Diabetes

CLASSIFICATION AND DIAGNOSIS OF

physiologic insulin resistance. In a number of

DIABETES

woman the physiologic increase in insulin resistance

Traditionally, diabetes mellitus has been divided into

insulin dependent (type 1) and noninsulin dependent
(type 2) form. More recently, a classification into
five groups (see table 45-1) has been advanced,
based on paterns of inheritance and clinical
presentation.

Pregnancy

itself

is

state

of

during pregnancy on a background of inherited

insulin resistance or obesity is enough to make them
overtly diabetic. GDM refers to woman who are
shown to be diabetic for the first time during
pregnancy, regardless of whether the diabetes persist
after pregnancy.

The diagnosis of diabetes in nonpregnant

recognized as diaseases, but their presence does

subject is made on the finding of elevated fasting

indicate an increased likelihood of developing

blood glucose and/or elevated blood glucose

diabetes.

following an oral glucose challenge. Multiple

genetic and epigenetic factors modify fasting
glucose concentrations and response to an oral
glucose challenge, so that there is not a clear
bemodal separation of normal gluvcose tolerance
and diabetic states. Instead there is continuum of
fasting blood glucose concentrations and the
response to an oral glucose challenge. The accepted
criteria used to diagnose diabetes are shown in table
45-2. In addition, for glucose values falling
between normal and diabetic, the terms
impaired glucose tolerance and impaired fasting
glycemia have been coined. Impaired glucose

MATERNAL AND

FETAL

GLUCOSE

homeostasis and impaired fasting glycemia are not

HOMEOSTASIS IN PREGNANCY

mediated by hyperglycimea. In animal models

During pregnancy there is a physiologic increase in
insulin resistance in maternal tissues, presumably to
satisfy the nutritional demands of the fetus.
Placental glucose transport is noninsulin sensitive.

endothelial-dependent vasolidation is sequentially

increased,

unaltered

and

impaired

by

hyperglycimea. Studies in pregnant humans have

Instead glucose is moved across the placenta by

found either normal or impaired function.

The fetal placental circulation by definition

facilitated diffusion down a concentration gradient.

develops

High levels of maternal glucose result in high levels

researchers have sought evidence for abnormal

of fetal glucose. The fetal pancreas is stimulated by

development of the placental circulation in diabetic

hyperglycimea, and there is an early increase in

pregnancies. Any structural changes are relatively

beta cell mass of the pancreatic islets, so that the

subtle. The regulation of fetal placental blood flow

pancreas

repeated

is poorly understood, but in the absence of

hyperglycemia, secretes relatively more insulin than

autonomic or cholinergic innervations is entirely

that of normoglycemic futuses. Insulin appears to

dependent on circulating hormonal and autocrine

promote eatal growth, either directly through

factors. There is evidence for disturbances in the

insulin receptors or by increasing the bioactivity of

activity of endothelial-derived nitric oxide in the

insulin-like

diabetic placenta.

of

futuses

growth

exposes

factor-1

to

(IGF-1).

The

mechanism of fetal macrosomia in likely due to

accelerated pancreatic maturation and higher fetal

during

pregnancy,

and

numerous

ESTABLISHED/PREEXING DIABETES

insulin levels, and this has come to be known as the

Maternal Risks
Prior to the discovery of insulin in 1921 by Frederic

Pedersen Hypothesis. Other factors besides glucose

Banting and Charles Best, woman with diabetes

stimulate fetal insulin relase, and this may be one

rarely became pregnant, and those who did

reason why maternal glucose levels explain only

experienced a high incidence of maternal and fetal

the limited amount of birth weight variation.

morbidity.

