetes, poor glycemic control, defined by

6
glycohemoglobin A1c concentrations 7 percent, was associ- ated with a threefold increase
in the spontaneous abortion rate (Galindo, 2006).

2.2.1.2. Preterm Delivery

Overt diabetes is an undisputed risk factor for preterm birth. Eidem and associates
(2011) analyzed 1307 births in women with pregestational type 1 diabetes from the Norwegian
Medical Birth Registry. More than 26 percent were delivered preterm compared with 6.8
percent in the gen- eral obstetrical population. Moreover, almost 60 percent were indicated
preterm births, that is, due to obstetrical or medical complications. In the Canadian study shown
in Table 57-5, the incidence of preterm birth was 28 percent a vefold increase compared with
that of their normal population.

2.2.1.3. Malformations

The incidence of major malformations in women with type 1 diabetes is doubled and
approximates 5 percent (Eidem, 2010; She eld, 2002). ese account for almost half of perinatal
deaths in diabetic pregnancies. A twofold increased risk of major congenital defects in
Norwegian women with pregestational type 1 diabetes included cardiovascular mal- formations
that accounted for more than half of the anomalies (Table 57-6). In the National Birth Defects
Prevention Study, the risk of an isolated cardiac defect was fourfold higher in women with
pregestational diabetes compared with the twofold increased risk of noncardiac defects (Correa,
2008). The caudal regression sequence is a rare malformation frequently associated with mater-
nal diabetes (Garne, 2012).

TABLE 57-6. Congenital Anomalies of 91 Women with Diabetes (Eidem, 2010)

7
 Poorly controlled diabetes, both preconceptionally and early in pregnancy, is thought
to underlie this increased severe-malformation risk. As shown in Figure 57-2, Galindo and
colleagues (2006) demonstrated a clear correlation between increased maternal
glycohemoglobin A1c at rst prenatal visit and major malformations. Eriksson (2009) concluded
that the etiology was multifactorial. At least three interrelated molecular chain reactions have
been linked to maternal hyperglycemia and can potentially explain the mechanism behind poor
glycemic control and increased risk for major malformations (Reece, 2012). ese include
alterations in cellular lipid metabolism, excess production of toxic superoxide radicals, and
activation of programmed cell death. For example, Morgan and associ- ates (2008)
demonstrated that hyperglycemia-induced oxidative stress inhibited migration of cardiac
neural-crest cells in embryos of diabetic mice.

FIGURE 57-2. The Frequency of Major Congenital Malformation in Newborn of

Women with Pregestional Diabetes Statified by Hemoglobin (Galindo, 2006)

2.2.2.4. Altered Fetal Growth

Diminished growth may result from congenital malformations or from substrate

deprivation due to advanced maternal vascular disease. However, fetal overgrowth is more
typical of pregestational diabetes. Maternal hypergly- cemia prompts fetal hyperinsulinemia,
particularly during the second half of gestation. is in turn stimulates excessive somatic growth
or macrosomia. Except for the brain, most fetal organs are a ected by the macrosomia that

8
characterizes the fetus of a diabetic woman. Such infants are described as being
anthropometrically di erent from other large-for-gestational age (LGA) infants (Durnwald,
2004; McFarland, 2000). Speci cally, those whose mothers are diabetic have excessive fat
deposition on the shoulders and trunk, which predisposes to shoulder dystocia or cesarean
delivery (Fig. 57-3).

FIGURE 57-3. Macrosomic infant (Hay, 2012)

The incidence of macrosomia rises significantly when mean maternal blood glucose
concentrations chronically exceed 130 mg/dL (Hay, 2012). Hammoud and coworkers (2013)
reported that the macrosomia rates for Nordic women with type 1, type 2, or gestational
diabetes were 35 percent, 28 percent, and 24 percent, respectively. As shown in Figure 57-4,
the birthweight distribution of neonates of diabetic mothers is skewed toward consistently
heavier birthweights compared with that of normal pregnancies.

In the study by Hammoud and colleagues (2013), fetal growth pro les from 897
sonographic examinations in 244 women with diabetes were compared with 843 examinations
in 145 control women. e abdominal circumference evolved di erently in the diabetic groups.

