Hyperglycemia and
Adverse Pregnancy
Outcomes
Aghaei Meybodi HR, MD
Assistant Professor of Endocrinology and Metabolic Diseases
Endocrine and Metabolism Research Institute
Tehran University of Medical Sciences
16 th June 2010
Zanjan
Agenda
• Overview
• Adverse Outcome of GDM (HAPO Study)
• Pre-GDM
- Maternal outcomes
- Fetal outcomes
• Summary
3
Overall Prevalence of Pregnancy
Complicated by DM
• Pre-GDM 0.81% in 1999
1.82% in 2005
• The prevalence of GDM remained constant at
about 7.5% during the same interval
Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the prevalence of preexisting diabetes
and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant
women, 1999-2005. Diabetes Care 2008; 31:899
4
Gestational Diabetes Mellitus
• “glucose intolerance with onset or first recognition
during pregnancy” ; whether or not insulin is used
for treatment or hyperglycemia persists after
pregnancy
• Criteria for the diagnosis were initially established
more than 40 years ago
• With minor modifications, remain in use today
O’sullivan JB, Mahan CM. Criteria for oral glucose tolerance test in pregnancy.
Diabetes 1964;13:278–285
5
Recommendations on Diagnostic Criteria for GDM
The Review of Diabetic Studies 2008; 5:194-202
6
International Association of Diabetes and
Pregnancy Study Groups (IADPSG)
• Was formed in 1998; 225 conferees from 40
countries.
• The principal objectives of IADPSG are to
foster an international approach to
enhancing the quality of care, facilitating
research, and advancing education in the
field of diabetes in pregnancy.
Diabetes Care 2010; 33(3): 676-82
7
Hyperglycemia and Adverse Pregnancy
Outcome (HAPO) study
• 25,505 pregnant women at 15 centers in nine countries
• Primary outcomes were birth weight above the 90th
percentile for gestational age, primary cesarean delivery,
clinically diagnosed neonatal hypoglycemia, and cord-blood
serum C-peptide level above the 90th percentile.
• Secondary outcomes were delivery before 37 wks of
gestation, shoulder dystocia or birth injury, need for
intensive
neonatal
care,
hyperbilirubinemia,
and
preeclampsia.
N Engl J Med 2008; 358:1991-2002
8
Primary outcomes
N Engl J Med 2008; 358:1991-2002
9
Adjusted Odds Ratios for Associations between Maternal Glycemia as a
Continuous Variable and Primary and Secondary Perinatal Outcomes.*
N Engl J Med 2008; 358:1991-2002
10
Key Messages
• The frequency of birth weight, C-peptide, or percent
infant body fat >90th percentile was approximately
twofold greater when any of the glucose values
were greater than or equal to the threshold
• The frequency of preeclampsia was twofold higher
when one or more glucose values met or exceeded
threshold, and frequencies of preterm delivery and
primary cesarean section were >45% higher
Diabetes Care 2010; 33(3): 676-82
11
Adverse Pregnancy Outcomes in
Women with Pre-GDM
• Prospective series from Sweden
• 5089 singleton pregnancies in women
with type 1 diabetes
• 1.2 million singleton pregnancies in the
general obstetrical population
• From 1991 and 2003
Persson M, Norman M, Hanson, U. Obstetric and perinatal outcomes in type 1 diabetic pregnancies:
A large, population-based study. Diabetes Care 2009; 32:2005.
12
Adverse Pregnancy Outcomes in
Women with Pre-GDM
Pre-GDM
General Population
Cesarean delivery
46
12
LGA
31
3.6
13.7
0.2
mild
9.7
2.0
severe
4.3
0.8
Major malformations
4.7
1.8
Preterm birth < 37 week
21
5.1
Respiratory Distress Synd.
1.0
0.2
Stillbirth
1.5
0.3
Perinatal mortality
20/1000
4.8/1000
Neonatal death
7/1000
2.2/1000
Shoulder dystocia
Preeclampsia
Persson M, Norman M, Hanson, U. Obstetric and perinatal outcomes in type 1 diabetic pregnancies:
A large, population-based study. Diabetes Care 2009; 32:2005.
