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id20209375 pdfMachine by Broadgun Software - a great PDF writer! - a great PDF creator! - http://www.pdfmachine.com http://www.broadgun.com Management of Diabetes in Pregnancy JOSE L. GONZALEZ, MD
Division of Maternal Fetal Medicine, Department of Obstetrics and
Gynecology, School of Medicine, University of New Mexico,
Albuquerque, New Mexico
Management of the diabetic pregnant pa-tient
has changed dramatically during the
last 80 years. Since 1920 when insulin was
discovered until today when researchers are
talking about genetic manipulation, stem
cells, and pancreatic islet capsules, provid-ers
of health care during pregnancy face the
dilemma of choosing adequate therapies for
individual patients. It is the task of the ob-stetrician
to balance the need for extra fuel
by the fetus with complications associated
with excessive maternal blood glucose.
Key elements in the management of preg-nancies
complicated with diabetes include a
balance of diet, exercise, and medications.
Important factors in the clinical manage-ment
of patients with diabetes include fre-quent
contact with the providers, psycho-logic
and social support, prenatal diagnosis
and counseling, fetal surveillance, and ad-equate
postpartum follow-up. Several areas
of controversy exist, including when and
how to screen populations for diabetes,
which glycemic levels reduce fetal compli-cations
without affecting maternal compli-
ance, and appropriate timing and mode of
delivery.
Management of patients with diabetes
during pregnancy is guided to obtain target
plasma glucose concentrations. Most inves-tigators
agree that fasting plasma glucose
concentrations should be kept under 95
mg/dL and postprandial levels under 120
mg/dL. In 1991 Jovanovic-Peterson et al 1
published that the glucose value 1 hour after
a meal is the most predictive of fetal macro-somia.
Other investigators have used differ-ent
laboratory tools to manage patients with
diabetes during pregnancy such as serum he-moglobin
A 1 C levels. This test is not rou-tinely
used to follow glucose levels since it
only reflects average values without taking
into consideration peaks in plasma glucose
concentrations after meals.
Patients with glucose intolerance during
pregnancy need specific diet instructions. A
typical diet includes three meals with three
snacks during the day. The diet is often
based on 30 kcal/kg of actual weight. This
recommendation has to be modified in pa-tients
who are obese or underweight. Distri-bution
of calories usually consists of ap-proximately
40–50% carbohydrates, 20%
protein, and 30–40% fat. If dietary manipu-lation
does not provide adequate metabolic
Correspondence: Jose L. Gonzalez, MD, University of
New Mexico, 2211 Lomas Blvd. NE, ACC4, Department
of Obstetrics and Gynecology, Albuquerque, NM 87131.
E-mail: CLINICAL OBSTETRICS ANDGYNECOLOGY
Volume 45, Number 1, 165–169
2002, Lippincott Williams & Wilkins, Inc.
CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 45 / NUMBER 1 / MARCH 2002
165control, as reflected by abnormally high
plasma glucose concentrations, then medi-cal
therapy with meticulous capillary blood
glucose self-monitoring is necessary.
Insulin Therapy
FORMULATIONS
Exogenous insulin lowers blood glucose
levels in all types of diabetes. Optimal
therapy, should approximate physiologic in-sulin
delivery, which may be difficult. There
are many insulin formulations (Table 1).
These insulin products differ in their onset,
peak, and duration of action. Rapid or pran-dial
insulins are used to cover the glucose
excursions after meals. Subcutaneous regu-lar
insulin has been prescribed most often.
Insulin Lispro, a semisynthetic insulin mol-ecule
that maintains the activity of regular
insulin, offers the advantage of being ab-sorbed
more quickly. Initial concerns re-garding
development or progression of dia-betic
retinopathy with the use of insulin Lis-pro
have not been supported by recent
studies.2 Intermediate-acting insulins, like
neutral Hagedorn, offer an extended release
from a subcutaneous site. Long acting insu-lins
are used to suppress the hepatic produc-tion
of glucose. Ultralente is an example of a
long acting insulin that produces a nearly
constant level of circulating insulin when
given subcutaneously once or twice daily.
Almost all insulins used in adults are pre-pared
as 100 U/mL. Being less immuno-genic,
human insulin is preferred over bo-vine
insulin. Commercially prepared mix-tures
of regular and neutral Hagedorn
insulin are not routinely used during preg-nancy.
When two different insulins are
drawn into the same syringe, care must be
taken to avoid cross-contamination of bottles.
MAINTENANCE THERAPY
The actual patient’s body weight is used to
calculate the daily insulin dose. During the
first trimester the recommendation is 0.5
U/kg. In the second trimester 0.75 U/kg is
recommended, while 1.0 U/kg is recom-mended
in the third trimester.3 Postpartum,
the patient should be placed on her prepreg-nancy
dose or 50% of the last total daily dose
before delivery.
