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Detail-Document #230913
This Detail-Document accompanies the related article published in
PHARMACISTS LETTER / PRESCRIBERS LETTER
September 2007 ~ Volume 23 ~ Number 230913


Treatment of Diabetes in Women Who Are Pregnant


Introduction
Diabetes during pregnancy is a challenging
condition which must be closely monitored and
carefully treated. Within the last 15 years, a
number of new agents have been approved for
the treatment of diabetes. However, the role of
these agents in pregnancy is unclear. In
addition, there is controversy regarding many
issues including how to diagnose gestational
diabetes, whether treatment is necessary, and the
risks of hyperglycemia for the mother and fetus.
1


Prevalence and Risk Factors
Diabetes in a pregnant woman can be
classified as either pregestational (diabetes
existing before the onset of pregnancy) or
gestational (diabetes which begins or is first
recognized during pregnancy and goes away
after pregnancy).
1
It is estimated that more than eight million
women in the United States have pregestational
diabetes, with the majority of these cases
considered type 2 diabetes.
2,3
However, by far,
the majority of cases of diabetes in pregnancy
are gestational. It is estimated that up to 95% of
all cases of diabetes during pregnancy are
gestational diabetes.
4
The incidence of gestational diabetes varies
considerably depending on the population being
studied. Two of the most important factors
appear to be age and ethnic origin.
1
Although
there are a variety of other risk factors for the
development of gestational diabetes, the degree
to which these factors increase the risk of
gestational diabetes is difficult to quantify.
Consequently, it is easier to define low risk
individuals. In general, a woman is considered
low risk for the development of gestational
diabetes if she meets all of the following:
1,2
less than 25 years old
not a member of a high-risk ethnic group
such as Hispanic, African American, or
Native American
body mass index of 25 or less
no previous history of abnormal glucose
tolerance or adverse neonatal outcome
commonly associated with
hyperglycemia during pregnancy
no known family history of diabetes in a
first degree relative

Pathophysiology
In general, during pregnancy, an increase in
insulin resistance and reduction in the action of
insulin is noted. During the first trimester,
however, high estrogen concentrations increase
insulin sensitivity. In combination with nausea
and vomiting, this increase in insulin sensitivity
can lead to maternal hypoglycemia. As the
pregnancy continues, placental hormones such
as progesterone, prolactin, placental growth
hormone, and others lead to an increase in
insulin resistance.
3


Diagnosis of Gestational Diabetes
Although there are a number of different
screening tests, the most information exists
using a 100 gram oral glucose load. In this test,
a 100 gram oral glucose load is given in the
morning after an overnight (eight to 14 hours)
fast. Prior to the test, there should be at least
three days of unrestricted diet and unlimited
physical activity. Two or more of the following
values must be exceeded in order to establish the
diagnosis of gestational diabetes:
5,6

fasting venous plasma concentration
95 mg/dL or higher
one hour venous plasma concentration
180 mg/dL or higher
two hour venous plasma concentration
155 mg/dL or higher
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three hour venous plasma concentration
140 mg/dL or higher

Preconception Care in a Woman with
Diabetes
In a woman with pregestational diabetes,
preconception care should focus on control of
diabetes, most commonly with insulin, and
maintenance of an A1c less than 1% above the
normal A1c range.
6
Glucose goals include
fasting capillary plasma glucose of 80 to
110

mg/dL and a two-hour postprandial capillary

plasma glucose less than 155 mg/dL.
6


Treatment of Diabetes During Pregnancy
Despite the differences in the pathogenesis of
pregestational and gestational diabetes,
treatment is similar. Ultimately, the goal of
treatment is a reduction of pregnancy
complications associated with hyperglycemia
such as macrosomia (babies who are large for
their gestation age), shoulder dystocia (condition
where the shoulders of the baby are stuck during
delivery), and other birth trauma, and metabolic
effects in the neonate such as hypoglycemia,
hypocalcemia, and hyperbilirubinemia.
1,7

Tight glucose control is imperative during
pregnancy. This is best achieved by a
combination of diet, exercise and pharmacologic
therapy.
2,3