9
Analysis of head circumfer- ence/abdominal circumference (HC/AC) ratios shows that this
disproportionate growth occurs mainly in diabetic pregnancies that ultimately yield
macrosomic newborns (Fig. 57-5). ese ndings comport with the observation that virtually all
neo- nates of diabetic mothers are growth promoted. Ben-Haroush and associates (2007)
analyzed fetal sonographic measurements between 29 and 34 weeks gestation in 423 diabetic
pregnancies and found that accelerated fetal growth was particularly evident in women with
poor glycemic control.

2.2.1.5. Unexplained Fetal Demise

The risk of fetal death is three to four times higher in women with type 1 diabetes
compared with that of the general obstetrical population (Eidem, 2011). Stillbirth without an
identi able cause is a phenomenon rela- tively limited to pregnancies complicated by overt
diabetes. these stillbirths are unexplained because common factors such as obvious placental
insu ciency, abruption, fetal-growth restriction, or oligohydramnios are not identi ed. ese
infants are typically LGA and die before labor, usually after 35 weeks gestation or later
(Garner, 1995).

These unexplained stillbirths are associated with poor glycemic control. Lauenborg and
coworkers (2003) identified suboptimal glycemic control in two thirds of unexplained
stillbirths between 1990 and 2000. Also, fetuses of diabetic mothers often have elevated lactic
acid levels. Salvesen and colleagues (1992, 1993) analyzed fetal blood samples and reported
that mean umbilical venous blood pH was lower in diabetic pregnancies and was signi cantly
related to fetal insulin levels. Such nd- ings support the hypothesis that hyperglycemia-
mediated chronic aberrations in oxygen and fetal metabolite transport may underlie these
unexplained fetal deaths (Pedersen, 1977). However, the exact mechanisms by which
uncontrolled hyperglycemia leads to elevated lactic acid levels and fetal acidosis remain
unclear.

Explicable stillbirths due to placental insu ciency also occur with increased frequency
in women with overt diabetes, usu- ally in association with severe preeclampsia. In a
retrospective analysis of more than 500,000 singleton deliveries, Yanit and associates (2012)
found that the fetal death risk was sevenfold higher in women with hypertension and
pregestational diabetes compared with the threefold increased risk associated with dia- betes
alone. Stillbirth is also increased in women with advanced diabetes and vascular complications.

10
Maternal ketoacidosis can also cause fetal death.

2.2.1.6. Hydramnions

Diabetic pregnancies are often complicated by excess amnionic uid. According to Idris
and coworkers (2010), 18 percent of 314 women with pregestational diabe- tes were identi ed
with hydramnios, de ned as an amnionic uid index (AFI) greater than 24 cm in the third
trimester. A likely albeit unproven explanation is that fetal hyperglycemia causes polyuria
(Chap. 11, p. 234). In a study from Parkland Hospital, Dashe and colleagues (2000) found that
the AFI parallels the amnionic uid glucose level among women with diabetes. is nding suggests
that the hydramnios associated with diabetes is a result of increased amnionic uid glucose
concentration. Further support for this hypothesis was provided by Vink and associates (2006),
who linked poor maternal glucose control to macrosomia and hydramnios. In their retrospective
analysis of diabetic pregnancies, Idris and coworkers (2010) also found that women with
elevated glycohemoglobin A1c values in the third trimester were more likely to have
hydramnios.

2.2.1.7. Neonatal Effects

Before tests of fetal health and maturity became available, delivery before term was
deliberately selected for women with diabetes to avoid unexplained fetal death. Although this
practice has been abandoned, there is still an increased frequency of preterm delivery in women
with dia- betes. Most are due to advanced diabetes with superimposed preeclampsia. ankfully,
modern neonatal care has largely eliminated neonatal deaths due to immaturity. Conversely,
neonatal morbidity due to preterm birth continues to be a serious consequence.

Respiratory Distress Syndrome. Historically, newborns of diabetic mothers were

thought to be at increased risk for respiratory distress from delayed lung maturation.
Subsequent observations challenged this concept, and gestational age rather than overt diabetes
is likely the most signi cant factor associ- ated with respiratory distress syndrome. Indeed, in
their analy- sis of 19,399 very-low-birthweight neonates delivered between 24 and 33 weeks
gestation, Bental and colleagues (2011) were unable to demonstrate an increased rate of
respiratory distress syndrome in newborns of diabetic mothers. is is discussed further in
Chapter 33 (p. 637).