Insulin therapy during pregnancy usually
involves a combination of usually two insu-lin
formulations to more closely resemble
what the normal human pancreas does.
Methods and timing of insulin administra-tion
are as important as the insulin dose in
avoidance of hyperglycemia. Shown in Fig-ure
1 are three examples of individualized
programs. None is clearly most preferred.
An alternative for patients with type 1
diabetes is the use of insulin pumps.4 These
calibrated pumps deliver insulin in a pattern
that most closely resembles physiologic in-sulin
secretion. Advantages to the pump in-clude
basal rates of insulin that reduce the
risk of hyperglycemia, decrease in the inci-dence
of the ‘dawn’ phenomenon (fasting
hyperglycemia) by reducing maternal hypo-
TABLE 1. Insulin Formulations
Onset Peak Duration
Lispro 15–20 min 1–2 hrs 4 hrs
Regular 30–60 min 2–4 hrs 4–6 hrs
NPH 1–2 hrs 5–7 hrs 10–12 hrs
Lente 1–2 hrs 10–12 hrs 14–18 hrs
Ultralente 1–2 hrs none 20–24 hrs
Lantus 1–2 hrs none 20 hrs
TABLE 2. Guidelines for Continuous
Insulin Infusion During
Pregnancy
Blood
Glucose
(mg/100 mL)
Insulin
Dosage
(U/hour)*
Fluids
(125 mL/hour)
<100 0.5 D5/Ringer’s lactate
100–140 1.0 D5/Ringer’s lactate
141–180 1.5 Normal saline
181–220 2.0 Normal saline
>220 2.5 Normal saline
* as 25 U regular insulin in 250 ml normal saline with intrave-nous
line flushed before IV administration is started.
166 GONZALEZglycemia, and improved patient compliance
since the patient does not constantly have to
inject insulin. Other advantages include in-creased
contact with health care providers
and greater flexibility with lifestyle. Disad-vantages
of the pump include cost of the de-vice,
infection at the needle insertion site,
and pump malfunction that may produce hy-perglycemia
and ketoacidosis. These factors
make the insulin pump an alternative only
for patients who are very compliant with
blood glucose self-monitoring. The insulin
pump dose is often calculated based on 80%
of the total daily dose requirement. This to-tal
dose of regular insulin is divided into
60% being given continuously and 40% be-ing
administered in boluses before meals to
cover the carbohydrate load.
INTRAVENOUS THERAPY
Ketoacidosis is fortunately uncommon in
closely regulated type 1 diabetic patients but
may result from profound hyperglycemia
and ketosis. Along with the appropriate re-
FIG. 1. Examples of three individualized programs for administering in-sulin
subcutaneously each day. These programs include a combination of
regular and neutral Hagedorn insulin (A), Lispro and neutral Hagedorn in-sulin
(B), and Lispro and ultralente insulin (C).
Management of Diabetes in Pregnancy 167placement of fluids and electrolytes and the
infusion of bicarbonate, insulin administra-tion
is necessary. The desired goal is a serum
glucose level of less than 300 mg/dL with no
urinary ketone bodies. The author usually
begins regular insulin as a 10 to 20 U of in-travenous
bolus plus 0.15 U/kg/h of constant
intravenous infusion. The dose is increased
hourly if serum glucoses do not fall despite
adequate fluid therapy. As acidosis is re-versed,
the insulin dose is decreased to 5 to
10 U every 2 to 4 hours. Once satisfactory
control is achieved, only subcutaneous regu-lar
insulin is required using a sliding scale
dose regimen. When the patient is eating, in-termediate
acting insulin may be started.
The intrapartum management of diabetes
is similar to the management of a woman
with diabetes about to undergo surgery.
Monitoring of the blood glucose level by
finger stick or venipucture every hour is vi-tal,
because strict glucose control (less than
100 mg/dL) is desired to avoid maternal hy-perglycemia
or hypoglycemia. Uncon-trolled
maternal blood glucose levels during
the intrepartum period may result in neona-tal
hypoglycemia with the potential for tem-porary
or permanent neuronal damage.5 In-trapartum
blood glucose control is achieved
by using intravenous infusion of dextrose
solutions with minimal or no insulin
therapy. Continuous intravenous infusion of
regular insulin or Lispro is preferred since
the rapid onset and short duration of action
make them ideal to titrate the therapy. A
constant intravenous infusion pump should
be used for this.
Oral Hypoglycemic Agents
Oral hypoglyemic drugs include agents with
differing chemistries and mechanisms of ac-tion.
Sulfonylurea, biguanide, alpha-glu-cosidase
inhibitors, and thiazolidinedione
drugs are indicated in the management of
nonpregnant adults with type 2 diabetes.