Impact of Maternal Diabetic Vascular Disease

Diabetes is associated with both microvascular and

Nowadays,

most

woman

starting

pregnancy with a preexisting diagnosis of diabetes

have their diabetes relatively well contolled.

disease

Nonetheless pregnancy is associated with a

leads to retinopathy, nephropathy, and neuropathy,

physiologic worsening of tissue insulin resistance

whereas accelerated atheroscleroris of large vessels

and with renal and cardiovascular adaptations that

predisposes to myocardinal infraction, stroke, and

might be expected to accelerate the progression of

limb ischimea. Microvascular diaseas seem to be a

diabetic complication such as retinopathy and

result of sustained episodes of hyperglycemia with

neiropathy. Diabetic woman are more prone to

increased production of metabolites that lead to

developing hypertantion in pregnancy, and the

vascular damage. The endothelial lining of blood

increased susceptibility to infection means that

vessels play a pivotal role in the regulation of tissue

diabetic woman are more likely to suffer form

blood flow, and hyperglycemia-induced endothelial

pyelon phritis and perhaps from other infection-

dysfunction of small-resistance arteries leads

mediated adverse obstetric events. Several large

ultimately to tissue hypoperfusion. There are

studies in nonpregnant subject have convincingly

probably several phases to vascular damage

shown that intensive glucose control reduces the

microvascular

diseases.

Microvascular

development

and

progression

of

diabetic

complication. The same is true during pregnancy;

prolonged, and it may be appropriate to use sliding

woman can be encouraged that improvement in

scale

glycemic control during pregnancy has long-term

normoglycemia.

health benefits. At the same time, intensive

of

intravenous

insulin

to

maintain

glycemic control increases the risk of hypoglycemia

Retinopathy
Diabetic retinopathy complicates both type 1 and

and may be one reason why some women choose

type 2 diabetes milletus. In patients who developed

not to comply with suggested treatment.

diabetes before age 30 and who have had diabetes

Hypoglycemia
For many women, the degree of glycemic control

for more than 20 years, almost all will have

retinopathy, and about half of these will have

encouraged during pregnancy is much tighter than

proliferative retinopathy. In women with minimal or

normal. Concerns about hypoglycemia may be a

early retinopathy, there is a 10% chance of

reason for poor compliance with diet and insulin

progression during pregnancy; in those with

regimens. Most hypoglycemic episodes occur in the

proliferative retinopathy, there is 50% chance of

first 20 weeks and in women who have experienced

progression. Hypertention and preeclampsia further

hypoglycemic episodes before pregnancy. It has

increase the risk of progressive retinopathy.

been estimated that for every 1% fall in

Instituting a regimen of intensive glycemic control

glycosylated hemoglobin (HbA1c) levels, there is

in patients with moderate to severe nonproliferative

approximately a 33% increase in hypoglycemic

retinopathy

attacks. It is important that family members are

retinopathy; it is usual to increase the frequency of

educated about the use of glucagon injection for

funduscopic examination.

emergency treatment of profound hypoglycemia.

Diabetic Ketoacidosis
In established diabetics ketoacidosis is rare,

may

result

in

progression

of

Nephropathy
End-stage renal disease is one of the major
complications of diabetes and account for 40% of

affecting less than 1% of pregnancies, due to the

all patients on dialysis. The incidence of diabetic

increased level of supervision and tighter glycemic

nephropathy increase with duration of disease and

control

pregnancy.

is present in around 25% of diabetic after 15 years.

Occasionally the first presentation of type 1

It is estimated that about 6% of pregnant type 1

diabetes mellitus may be with ketoacidosis in

diabetics will have clinically significant renal

pregnancy. The 1994-1996 Report of Confidential

impairmement.
The impact of pregnancy on diabetic

generally

seen

during

Enquiries into Maternals death in the United

Kingdom reported two indirect maternal death from
diabetes milletus and two late death from diabetic
ketoacidosis. The risk of ketoacidosis increase in
the presence of obivious precipitans such as
hyperemesis and infection. Obstetricians should be
aware

that

tocolityc

therapy

with

betasympathomimetics and corticosteroid therapy

result in increased insulin requirements. The
metabolic effect of atenatal corticosteroids, are