According to the American Diabetes
Association and the Canadian Diabetes
Association, all women with gestational diabetes
should receive nutritional counseling. The diet
should include adequate calories and nutrients to
meet the needs of pregnancy. In obese women,
a calorie restriction of approximately 30% can
reduce hyperglycemia and plasma triglycerides
and a restriction of carbohydrates to about 40%
of total calories can reduce maternal glucose
levels and improve maternal and fetal
outcomes.
2,8

The goals of glycemic control are lower in a
woman who is pregnant compared to a woman
who is not pregnant. In a woman prescribed diet
therapy, pharmacologic therapy for diabetes
should be considered when:
2

Fasting plasma glucose are 105 mg/dL or
greater, or
One hour postprandial plasma glucose


are 155

mg/dL or greater, or
Two hour postprandial plasma glucose


are 130

mg/dL or greater
Despite nonpharmacologic therapy, it is
estimated that approximately 30% to 40% of
women diagnosed with gestational diabetes
require pharmacologic therapy.
9
Of all of the
medications used in the treatment of diabetes,
insulin has the most data to support its use and
has been shown

to reduce fetal morbidities.
Human insulin should be used when insulin

is
prescribed and the woman should be instructed
to carefully monitor plasma glucose
concentrations at home.
2,3,5,8

No particular insulin regimen has been
shown to be more effective in a pregnant woman
who requires insulin. Consequently, a simple
regimen should be started. For example, NPH
insulin at bedtime to control fasting blood
glucose can be prescribed. It should be
remembered that insulin requirements usually
increase throughout pregnancy, especially
during weeks 28 to 32 of gestation.
1,5,8
If the
patient continues to experience elevated premeal
or postmeal hyperglycemia, regular human
insulin can be added at meals and at bedtime.
1,5

A recent guideline published by the
American College of Obstetrics and Gynecology
recommends that in women with pregestational
diabetes, the goal of therapy is to maintain
capillary glucose levels as close to normal as
possible.

In these women, the fasting glucose
should be 95 mg/dL or lower, and one-hour and
two-hour postprandial glucose concentrations
should be less than 140 mg/dL and 120 mg/dL,
respectively. An older guideline published by
the American College of Obstetrics and
Gynecology for the treatment of gestational
diabetes does not specify treatment goals in
women receiving insulin therapy.
1,2

Previously, the use of insulin analogs had not
been

adequately tested in women who are
pregnant. However, recently a number of
clinical trials evaluating some of the newer
insulins have been published.

Rapid-acting
insulin lispro (Humalog) and insulin aspart
(Novolog) are pregnancy category B and likely
as safe as regular human insulin.
10-13
No human
data exists for insulin glulisine (Apidra)
(Pregnancy Category C) and it is therefore not
yet recommended in women who are pregnant.
10

Long-acting insulin analogs insulin glargine
(Lantus) or insulin detemir (Levemir) are
(Detail-Document #230913: Page 3 of 5)
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typically not used in women who are pregnant.
Both of these agents are considered Pregnancy
Category C. Although preliminary studies have
demonstrated that these insulins are effective
and safe, more information is needed before
these agents can be routinely recommended.
10,14-
16

In the past, oral agents for diabetes were not
recommended

during pregnancy. Although oral
agents were studied in the 1970s and 1980s,
because of concerns about effects on the fetus,
oral agents were not recommended.
17
Early
sulfonylureas crossed the placenta and were able
to stimulate the pancreas of the fetus. In
addition, there was concern about the potential
for teratogenicity.
17
However, a number of
recent trials evaluating the use of glyburide, a
second-generation sulfonylurea which minimally
crosses the placenta, and metformin in women
who are pregnant have been published.
One of the first large, randomized, controlled
trials evaluating glyburide was published in
2000. Langer and colleagues compared
metabolic control in 404 women with gestational
diabetes who failed to achieve glycemic control
with diet and exercise treated with glyburide or
traditional insulin therapy. Overall, only eight
women

(4%) in the glyburide group did not
achieve adequate glycemic

control and those
who received glyburide had significantly less
hypoglycemia compared with those women who
received insulin. In addition, there were no
reports of neonatal hyperinsulinemia due to
transplacental passage of

the sulfonylurea drug,
and there was no difference in the incidence of
macrosomia or neonatal

hypoglycemia.
18

More recently, Jacobson and colleagues
found that after controlling for confounding
factors, in a study of more than 500 women with
gestational diabetes, women who were treated
with glyburide achieved better glycemic control
than those who received insulin. Although the
rates of macrosomia and large infants were
similar between the two treatment groups, there
was an increased rate of preeclampsia, neonatal
birth injury and the need for neonatal
phototherapy in the glyburide-treated group.
However, it is important to recognize that the
study was a retrospective review, and selection
bias of those women chosen to receive glyburide
may have occurred.
9,19