Oral hypoglycemics have been proposed as
alternative modalities in the treatment of
gestational diabetes. Studies from Coetzee
and Jackson 6 published in 1986 did not re-veal
any adverse perinatal outcomes when
patients with gestational diabetes were
treated with oral hypoglycemics. Piacqua-dio
et al 7 demonstrated an increase in
congenital malformations of Mexican-American
women treated during early preg-nancy
with oral hypoglycemic agents. In
1994, Denno and Sadler 8 found no embryo-toxicity
associated with use of these medica-tions
in an animal model.
Glyburide, a sulfonylurea that does not
cross the placenta, is appealing because of
its apparent safety to the fetus. Presumed
mechanisms of action include an increase in
the secretion of insulin and some effect pe-ripherally
to increase insulin receptor sensi-tivity.
A recent randomized study by Langer
et al 9 revealed that glucose levels in gesta-tional
diabetic patients could also be con-trolled
using glyburide. The need to treat
with insulin, rather than glyburide, for inad-equate
glucose control was observed in only
4% cases. There were no maternal or neona-tal
complications. Further investigation at
other institutions is necessary.
Areas of Ongoing
Investigation
Several alternative therapies are being ex-plored
for the management of patients with
diabetes during pregnancy. These include
the possibility of pancreatic islet transplan-tation,
10 embryonic stem cells that could dif-ferentiate into insulin producing tissue, and gene therapy. In addition to glyburide, other hypoglyce-mic agents may be considered as alterna-tives for the treatment of patients with ges-tational diabetes. Medications that increase the receptor-sensitivity to insulin may be
more appropriate, since this is the main
problem in gestational diabetes. Metformin,
a biguanide oral hypoglycemic agent, has
been used in patients with infertility and
polycystic ovaries.11 Preliminary findings
in small groups of patients have reported fa-vorable outcomes with continued use of this
drug during pregnancy.
Another area of interest is the develop-ment
of noninvasive glucose monitoring de-vices
as an alternative to performing mul-tiple
finger sticks. These noninvasive glu-cose
monitor devices could dramatically
change the lifestyle of patients with diabetes
in pregnancy.
Summary
Pregnancies complicated with diabetes are
best managed using a multidisciplinary team
approach to individualize diet and insulin
regimens. The combination of rapid and in-termediate
acting insulins more closely re-sembles
what happens physiologically with
the pancreatic secretion of insulin. In pa-tients
with type 1 diabetes, the insulin pump
is an alternative if she is highly motivated
and compliant with frequent monitoring
blood glucose levels. In gestational diabetes,
oral hypoglycemic agents like glyburide
may be alternative therapies. More studies
are needed to determine if any oral hypogly-cemic
agent is safest and most effective in
controlling maternal hyperglycemia.
References
1. Jovanovic-Peterson L, Peterson CM, Reed
GF, et al. NiHCD Diabetes in early preg-nancy
study. Maternal port prandial glucose
level and infant birth weight: The diabetes in
early pregnancy study. Am J Obstet Gyne-col.
1991;164:103–111.
2. Buchbinder A, Miodounik M, McElvy S, et
al. Is insulin Lispro associated with the de-velopment
or progression of diabetic retro-pathy
during pregnancy? Am J Obstet Gy-necol.
2000;183:1162–1165.
3. Jovanovic L. Role of diet and insulin treat-ment
of diabetes in pregnancy. Clin Obstet
Gynecol. 2000;43:46–55.
4. Gabbe S. New concepts and applications in
the use of insulin pump during pregnancy. J
Matern Fetal Med. 2000;9:42–45.
5. Halamek LP, Stevenson DK. Neonatal hy-poglycemia,
part II: Pathophysiology and
therapy. Clin Ped. 1998:37:11–16.
6. Coetzee EJ, Jackson WPU. The manage-ment
of noninsulin dependent diabetes dur-ing
pregnancy. Diabetes Res Clin Pract.
1986;1:281–287.
7. Piacquadio K, Hollingsworth DR, Murphey
H. Effects of in utero exposure to oral hypo-glycemic
drugs. Lancet. 1991;338:866–
869.
8. Denno KM, Sadler TW. Effects of the bi-guanide
class of oral hypoglycemic agents
on mouse embryo-genesis. Teratology.
1994;49:260–266.
9. Langer O, Conway DL, Berkus MD, et al. A
comparison of glybuide and insulin in
women with gestational diabetes mellitus. N
Engl J Med. 2000;343:1134–1138.
10. Hunter SK. Present and future perspectives
of the use of free or encapsulated pancreatic
islet cell trasplantation on a treatment of
pregnancy complicated with Type I diabe-tes.
J Matern Fetal Med. 2000;9:46–51.
11. Gluek CJ, Phillips H, Cameron D, et al. Con-tinuing
metformin thoughout pregnancy in
women with polycystic ovary syndrome ap-plies
to safety reduce first trimester sponta-neous
abortion: a pilot study. Fertil Steril.
2001;75:46–52.
Management of Diabetes in Pregnancy 169
168 GONZALEZ

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