nephropathy

depends

on

prepregnancy

renal

function. Most case series are small, but in general

in women with good renal function (creatinine
<150 micromol/L; <1.70mg/dL), there is little
evidence of worsening of renal function. In women
with markedly decreased glomerular filtration rates
prior to pregnancy there is significant risk of
permanent decline in renal function. Renal disease
is a risk factor for the development of hypertension

in pregnancy, and hypertention further accelerates

consideration

the decline in renal function. Microalbuminuria in

neuropathy also result in lack of hypoglycemic

early pregnancy is a sensitive predictor of those

awareness. Painful insulin neuritis, often described

women likely to develop hypertention. Women with

as an ache or burning sensation, sometimes

nephropathy are more likely to suffer from

complicates a rapid tightening of glycemic control.

pregnancy complications. The incidences of low

are

not

common.

Autonomic

birth weight, preeclampsia, and preterm delivery

Infection
Maternal infections are more common in diabetics.

are increased in women with nephropathy.

It has been estimated that about 80% of pregnancies

Hypertension
In diabetic women with chronic hypertension, the

in women with type 1 diabetes milletus will have at

least one episode of infection, compared with 25%

normal physiologic change in blood pressure occur

of pregnancies in nondiabetic women. Infaction is

during pregnancy but start from the higher baseline.

a risk factor for preterm labor and for ketoacidosis.

Chronic hypertension is a risk factor for the

Chronic urinary tract infaction, besides being a risk

development of preeclampsia, and worsening

factor for preterm labor, contributes to nephropathy

proteinuria and hypertension in later pregnancy

Pyelonephritis complicates about 4% of diabetic

may

superimposed

pregnancies and only 1% nondiabetic pregnancies.

preeclampsia. Clinically, however, it can be difficult

Postpartum endometritis and wound infaction are

to distinguish between preeclampsia and worsening

also more common in diabetics.

indicate

the

development

nephropathy. The development of proteinuric

hypertension is reported to complicate 12% to 40%

Other Associated Endocrine Diseases

Type 1 diabetes milletus is an autoimmune

of

of

condition, and women with type 1 diabetes are at

microvascular disease (as indicated by the presence

risk of other autoimmune endocrine diseases,

of retinopathy) increase the risk of developing

notably those effecting the thyroid. The incidence

hypertension.

of thyroid dysfunction during pregnancy and the

diabetic

pregnancies.

The

presence

Atherosclesis
Microvascular disease is also a feature of diabetes,
exaggerated lipid changes in pregnancy, a long with

first years postpartum in type 1 diabetes it about 3

time higher than that of the normal population.

rheologic and prothrombotic changes, might be

Operative Delivery
Maternal diabetes is risk factor for cesarean

expected to eccelerate atherosclerosis. Myocardinal

delivery. Reported rate of cesarean section in

infraction, however, remains a rare event in

diabetic women range from 25% to 80% and reflect

pregnant diabetic; equally there is little evidence of

with divergences in obstetric practice. Many factors

progression of peripheral arterial diseases during

account for high cesarean section rate, incluiding

pregnancy.

prematuriry macrosomia, and presence of diabetic

Neuropathy
Peripheral neuropathy has usually developed to

complications such as nephropathy. The diagnosis

of diabetes, or the knowledge that women are being

some degree in most diabetics after 10 to 15 years.

treated with insulin, triggers an increase in

Autonomic neuropathy may delay gastric emptying

intervention among obstreticians.

and blunt cardiovascular reflexes, but there are few

case reports in the literature suggesting that these

Pelvic Floor Trauma

Macrosomia,

nulliparity,

episiotomy,

and

risk of congenital anomaly is found type 1 and type

instrumental delivery are estabilished risk factor for

2 diabetics who had hyperglycemia during early

third-and fourth-degree tears. Approximately 20%

pregnancy. Women

of diabetic women who deliver vaginally suffer

diagnosed later in pregnancy do not seem to be at

second-, third-, or fourth-degree tears. Shoulder

risk.

than 4000 g. furthermore, as a groups, nondiabetic

women had shoulder dytosia rate of 0.5% compared

gestational

diabetes

The congenital abnormalities found in the

dystocia is also a risk factor for perineal trauma.