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2.2.1.8. Hypoglycemia

Newborns of a diabetic mother experience a rapid drop in plasma glucose concentration

after delivery. is is attributed to hyperplasia of the fetal -islet cells induced by chronic maternal
hyperglycemia. Low glucose concentrations defined as < 45 mg/dL are particularly common
in newborns of women with unstable glucose concentrations during labor (Persson, 2009). In
a recent analysis of prenatal outcomes during a 20-year period in Finnish women with type 1
diabetes, the incidence of neonatal hypoglycemia declined signi cantly over time (Klemetti,
2012). The authors attributed this to frequent blood glucose measurements and active early
feeding practices in such neonates. Prompt recognition and treatment of the hypoglycemic
newborn minimizes adverse sequelae.

2.2.1.9. Hypocalcemia

Defined as a total serum calcium concentration < 8 mg/dL in term newborns,

hypocalcemia is one of the potential metabolic derangements in neonates of diabetic mothers.
Its cause has not been explained. eories include aberrations in magnesiumcalcium economy,
asphyxia, and preterm birth. In a randomized study by DeMarini and associates (1994), 137
pregnant women with type 1 diabetes were managed with strict versus customary glucose
control. Almost a third of neonates in the customary control group developed hypocalcemia
compared with only 18 percent of those in the strict control group.

2.2.1.10. Hyperbilirubinemia and Polycythemia

The pathogenesis of hyperbilirubinemia in neonates of diabetic mothers is uncertain. A

major contributing factor is newborn polycythemia, which increases the bilirubin load (Chap.
33, p. 643). Polycythemia is thought to be a fetal response to relative hypoxia. According to
Hay (2012), the sources of this fetal hypoxia are hyperglycemia-mediated increases in maternal
a nity for oxygen and fetal oxygen consumption. Together with insulin-like growth factors, this
hypoxia leads to increased fetal erythropoietin levels and red cell production. Venous
hematocrits of 65 to 70 volume percent have been observed in up to 40 percent of these
newborns (Salvesen, 1992). Renal vein thrombosis is reported to result from polycythemia.

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2.2.1.11. Cardiomyopathy

Infants of diabetic pregnancies may have hypertrophic cardiomyopathy that primarily

a ects the interventricular septum (Rolo, 2011). In severe cases, this cardiomyopathy may lead
to obstructive cardiac failure. Russell and coworkers (2008) performed serial echocardio-
grams on fetuses of 26 women with pregestational diabetes. In the first trimester, fetal diastolic
dysfunction was evident compared with that of nondiabetic controls. In the third tri- mester,
the fetal interventricular septum and right ventricular wall were thicker in fetuses of diabetic
mothers. The authors concluded that cardiac dysfunction precedes these structural changes.
Fortunately, most a ected newborns are asymp- tomatic following birth, and hypertrophy
resolves in the months after delivery. Relief from maternal hyperglycemia is presumed to
promote this resolution (Hornberger, 2006). Conversely, fetal cardiomyopathy may progress
to adult cardiac disease.

2.2.1.12. Long-Term Cognitive Development

Intrauterine metabolic conditions have long been linked to neurodevelopment in o

spring. is may also be true in children of diabetic mothers. Despite rigorous antepartum
management, Rizzo and col- leagues (1995) found numerous correlations between maternal
glycemia and intellectual performance in children up to age 11 years in 139 o spring of diabetic
women. In a study of more than 700,000 Swedish-born men, the intelligence quotient of those
whose mothers had diabetes during pregnancy averaged 1 to 2 points lower (Fraser, 2014).
DeBoer and associates (2005) demonstrated impaired memory performance in infants of dia-
betic mothers at age 1 year. Finally, results from the Childhood Autism Risks from Genetics
and the Environment (CHARGE) study indicated that autism spectrum disorders or
developmen- tal delay were more common in children of diabetic women (Krakowiak, 2012).
Although interpreting the ects of the intrauterine environment on neurodevelopment is certainly
confounded by postnatal events, emerging data at least support a link between maternal
diabetes, glycemic control, and neurocognitive outcome.

2.2.1.13. Inheritance of Diabetes

The risk of developing type 1 diabetes if either parent is a ected is 3 to 4 percent. Type
2 diabetes has a much stronger genetic component. If both par- ents have type 2 diabetes, the
risk of developing it approaches 40 percent. McKinney and coworkers (1999) studied 196
children with type 1 diabetes and found that older maternal age and maternal type 1 diabetes

13
are important risk factors. Plagemann and colleagues (2002) have implicated breast feeding by
diabetic mothers in the genesis of childhood diabetes. Conversely, breast feeding has also been
associated with a reduced risk of type 2 diabetes (Owen, 2006). The Trial to Reduce Insulin-
dependent Diabetes Mellitus in the Genetically At Risk (TRIGR) was designed to analyze
hydrolyzed formula use, rather than breast milk, to reduce rates of type 1 diabetes in at-risk
children by age 10. is study will be complete in 2017 (Knip, 2011).