13
Pregnancy Complications
• Three major potential fetal/pregnancy
complications among women with pre-GDM:
- congenital malformations
- spontaneous abortion
- macrosomia
• Hyperglycemia is probably
important determinant
the
most
14
Congenital Malformations
• The overall risk of one or more major
anomalies is 6 - 7 percent, which is double
the risk in the general obstetric population
Greene MF. Spontaneous abortions and major malformations in women
with diabetes mellitus. Semin Reprod Endocrinol 1999; 17:127.
• Increasing glucose concentration causes
embryopathy in a dose-dependent fashion
Fraser RB, Waite SL, Wood KA, Martin KL. Impact of hyperglycemia on early
embryo development and embryopathy: in vitro experiments using a mouse model.
Hum Reprod 2007; 22:3059.
15
Spontaneous Abortion
• Probably related, in part, to an increased
frequency of dysmorphogenesis
• But in the general population, at least onehalf of spontaneous abortions are related
to chromosomal abnormalities
Pregnancy outcomes in the Diabetes Control and Complications Trial.
Am J Obstet Gynecol 1996; 174:1343.
17
Macrosomia
• The most serious potential complication of
macrosomia is shoulder dystocia
• ↑likelihood need of cesarean delivery
Boulet SL, et al. J Perinatol 2005; 25:569.
• Macrosomia does not appear to increase the
propensity for adult obesity, though existing
data are sparse
Seidman DS, et al. Acta Obstet Gynecol Scand 1998; 77:58.
18
Macrosomia
• Although is typically considered a late pregnancy
problem, the pathogenetic factors appear to be
present in early pregnancy.
• Tight control of maternal blood glucose at
conception and in the first trimester has a greater
impact on reducing the risk of delivering a
macrosomic neonate than late pregnancy glycemic
control
Rey E, et al. Am J Obstet Gynecol 1999; 181:202.
Gold AE, et al. Diabetes Care 1998; 21:535.
19
Macrosomia
• Episodic hypoglycemia during pregnancy has
also been associated with an increased
frequency of macrosomia
• Presumably due to rebound hyperglycemia
Langer O, et al. Am J Obstet Gynecol 1989; 161:646.
20
Preterm Birth
• The reasons are not well-defined
• May be related to preeclampsia, worsening
nephropathy, macrosomia, and poor glycemic
control
• Is associated with a higher risk of late fetal
death and hyaline membrane disease
Sibai BM, et al. Am J Obstet Gynecol 2000; 183:1520.
21
Perinatal Mortality
• Congenital malformations now account for
approximately 50 percent of the perinatal
deaths in infants of diabetic mothers
Weintrob N, et al. J Diabetes Complications 1996; 10:294.
22
Neuro-developmental Outcome
• Maternal hypoglycemia has not been shown
to adversely affect the fetus's long-term
neurodevelopment, but data are sparse.
Ter Braak EW, et al. Diabetes Metab Res Rev 2002; 18:96.
23
Neonatal Complications
• Morbidity associated with preterm birth
• Macrosomia increases the risk of birth injury (brachial
plexus injury)
• Morbidity associated with growth restriction (in women
with vascular or renal disease)
• Polycythemia
• Hyperbilirubinemia
• Cardiomyopathy
• Hypoglycemia and other metabolic abnormalities
• Respiratory problems
• Congenital anomalies and their management
24
Fetal Effects
• Diabetic embryopathy (birth defects and
spontaneous abortions) occurs in the
sixth to seventh weeks of gestation
• Diabetic
fetopathy
(predominantly
macrosomia and fetal hyperinsulinemia)
occurs in the second and third trimesters
Buchanan TA, Kitzmiller JL. Metabolic interactions of diabetes and pregnancy. Annu Rev Med 1994; 45:245.
25
Diabetic Embryopathy
• Mostly related to the degree of hyperglycemia
Greene MF, et al.Teratology 1989; 39:225.
26
Diabetic Fetopathy
• Pedersen hypothesis:
intermittent maternal hyperglycemia causes
fetal hyperglycemia  premature maturation
and hypertrophy of fetal beta cells and
resultant hyperinsulinemia
Pedersen J. Acta Endocrinol (Copenh) 1954; 16:330.
27
Diabetic Fetopathy
• Amniotic fluid insulin concentrations in women with T1DM
were higher with macrosomic fetuses than with those
appropriate for gestational age (34 vs 13 mU/L)
Fraser RB . Diabet Med 1999; 16:568.