Langer reported that when the birth weigh was less

with

infantsof diabetic women do not form a clear

syndrome.

Neural

tube

defects

and

cardiac

malformations are more common than in the

nondiabetic population, and caudal regression (or

to 3.2% in women who were diabetic.

sacral agenesis) is reported to be 200 to 400 times

Fetal Risk
Maternal diabetes mellitus increase the risk of
congenital abnormalities, miscarriage, unexplained
stillbirth, premature delivery, microsomia, and
traumatic delivery, and also of a number of neonatal
complications. In the pre-insulin era, fetal and
neonatal losses were in the order of 65%.
Improvement in insulin therapy and obstetric
approaches

to

the

pregnant

diabetic

have

progressively improved outcomes. The perinatal

mortality rate of infants of diabetic mother has
decline from 250 per 1000 live births in the 1960s
to 20 per 1000 live birth in the 1980s. furthermore,
it has been established that tight glycemic control
before conception and during pregnancy can reduce
the rate of congenital malformations, miscarriage,
and

fetal

macrosomia.

Fatal

congenital

abnormalities now appear to be the leading cause of

perinatal death, but unexplained late stillbirth
remains a problem.
Congenital Anomalies
Many center around the world continue to report
that approximately 3% to 8% of infant diabetic
mothers

suffer

from

major

congenital

abnormalities. The reduction in the incidence of

congenital anomalies remains a major goals,
especially when it is considered that congenital
anomalies account for between 20% and 50% of the
perinatal death to diabetic women. The increased

more common in infant of women with diabetes.

There is good evidence that the abnormalities arise
as a consequence of poor glycemic control
priconceptually and during embryogenesis. When
the HbA1c is less than 6 standart deviations above
the mean, the congenital anomaly rate is about 3%,
but when the HbA1c is more than 12 standart
deviation above the mean, the anomaly rises to rate
35%. Figure 45-1 shows the relationship between
the

first-trimester

HbA1c

and

conginetal

abnormalities. Small studies have reported low

rates

of

conginetal

preconceptual input has

abnormality

where

optimized glycenic control. In the larger diabetes in

increase wuth greater HbA1c levels. Figure 45-

early pregnancy study, where women were enrolled

shows the relationship between first-trimester

within 21 days of conception, infants of diabetic

HbA1c and miscarriage. The Diabetes Control and

mothers had higher rates of congenital abnormality

Complications Trial showed that intensive therapy

than those of nondiabetic mothers, but the

for blood glucose control reduce the rate of

investigators ware unable to rel;ate the risk of

spontaneous abortion to that in the nondiabetic

abnormality to mean glucose or to glycosylated

population.

HbA1C. the

randomized prospective Diabetes

Control and Complication Trial showed that the

Preterm Labor
The prequency of spontaneous paterm labor is

timely institution of intensive therapy for blood

reported to be higher in diabetic (in one series

glucose control is associated with rates of

complicating about 20% of pregnancies) the

spontaneous abortion ad congenital malformation

mechanism of preterm labor is not known.

that are similar to those in the nondiabetic

Polyhydramnios and increased susceptibility to

population.
Both hyperglycemia and hypoglycemia

infection in poorly controlled diabetics may both

the contributory factors.

have been suggested as possible cause of congenital

anomaly studies with nonhuman embryos culture
identified that hypoglycemia teratogenic in clinical
practice,

however,

increased

frequency

of

hypoglycemic episodes deos not increase the

incidence of congenital anomaly, suggesting that
human embryos min utero can tolerate short-llived
periods

of

hypoglycemia.