2.3. MATERNAL EFFECT

Diabetes and pregnancy interact significantly such that maternal welfare can be
seriously jeopardized. With the possible exception of diabetic retinopathy, however, the long-
term course of diabetes is not afected by pregnancy.

Maternal death is uncommon, but rates in women with diabetes are still increased. In
an analysis of 972 women with type 1 diabetes, Leinonen and associates (2001) reported a
maternal mortality rate of 0.5 percent. Deaths resulted from diabetic ketoacidosis,
hypoglycemia, hypertension, and infection. Especially morbid is ischemic heart disease.
Pombar and coworkers (1995) reviewed 17 women with coronary artery disease class H
diabetes and reported that only half survived pregnancy.

2.3.1. Preeclampsia

Hypertension that is induced or exacerbated by pregnancy is the complication that most

often forces preterm delivery in diabetic women. The incidence of chronic and gestational
hypertension and especially preeclampsia is remarkably increased in diabetic mothers. In the
study cited earlier by Yanit and colleagues (2012), preeclampsia developed three to four times
more often in women with overt diabetes. Moreover, those diabetics with coexistent chronic
hyperten- sion were almost 12 times more likely to develop preeclampsia. Special risk factors
for preeclampsia include any vascular complication and preexisting proteinuria, with or
without chronic hypertension. As shown in Figure 57-6, women with type 1 diabetes who are
in more advanced White classes of overt diabetes increasingly developed preeclampsia. is
increasing risk with duration of diabetes may be related to oxidative stress, which plays a key
role in the pathogenesis of diabetic complica- tions and preeclampsia. With this in mind, the
Diabetes and Preeclampsia Intervention Trial (DAPIT) randomly assigned 762 women with
type 1 diabetes to antioxidant vitamin C and E supplementation or placebo in the rst half of
pregnancy (McCance, 2010). ere were no di erences in preeclampsia rates except in a few

14
women with a low antioxidant status at baseline. Temple and coworkers (2006) prospectively
studied hemoglobin A1c levels at 24 weeks gestation in 290 women with type 1 diabetes and
found that preeclampsia was related to glucose control. Management of preeclampsia is
discussed in Chapter 40 (p. 749).

2.3.2. Diabetic Nephropathy

Diabetes is the leading cause ofen d-stage renal disease in the United States (Chap. 53,
p. 1060). Clinically detectable nephropathy begins with microalbumin- uria30 to 300 mg/24
hours. is may manifest as early as 5 years after diabetes onset. Macroalbuminuriamore than
300 mg/24 hoursdevelops in patients destined to have end- stage renal disease. Hypertension
almost invariably develops during this period, and renal failure ensues typically in the next 5
to 10 years. e incidence of overt proteinuria is nearly 30 percent in individuals with type 1
diabetes and ranges from 4 to 20 percent in those with type 2 diabetes (Reutens, 2013).
Progression from microalbuminuria is not inexorable, and regression is common. Presumably
from improved glu- cose control, the incidence of nephropathy in individuals with type 1
diabetes has declined in the past few decades. Investigators for the Diabetes Control and
Complications Trial (2002) reported that there was a 25-percent decrease in the rate of
nephropathy for each 10-percent decrease in hemoglobin A1c levels.

Approximately 5 percent of pregnant women with diabe- tes already have renal
involvement. Approximately 40 percent of these will develop preeclampsia (Vidae , 2008).
High rates are also illustrated in Figure 57-6. However, this may not be the case with
microproteinuria. In one analysis of 460 women, How and colleagues (2004) found no
association between preeclampsia and microproteinuria. Nevertheless, they found that chronic
hypertension with overt diabetic nephropathy increased the risk of preeclampsia to 60 percent.

In general, pregnancy does not appear to worsen diabetic nephropathy. In their

prospective study of 43 women with diabetes, Young and associates (2012) could not
demonstrate diabetic nephropathy progression through 12 months after delivery. Most of these
women had only mild renal impair- ment. Conversely, pregnancy in women with moderate to
severe renal impairment may accelerate progression of their disease (Vidae , 2008). As in
women with glomerulopathies, hypertension or substantial proteinuria before or during preg-
nancy is a major predictive factor for progression to renal fail- ure in women with diabetic
nephropathy (Chap. 53, p. 1062).