• Higher C-peptide in cord blood of infants with diabetic
mothers compared to control infants of nondiabetic mothers.
• Elevated cord blood c-peptide were associated with neonatal
hypoglycemia and macrosomia, but not hyaline membrane
disease.
Sosenko IR, et al. N Engl J Med 1979; 301:859.
28
Fetal Growth
• is similar in diabetic and nondiabetic women
during the first and early second trimesters.
• After 24 weeks gestation, hyperglycemia results
in disproportionally increased abdominal
circumference secondary to fat deposition and
visceromegaly, while head growth remains
normal.
Reece EA, et al. Am J Perinatol 1990; 7:18.
29
Fetal Hypoxemia
Chronic fetal hyperinsulinemia
Accumulation of glycogen in the liver
↑ activity of hepatic enzymes involved in
lipid synthesis
Accumulation of fat
↑ metabolic rate
McCormick KL, et al. Diabetes 1979; 28:1064.
30
Fetal Hypoxemia
Fetal hypoxemia
↑Erythropoietin synthesis  Polycythemia
Promotes catecholamine production
HTN and cardiac hypertrophy
20 to 30 percent of stillbirth seen in poorly
controlled diabetic pregnancy
Widness JA, et al. Diabetologia 1990; 33:378.
Kitzmiller JL. Diabetes Care 1993; 16 Suppl 3:107.
31
Polycythemia
May lead to hyperviscosity syndrome
↑ incidence of renal vein thrombosis
Hct should be measured within 12 hours
of birth
32
Congenital Anomalies
• account for approximately 50 percent of the
perinatal deaths in IDMs
Weintrob N, et al. J Diabetes Complications 1996; 10:294.
• Two-thirds of the anomalies in IDMs involve
the cardiovascular (8.5 per 100 live births) or
central nervous system (5.3 per 100 live
births)
Becerra JE, et al. Pediatrics 1990; 85:1.
33
Cardiomyopathy
In one retrospective study:
• About half of IDMs with T1DM developed hypertrophic
cardiomyopathy, and 20 % had congenital heart disease
• One-quarter of IDMs with T2DM developed hypertrophic
cardiomyopathy, and ≈ 6 % had CHD
•
≈ < 2 %
of infant mothers with GDM developed
hypertrophic cardiomyopathy or CHD
Ullmo S, et al. Eur Heart J 2007; 28:1319.
34
Cardiomyopathy
• Usually transient and
concentrations normalize
resolves
as
insulin
• Symptomatic infants typically recover after two to
three weeks of supportive care
• Echocardiographic findings resolve within 6 to 12
months
Way GL, et al. J Pediatr 1979; 95:1020.
35
Metabolic Complications
• Hypoglycemia
• Hypocalcemia
• Hypomagnesemia
36
Hypoglycemia
• Occurs frequently in IDMs (27 % in one large series)
Cordero L, et al. Arch Pediatr Adolesc Med 1998; 152:249.
• Most common in macrosomic infants
• Typically occurs in the first few hours after birth
• related to persistent hyperinsulinemia in the
newborn after interruption of the intrauterine
glucose supply from the mother
37
Hypocalcemia
• Occurs in 10 - 50 % of IDMs
• Typically occurs between 24 to 72 hours after birth
• Often is associated with hyperphosphatemia
• Is related to the severity and duration of maternal diabetes
• Is thought to be caused by the lower PTH concentrations
after birth in IDMs compared to normal infants
• In term IDMs usually is asymptomatic and resolves without
treatment
Mimouni F, et al. Am J Dis Child 1986; 140:798.
Tsang RC, et al. J Pediatr 1975; 86:399.
38
Hypomagnesemia
• Occurs in up to 40 percent of IDMs within the first
three days after birth
• The mechanism is thought to be maternal
hypomagnesemia caused by increased urinary loss
secondary to diabetes.
• Prematurity may be a contributing factor
• Usually transient and asymptomatic
Tsang RC, et al. J Pediatr 1976; 89:115.
Freitag JJ, et al. J Clin Invest 1979; 64:1238.
39
Hyper-bilirubinemia
• In 11 to 29 percent of IDMs
• Macrosomia, polycythemia and prematurity are
contributing factors
• Mechanism is thought to be increased hemolysis
• Excess hemolysis may result from glycosylation of
RBC membranes
Peevy KJ, et al. Pediatrics 1980; 66:417.