More

likely,

hyperglycemia or some metabolic derangement

consequent or hyperglycemia is responsible for
demage to the developing embryo. Intensive control
of glucose concentrations around the time of
conception and embryogenesis can reduce the
incidence of congenitas abnormalities in infant of
diabetic women to that seen in nondiabetic women.
The higher incidence of neural tube defect in
diabetic pregnancies does not seen to be associated
with deranged folate metabolism though this is not
to

argue

against

to

importance

of

folate

supplementation.
Early Pregnancy Losses
The incidence of miscarriage in increased in
diabetic pregnancies and, as with all complicated, is
related to the degree of glycemic control since it

Fetal Growth
The birth weight of infant of diabetic mother is
greater than those of nondiabetic mother, and the
incidence of obstructed labor and shoulder dystocia
are correspondingly increased. The distribution of
standardized birth weight in infants of diabetic
women is unimodal and

shifted about 1.2 to 1.5 standart deviation to the

right. Between 20% and 40% infants of diabetic
mother have a birth weight over the 90 th percentile
for gestation. Fetal microsomia develops from
about 20 weeks gestation on. At birth, diabetic
infants have significantly more adipose tissue,
larger shoulder, nad decreased head-to-shoulder
ratio compared to nondiabetic infants of similar
birth weight and length. The widely accepted
Pedersen

model

suggest

that

maternal

hyperglycemia leads to fetal hyperglycemia, and

this in turn leads to hyperplasia of fetal pancreatic
beta cell and increased fetal insulin concentrations.

6.7 mmol/L (120 mg/dL) was associated with a

Insulin can be detected in increased amount in the

30% chance of macrosomia.

Polyhydramnios
is

cord blood and amniotic fluid of diabetic women

considered

from 20 weeks gestation onward.

Much effort has been devoted to identifying

complication of diabetes. The precise mechanism of

wich parameter of glycenic control best predict the

the higher incidence of conginetal anomalies, to

development of macrosomia. Mean daily glucose,

increased osmotic pressure in amniotic fluid (due to

prepandial glucose, and postprandial glucose

high glucose concentrations), or to fetal polyuria.

concentrations have all been advocated. At the

Polyhydramnios does not necessarily indicate that

center of the debate is the concept that the peak

the pregnancy is at risk. A review of all cases of

excursion of hyperglycemia associated with meals

polydramnios, regardless of diabetic status from a

may be relatively more importans in determining

diabetes of over 40,000 women concluded that the

microsomia than the average backround glucose. In

overall incidence of polyhydramnios was about 1%

both diabetic and nondiabetic women, postprandial

and that the diagnosis of polyhydramnios was

glucose concentration in the third trimester rather

associated with an increase in perinatal mortality

than fasting glucose levels are correlated with fetal

and congenital anomalies.

size and birth weight. Figure 45-3 shows the

polyhydramnios is not known, but it may relate to

relationship between birth weight and the 2-hour

Perinatal Mortality
The perinatal mortality rate in diabetic pregnancies

plasma glucose following a 100-g oral glucose

remains consistenly higher than the background

tolerance test (GTT) in women, mean postprandial

perinatal mortality rate. It is estimated that between

whole blodd glucose above

10% and 50% of perinatal mortality in women with

diabetes is due to congenital abnormalities. There is
also a significantly higher rate of stillbirth unrelated
to congenital anomaly in diabetic pregnancies in
mose case series. It is likely that some of the
stillbirth seen in diabertic pregnancies are due to
intrauterine growth restriction (IGR) produced by

usual

mechanism

nondiabetic

insufficiency are involved (figure 45-4). It is

pregnancies. The rightward shift in the birth weight

generally stated that poor glycemic control is

distribution of diabetic infant can mask the

associated with stillbirth. In animals models, fetal

diagnosis of significant IUGR.

Stillbirth are more common in diabetic

hyperglycemia

pregnancies
suggesting

across
that

that

effect

all

infant

factors

other

birth
than

weight,
placental

result

in

increased

oxygen

consumption and ultimately hypoxia and acidosis.

Fetal cord