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2.3.3. Diabetic Retinopathy

Retinal vasculopathy is a highly speci c complication of both type 1 and type 2 diabetes.
In the United States, diabetic retinopathy is the most important cause of visual impairment in
persons younger than age 60 years (Frank, 2004). Therst and most common visible lesions are
small microaneurysms followed by blot hemorrhages that form when erythrocytes escape from
the aneurysms. ese areas leak serous uid that creates hard exudates. Such features are termed
benign or background or nonproliferative retinopathy. With increasingly severe retinopathy,
the abnormal vessels of background eye disease become occluded, leading to retinal ischemia
and infarctions that appear as cotton wool exudates. These are considered preproliferative
retinopathy. In response to ischemia, there is neovascularization on the retinal surface and out
into the vitreous cavity. Vision is obscured when there is hemorrhage. Laser photocoagulation
before hemorrhage, as shown in Figure 57-7, reduces the rate of visual loss progression and
blindness by half. The procedure is performed during pregnancy when indicated.

FIGURE 57-7. Retinal Photographs from a 30 year-old Diabetic Woman (Elman, 1990)

16
 Vestgaard and coworkers (2010) reported that almost two thirds of 102 pregnant
women with type 1 diabetes examined by 8 weeks gestation had background retinal changes,
pro- liferative retinopathy, or macular edema. A fourth of these women developed progression
of retinopathy in at least one eye. e same group of investigators evaluated 80 type 2 diabetics
and identi ed retinopathy, mostly mild, in 14 percent during early pregnancy. Progression was
identi ed in only 14 percent (Rasmussen, 2010). is complication is believed to be a rare example
of a long-term adverse e ect of pregnancy. However, in a prospective postpartum 5-year
surveil- lance of 59 type 1 diabetic women, Arun and Taylor (2008) found that baseline
retinopathy was the only independent risk factor for progression.

Other risk factors that have been associated with progression of retinopathy include
hypertension, higher levels of insulin-like growth factor-I, and macular edema identi ed in early
pregnancy (Bargiota, 2011; Mathiesen, 2012; Ringholm, 2011; Vestgaard, 2010). The National
Institute for Health and Clinical Excellence (2008) established guidelines recommend- ing that
pregnant women with preexisting diabetes should rou- tinely be o ered retinal assessment after
the rst prenatal visit. Currently, most agree that laser photocoagulation and good glycemic
control during pregnancy minimize the potential for deleterious efects of pregnancy.

Ironically, acute rigorous metabolic control during pregnancy has been linked to
acute worsening of retinopathy. In a study of 201 women with retinopathy, McElvy and
associates (2001) found that almost 30 percent su ered eye disease progression during
pregnancy despite intensive glucose control. That said, Wang and coworkers (1993) have
observed that retinopathy worsened during the critical months of rigorous glucose control, but
long term, deterioration of eye disease slowed. In their study mentioned above, Arun and
Taylor (2008) found that only four women required laser photocoagulation during pregnancy,
and none required laser in the next 5 years.

2.3.4. Diabetic Neuropathy

Peripheral symmetrical sensorimotor diabetic neuropathy is uncommon in pregnant

women. But a form of this, known as diabetic gastropathy, is troublesome during pregnancy.
It causes nausea and vomiting, nutritional problems, and di culty with glucose control. Women
with gastroparesis should be advised that this complication is associ- ated with a high risk of
morbidity and poor perinatal outcome (Kitzmiller, 2008).

Treatment with metoclopramide and H-2 receptor antagonists is sometimes successful.

17
Hyperemesis gravidarum is further discussed in Chapter 54 (p. 1070).

2.3.5. Diabetic Ketoacidosis

This serious complication develops in approximately 1 percent of diabetic pregnancies

(Hawthorne, 2011). It is most often encountered in women with type 1 diabetes. It is
increasingly being reported in women with type 2 or even those with gestational diabetes (Sibai,
2014). Diabetic ketoacidosis (DKA) may develop with hyperemesis gravidarum, -mimetic
drugs given for tocolysis, infection, and corticosteroids given to induce fetal lung maturation.
DKA results from an insulin de ciency combined with an excess in counter-regulatory
hormones such as glucagon. This leads to gluconeogenesis and ketone body formation. e ketone
body -hydroxybutyrate is synthesized at a much greater rate than acetoacetate, which is
preferentially detected by commonly used ketosis detection methodologies. erefore, serum or
plasma assays for -hydroxybutyrate more accurately reflect true ketone body levels.