In another study, Kahn and colleagues
conducted a trial to attempt to identify patient
characteristics which could predict glyburide
treatment failure in women with gestational
diabetes. A total of 95 women were included in
the study. Of these women, 19% failed
glyburide therapy and subsequently required
insulin therapy. The authors found that
predictors of glyburide failure included older
maternal age, earlier diagnosis of gestational
diabetes, higher number of previous
pregnancies, multiparity, and higher
pretreatment fasting blood glucose. The authors
hypothesized that these factors were associated
with more advanced insulin resistance.
20,21
At this time, glyburide therapy, which is
considered Pregnancy Category C, is not

approved by the Food and Drug Administration
for the

treatment of diabetes in women who are
pregnant. Additional, randomized controlled
trials evaluating the efficacy and safety of
glyburide are needed before it can be routinely
recommended for treatment of gestational
diabetes.


Metformin (Glucophage, others) is
Pregnancy Category B meaning that although
there are no adequate and well-controlled studies
in pregnant women, in rats and rabbits no
teratogenic effects were noted at high doses.
However, because metformin crosses the
placenta, concern over its use in pregnancy
continues.
There is evidence to support the use of
metformin in women with polycystic ovary
syndrome [Evidence level B; lower quality
RCT]. In these women, metformin has been
shown to be effective in the treatment of
anovulation, thereby increasing the rate of
pregnancy.
22-24
In addition, in preliminary trials,
continued use of metformin throughout
pregnancy may reduce the rate of spontaneous
abortion, and reduce fasting insulin levels.
22-24

Although there are no well-controlled,
published clinical trials evaluating the use of
metformin in women without polycystic ovary
syndrome, many case reports suggest that it is
safe to use in women with gestational diabetes.
In these reports, metformin was shown to reduce
the rate of spontaneous abortion, with no effects
on birth weight or height, or social or motor
development up to six months of age.
22-24

(Detail-Document #230913: Page 4 of 5)
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In an audit by Hughes and colleagues, the
outcomes of 93 women who took metformin
during pregnancy were compared with the
outcomes in 121 pregnancies which were the
controls. A total of 32 of the women continued
metformin until delivery and 23 of these women
took metformin throughout their pregnancy.
Although the women treated with metformin
weighed more and had a higher rate of chronic
hypertension, there was no difference in the
rates of pre-eclampsia, perinatal mortality, or
neonatal morbidity between those who received
metformin and those who did not.
25

As with glyburide, although preliminary
evidence shows that metformin appears to be
effective and safe, caution should be used until
more information is available.

Conclusion
Treatment of diabetes in women who are
pregnant remains a common yet challenging
issue. Although the most clinical data is with
NPH and regular human insulin therapy, recent
information supports the efficacy and safety of
the rapid-acting insulin lispro and insulin aspart.
In addition, there is increasing evidence that the
oral agents, glyburide and metformin may be
effective and safe in women who are pregnant
and are sometimes used. Although these agents
seem to be effective and safe, insulin therapy is
still preferred.


Users of this document are cautioned to use their
own professional judgment and consult any other
necessary or appropriate sources prior to making
clinical judgments based on the content of this
document. Our editors have researched the
information with input from experts, government
agencies, and national organizations. Information
and Internet links in this article were current as of
the date of publication.