Stevenson DK, et al. J Pediatr 1981; 98:822.
40
Risk of developing T1DM
Proband with T1DM
Father
Mother
Both Parents
Pregnancy < 25 years
Pregnancy ≥ 25 years
Risk
1 in 17
1 in 25
1 in 100
10 – 25 %
* These risks are doubled if the affected parent developed diabetes before age 11
ADA. www.diabetes.org/diabetes-basics/genetics-of-diabetes.html. Last accessed 2 May 2010
41
Risk of developing T2DM
Proband with T2DM
One Parent* Dx before 50 years
Dx after 50 years
Both Parents
Risk
1 in 7
1 in 13
1 in 2
* Mother brings greater risk
ADA. www.diabetes.org/diabetes-basics/genetics-of-diabetes.html. Last accessed 2 May 2010
42
Obestity
• Macrosomia resolved by one year of age
• Obesity recurred in childhood, resulting in a greater
BMI in IDMs than controls (24.6 versus 20.9 kg/m2)
Silverman BL, et al. Diabetes Care 1998; 21 Suppl 2:B142.
43
Maternal Issues
• Two large prospective studies of women with
T1DM, DCCT and the EURODIAB Prospective
Complications Study (PCS), concluded that
pregnancy was not a risk factor for development
of
early
nephropathy,
retinopathy,
or
neuropathy after adjusting for confounders such
as age, duration of diabetes, and A1C
Diabetes Care 2000; 23:1084.
Diabet Med 2005; 22:1503.
44
Diabetic retinopathy
• Diabetic retinopathy worsens in some
women during pregnancy, although it is not
likely to develop de novo
• The likelihood of retinopathy being present is
related to the duration of diabetes and to the
degree of glycemic control
Star J, et al. Clin Perinatol 1998; 25:887.
45
Diabetic retinopathy
• Strict glycemic control, though is clearly beneficial
to the developing fetus, has been associated with
worsening retinopathy, with a particular increase in
the formation of soft exudates
Chew EY, et al. The Diabetes in Early Pregnancy Study. Diabetes Care 1995; 18: 631.
• Is related to the baseline level of retinal disease
and, in part, to the acute reduction of chronic
hyperglycemia
Arch Ophthalmol 1998; 116:874.
46
Diabetic retinopathy
• After pregnancy, milder
retinopathy typically regress
forms
of
diabetic
Serup L, et al. Acta Endocrinol (Copenh) 1986; 22:122.
• Some women with severe forms of diabetic
retinopathy may show persistence or progression
• Therefore, treatment during pregnancy should be
considered and close follow-up postpartum is
warranted.
Chan WC, et al. Eye 2004; 18:826.
47
Diabetic Nephropathy
• Pregnancy does not appear to increase the risk of dialysis and
diabetic nephropathy if neither was present before conception
Miodovnik M, et al. Am J Obstet Gynecol 1996; 174:1180.
• GFR declines during pregnancy in about one-third of women
with diabetic nephropathy, while another one-third do not
have the normal pregnancy-induced rise;even if strict glycemic
control is maintained
Jovanovic R. Am J Obstet Gynecol 1984; 149:617.
48
Diabetic Nephropathy
• Women with overt proteinuria at baseline, urinary
protein excretion can rise
dramatically as
pregnancy progresses
• After delivery, protein excretion decreases in most
women
• Pregnancy is not associated with permanent
worsening of renal function in the majority of
diabetic women in the absence of uncontrolled HTN
or a baseline serum Cr >1.5 mg/dL
Kitzmiller JL, et al. Am J Obstet Gynecol 1981; 141:741.
49
Diabetic Nephropathy
Renal function in women with Cr > 1.4 mg/dl at
the onset of pregnancy
• Remained stable in 27 %
• Transiently worsened in 27 %
• Permanently declined in 45 %
Irfan S, et al. J Coll Physicians Surg Pak 2004; 14:75.
50
Hypertension - Preeclampsia
• The prevalence of preeclampsia in diabetics
with and without vascular disease was 17
and 8 percent, respectively
• 5 to 8 percent in non-diabetic pregnancies
Acker, DB, Barss, VA. Obstetrical complications. In: Diabetes Complication Pregnancy, 2nd edition,
Brown, FM, Hare, JW (Eds), Wiley-Liss, New York 1995. p.153.
51
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