The incidence of fetal loss can be as high as 20 percent with DKA. Noncompliance is
a prominent factor, and this and keto- acidosis were historically considered prognostically bad
signs in pregnancy (Pedersen, 1974). Pregnant women usually develop ketoacidosis at lower
blood glucose thresholds than when non- pregnant. In a study from China, the mean glucose
level for pregnant women with DKA was 293 mg/dL compared with 495 mg/dL for
nonpregnant women (Guo, 2008). Chico and associates (2008) reported ketoacidosis in a
pregnant woman whose plasma glucose was only 87 mg/dL.

One management protocol for diabetic ketoacidosis is shown in Table 57-7. An

important cornerstone of management is vigorous rehydration with crystalloid solutions of
normal saline or Ringer lactate.

18
TABLE 57-7. Protocol Recommended of Diabetic Ketoacidosis During Pregnancy

(ACOG, 2012)

2.3.6. Infections

Almost all types of infections are increased in diabetic pregnancies. Stamler and
coworkers (1990) reported that almost 80 percent of women with type 1 diabetes develop at
least one infection during pregnancy compared with only 25 percent in those without diabetes.
Common infections include Candida vulvovaginitis, urinary and respiratory tract infections,
and puerperal pelvic sepsis. In their population- based study of almost 200,000 pregnancies,
Sheiner and colleagues (2009) found a twofold increased risk of asymptomatic bacteruria in
women with diabetes. Similarly, Alvarez and associates (2010) reported positive urine cultures
in a fourth of diabetic women compared with 10 percent of nondiabetic pregnant women. In a
2-year analysis of pyelonephritis at Parkland Hospital, 5 percent of women with diabetes
developed pyelonephritis compared with 1.3 percent of the non- diabetic population (Hill,

19
2005). Fortunately, these latter infections can be minimized by screening and eradication of
asymptomatic bacteriuria (Chap. 53, p. 1053). Takoudes and colleagues (2004) found that
pregestational diabetes is associated with a two to threefold increase in wound complications
after cesarean delivery.

2.4. MANAGEMENT OF DIABETES IN PREGNANCY

Because of the relationship between pregnancy complications and maternal glycemic

control, e orts to achieve glucose targets are typically more aggressive during pregnancy.
Management preferably should begin before pregnancy and include specific goals during each
trimester.

Preconceptional Care

To minimize early pregnancy loss and congenital malformations in off spring of

diabetic mothers, optimal medical care and education are recommended before conception
(Chap. 8, p. 157). Unfortunately, nearly half of pregnancies in the United States are unplanned,
and many diabetic women frequently begin pregnancy with suboptimal glucose control (Finer,
2011; Kim, 2005).

The ADA has de ned optimal preconceptional glucose control using insulin to include
self-monitored preprandial glucose levels of 70 to 100 mg/dL, peak postprandial values of 100
to 129 mg/dL, and mean daily glucose concentrations < 110 mg/ dL (Kitzmiller, 2008).
Glycosylated hemoglobin measurement, which re ects an average of circulating glucose for the
past 4 to 8 weeks, is useful to assess early metabolic control. e ADA (2012) defines optimal
values to be < 7 percent. In their prospective population-based study of 933 pregnant women
with type 1 diabetes, Jensen and colleagues (2010) found the risk of congenital malformations
was not demonstrably higher with glycosylated hemoglobin levels < 6.9 percent compared with
that in more than 70,000 nondiabetic controls. ey also identified a substantial fourfold increased
risk for malformations at levels > 10 percent.

If indicated, evaluation and treatment for diabetic complications such as retinopathy or

nephropathy should also be instituted before pregnancy. Finally, folate, 400 g/day orally is
given periconceptionally and during early pregnancy to decrease the risk of neural-tube defects.

20
2.4.1. First Trimester

Careful monitoring of glucose control is essential. For this reason, many clinicians
hospitalize overtly diabetic women during early pregnancy to initiate an individualized glucose
control program and o er education. It also provides an opportunity to assess the extent of
diabetic vascular complications and precisely establish gestational age.