Project Leader in preparation of this Detail-
Document: Neeta Bahal OMara, Pharm.D.,
BCPS

References
1. Hollander MH, Paarlberg KM, Huisjes AJ.
Gestational diabetes: a review of the current
literature and guidelines. Obstet Gynecol Survey
2007;62:125-36.
2. American College of Obstetrics and Gynecology.
ACOG Practice Bulletin. Gestational diabetes.
Obstet Gynecol 2001;98:525-38.
3. American College of Obstetrics and Gynecology.
ACOG Practice Bulletin. Pregestational diabetes
mellitus. Obstet Gynecol 2005;105:675-85.
4. Langer O. Management of gestational diabetes:
pharmacologic treatment options and glycemic
control. Endocrinol Metab Clin North Am
2006;35:53-78.
5. American Diabetes Association. Gestational
diabetes mellitus. Diabetes Care 2004;27(Suppl
1):S88-S90.
6. American Diabetes Association. Preconception
care of women with diabetes. Diabetes Care
2004;27(Suppl 1):S76-S78.
7. Crowther CA, Hiller JE, Moss JR, et al. Effect of
treatment of gestational diabetes mellitus on
pregnancy outcomes. N Eng J Med
2005;352:2477-86.
8. Canadian Diabetes Association. Gestational
diabetes mellitus. Can J Diabetes 2003;27(Suppl
2):S99-105.
9. Durnwald C, Landon MB. Glyburide: the new
alternative for treating gestational diabetes? Am J
Obstet Gynecol 2005;193:1-2.
10. Briggs GG, Freeman RK, Yaffe, SJ. Insulin
aspart, insulin detemir, insulin glargine, insulin
glulisine updates. Briggs Update - Drugs in
Pregnancy and Lactation. 2007 Jun;20(2):11-4.
11. Mathiesen ER, Kinsley B, Amiel SA, et al.
Maternal glycemic control and hypoglycemia in
type 1 diabetic pregnancy. Diabetes Care
2007;30:771-6
12. Carr KJ, Lindow SW, Masson EA. The potential
for the use of insulin lispro in pregnancy
complicated by diabetes. J Matern Fetal
Neonatal Med 2006;19:323-9.
13. Product information for insulin aspart (Novolog).
Novo Nordisk, Inc. Princeton, NJ 08540. January
2007.
14. Price N, Bartlett C, Gillmer MD. Use of insulin
glargine during pregnancy: a case-control pilot
study. BJOG 2007;114:453-7.
15. Devlin JT, Hothersall L, Wilkis JL. Use of insulin
glargine during pregnancy in a type 1 diabetic
woman. Diabetes Care 2002;25:1095-6.
16. Graves DE, White JC, Kirk JK. The use of insulin
glargine with gestational diabetes mellitus.
Diabetes Care 2006;29:471-2. (letter)
17. Tran ND, Hunter SK, Yankowitz J. Oral
hypoglycemic agents in pregnancy. Obstet
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18. Langer O, Conway DL, Bekus M, Xenakis EMJ,
Gonzales O. A comparison of glyburide and
insulin in women with gestational diabetes. N
Engl J Med 2000;343;1134-8.
19. Jacobson GF, Ramos GA, Ching JY, et al.
Comparison of glyburide and insulin for the
management of gestational diabetes in a large
managed care organization. Am J Obstet
Gynecol 2005;193:118-24.
20. Kahn BF, Davies JK, Lynch AM, Reynolds RM,
Barbour LA. Predictors of glyburide failure in the
treatment of gestational diabetes. Obstet Gynecol
2006;107:1303-9.
(Detail-Document #230913: Page 5 of 5)

21. Rochon M, Rand L, Roth L, Gaddipati S.
Glyburide for the management of gestational
diabetes: risk factors predictive of failure and
associated pregnancy outcomes. Am J Obstet
Gynecol 2006;195:1090-4.
22. Lord JM, Flight IHK, Norman RJ. Metformin in
polycystic ovary syndrome: systematic review
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23. Hawthorne G. Metformin use and diabetic
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22.





Levels of Evidence
In accordance with the trend towards Evidence-Based
Medicine, we are citing the LEVEL OF
EVIDENCE for the statements we publish.

Level Definition
A High-quality randomized controlled trial (RCT)
High-quality meta-analysis (quantitative
systematic review)
B Nonrandomized clinical trial
Nonquantitative systematic review
Lower quality RCT
Clinical cohort study
Case-control study
Historical control
Epidemiologic study
C Consensus
Expert opinion
D Anecdotal evidence
In vitro or animal study
Adapted from Siwek J, et al. How to write an evidence-based
clinical review article. Am Fam Physician 2002;65:251-8.



Cite this Detail-Document as follows: Treatment of diabetes in women who are pregnant. Pharmacists
Letter/Prescribers Letter 2007;23(9):230913.


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