Insulin Treatment

The overtly diabetic pregnant woman is best treated with insulin. Although oral
hypoglycemic agents have been used successfully for gestational diabetes (p. 1141), these
agents are not currently recommended for overt diabetes except for limited and individualized
use (American College of Obstetricians and Gynecologists, 2012). Maternal glycemic control
can usually be achieved with multiple daily insulin injections and adjustment of dietary intake.
The action proles of commonly used short- and long-term insulins are shown in Table 57-8.

TABLE 57-8. Action Profiles of Commonly Used Insulins (Modified From Powers, 2012)

Subcutaneous insulin infusion by a calibrated pump may be used during pregnancy.

However, as demonstrated in a Cochrane Database review by Farrar and associates (2007),
there is scarce robust evidence for specific salutary pregnancy e ects. In a metaanalysis of six
small randomized trials compar- ing insulin pumps to multiple daily injections of insulin, there
were no signi cant di erences in LGA birthweight, maternal hypoglycemia, or retinopathy

21
progression (Mukhopadhyay, 2007). Notably, more women using insulin pumps developed
ketoacidosis. Roeder and colleagues (2012) noted with insulin pump use in women with type
1 diabetes that total daily doses declined in the rst trimester but later increased by more than
threefold. Postprandial glucose excursions accounted for most increases. Women who use an
insulin pump must be highly motivated and compliant to minimize the risk of nocturnal
hypoglycemia (Gabbe, 2003).

Monitoring

Self-monitoring of capillary glucose levels using a glucometer is recommended because

this involves the woman in her own care. Glucose goals recommended during pregnancy are
shown in Table 57-9. Advances in noninvasive glucose monitoring will undoubtedly render
intermittent cap- illary glucose monitoring obsolete. Subcutaneous continuous glucose
monitoring devices reveal that pregnant women with diabetes experience signi cant periods of
daytime hyperglycemia and nocturnal hypoglycemia that are undetected by traditional
monitoring (Combs, 2012). In one randomized trial of 71 women, those with periodic
supplemental access to continuous glucose data had lower glycosylated hemoglobin levels 5.8
versus 6.4 percentand delivered fewer overgrown newborns (Murphy, 2008). To date however,
there have been no trials evaluating the impact of personal continuous monitoring devices that
give immediate feedback to pregnant women. Such glucose monitoring systems, coupled with
a continuous insulin pump, ofer the potential of an arti cial pancreas to avoid undetected
hypo or hyperglycemia during pregnancy.

TABLE 57-9. Self-Monitored Capillary Blood Glucose Goals (Combs, 2012)

22
Diet

Nutritional planning includes appropriate weight gain through carbohydrate and caloric
modi cations based on height, weight, and degree of glucose intolerance (American Diabetes
Association, 2012; Bantle, 2008). e mix of car- bohydrate, protein, and fat is adjusted to meet
the metabolic goals and individual patient preferences, but a 175-g minimum of carbohydrate
per day should be provided. Carbohydrate should be distributed throughout the day in three
small- to moderate-sized meals and two to four snacks (Bantle, 2008). Weight loss is not
recommended, but modest caloric restriction may be appropriate for overweight or obese
women. An ideal dietary composition is 55 percent carbohydrate, 20 per- cent protein, and 25
percent fat, of which < 10 percent is saturated fat.

Hypoglycemia

Diabetes tends to be unstable in the rst trimester. Hellmuth and associates (2000)
reported that 37 percent of 43 women with type 1 diabetes had maternal hypoglycemia during
the rst trimester, and the average duration was more than 2 hours. Similarly, Chen and
coworkers (2007) identi ed hypoglycemic eventsblood glucose < 40 mg/dL in 37 of 60
women with type 1 diabetes. A fourth of these were considered severe because the women
were unable to treat their own symptoms. Rosenn and colleagues (1994) noted that maternal
hypoglycemia had a peak incidence between 10 and 15 weeks gestation. Caution is
recommended when attempting euglycemia in women with recurrent episodes of
hypoglycemia.

We have reported that good pregnancy outcomes can be achieved in women with mean
preprandial plasma glucose values up to 143 mg/dL (Leveno, 1979). In women with diabetes
who are not pregnant, the Diabetes Control and Complications Trial Research Group (1993)
found that similar glucose values delayed and slowed diabetic retinopa- thy, nephropathy, and
neuropathy. us, women with overt diabetes who have glucose values considerably above those
de ned as normal both during and after pregnancy can expect good outcomes.

2.4.2. Second Trimester

Maternal serum alpha-fetoprotein determination at 16 to 20 weeks gestation is used in

association with targeted sono- graphic examination at 18 to 20 weeks to detect neural-tube
defects and other anomalies (Chap. 14, p. 284). Maternal alpha-fetoprotein levels may be lower

23
in diabetic pregnancies, and interpretation is altered accordingly. Because the incidence of
congenital cardiac anomalies is ve times greater in moth- ers with diabetes, fetal
echocardiography is an important part of second-trimester sonographic evaluation (Fouda,
2013). Despite advances in ultrasound technology, however, Dashe and associates (2009)
cautioned that detection of fetal anoma- lies in obese diabetic women is more di cult than in
similarly sized women without diabetes.

Regarding second-trimester glucose control, euglycemia with self-monitoring

continues to be the goal in management. After the first-trimester instability, a stable period
ensues. is is followed by an increased insulin requirement. Recall that Roeder and coworkers
(2012) identi ed a threefold increase in total daily insulin after the rst trimester in women using
an insulin pump. is is due to the increased peripheral resistance to insulin described in Chapter
4 (p. 53).

2.4.3. Third Trimester and Delivery

During the last several decades, the threat of late-pregnancy fetal death in women with
diabetes has prompted recommendations for various fetal surveillance programs beginning in
the third trimester. Such protocols include fetal movement count- ing, periodic fetal heart rate
monitoring, intermittent biophysi- cal pro le evaluation, and contraction stress testing (Chap.
17, p. 335). None of these techniques has been subjected to prospective randomized clinical
trials, and their primary value seems related to their low false-negative rates. The American
College of Obstetricians and Gynecologists (2012) suggests ini- tiating such testing at 32 to 34
weeks gestation.

At Parkland Hospital, women with diabetes are seen in a specialized obstetrical

complications clinic every 2 weeks. During these visits, glycemic control is evaluated and
insulin adjusted. ey are routinely instructed to perform fetal kick counts beginning early in the
third trimester. At 34 weeks, admission is o ered to all insulin-treated women. While in the
hospital, they continue daily fetal movement counts and undergo fetal heart rate monitoring
three times a week. Delivery is planned for 38 weeks.

Labor induction may be attempted when the fetus is not excessively large and the cervix
is considered favorable (Chap. 26, p. 523). Cesarean delivery at or near term has frequently
been used to avoid traumatic birth of a large infant in a woman with diabetes. In women with
more advanced diabetes, especially those with vascular disease, the reduced likelihood of

24
successful labor induction remote from term has also contributed to an increased cesarean
delivery rate. In a nested case-control study of 209 women with type 1 diabetes, Lepercq and
colleagues (2010) reported a 70-percent cesarean delivery rate overall. Two thirds of these were
delivered without labor. Both maternal body mass index (BMI) > 25 kg/m2 and low Bishop
score were indepen- dently associated with cesarean delivery for those in labor. In another
study, a glycohemoglobin level > 6.4 percent at delivery was independently associated with
urgent cesarean delivery. is suggests that tighter glycemic control during the third trimester
might reduce late fetal compromise and cesarean delivery for fetal indications (Miailhe, 2013).
The cesarean delivery rate for women with overt diabetes has remained at approximately 80
percent for the past 35 years at Parkland Hospital.

Reducing or withholding the dose of long-acting insulin given on the day of delivery is
recommended. Regular insulin should be used to meet most or all of the insulin needs of the
mother during this time, because insulin requirements typically drop markedly after delivery.
We have found that continuous insulin infusion by calibrated intravenous pump is most
satisfactory (Table 57-10). roughout labor and after delivery, the woman should be ade- quately
hydrated intravenously and given glucose in su cient amounts to maintain normoglycemia.
Capillary or plasma glucose levels should be checked frequently, especially during active labor,
and regular insulin should be administered accordingly.

TABLE 57-10. Insulin Management During Labor and Delivery (Coustan DR, 2012)

25
2.4.4. Puerperium

Often, women may require virtually no insulin for the first 24 hours or so postpartum.
Subsequently, insulin requirements may uctuate markedly during the next few days. Infection
must be promptly detected and treated.

Counseling in the puerperium should include a discussion of birth control. Available

options are discussed in Chapter 38 (p. 695). Efective contraception is especially important in
women with overt diabetes to allow optimal glucose control before subsequent conceptions.

26
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