PERSPECTIVES IN OBSTETRICS
Educational Objectives
| The goals of this program are to improve obstetric care of women with gestational diabetes and to improve management of
cesarean delivery on maternal request. After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Describe classes of oral antidiabetic agents and their mechanisms of action.
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| 2. Discuss available clinical support for using antidiabetic agents during pregnancy.
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| 3. Recognize obstetric complications of diabetes mellitus (DM).
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| 4. Provide appropriate intrapartum care for pregnant patients with DM.
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| 5. Discuss evidence evaluating the benefits and risks of cesarean delivery on maternal request.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a
proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.
Acknowledgment
Dr. Kjos was recorded at the 63rd Annual Obstetrical and Gynecological Assembly of Southern California, sponsored
by the Obstetrical and Gynecological Assembly of Southern California, and held March 21-22, 2008, in Los Angeles,
CA. Dr. Olson was recorded at the 22nd Annual: A Day With The Perinatologists “Perspective in Practice,” sponsored
by Creighton University School of Medicine, and held September 14, 2007, in Omaha, NE. Dr. Meyer was recorded
at Women’s Health Issues for Primary Care Providers, sponsored by the University of Vermont College of
Medicine, and held May 7-9, 2008, in Burlington, VT. The Audio-Digest Foundation thanks the speakers and the
sponsors for their cooperation in the production of this program.
| ORAL ANTIDIABETIC AGENT USE IN GESTATIONAL DIABETES —Siri L. Kjos, MD, MSEd, Clinical Professor,
Obstetrics and Gynecology, the David Geffen School of Medicine at the University of California, Los Angeles
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| Choosing oral antidiabetic agents in pregnancy: must be able to lower maternal glucose levels in woman with
type 2 diabetes in pregnancy or insulin resistance in those in nonpregnant state (ie, polycystic ovary syndrome [PCOS]);
must have good safety profile and desirable side effects for maternal health; must not be teratogenic or have harmful effect
on intrauterine growth or newborn; possible beneficial effect on fetal growth; assessing effectiveness in mother—
does it lower maternal glucose levels? easiest, but likely oversimplistic; look at what improves pathophysiology of gestational
diabetes mellitus (GDM); high risk for morbidity in women with GDM; goal to lower insulin resistance and improve
insulin sensitivity; therapy not associated with large weight gain; insulin-sensitizing agent theoretically best
choice; assessing effectiveness in fetus—look for normal growth pattern (fetal-based therapy important); avoid biochemical
or somatic fetopathy; prevent fetal hyperinsulinemia; proxy measures include amniotic fluid insulin and growth
of fetal abdominal circumference; placental transfer—if none, presumed benefit to infant through maternal metabolism
of normalizing nutrient and glucose metabolism; if yes, drug should not cause hyperinsulinemia in fetus; need to know
long-term effect of in utero changes on insulin resistance and sensitivity; assessing effectiveness in newborn—infant
either not large for gestational age (LGA) or small for gestational age (SGA); no increased rate of stillbirth or morbidity;
no excess newborn morbidity; effects of hyperinsulinemia measured by insulin levels at birth in neonatal obesity or by
ponderal index (PI)
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| Classification and characteristics of oral agents: insulin secretagogues—bind to sulfonylurea receptor on β
cells; stimulate insulin secretion; improve postprandial glucose; must have residual β-cell function; can cause hypoglycemia;
high placental transfer and long half-life associated with first-generation drugs; can cause hypoglycemia in newborn;
minimal placental transfer with second-generation drugs (eg, glyburide); meglitinides—shorter half-life; no data
in pregnancy (category C); biguanides—metformin only one available; require insulin to work; enhance insulin action
primarily on liver and muscle via postreceptor effect; increase hepatic sensitivity to insulin; suppress hepatic glucose output;
lower fasting glucose levels; increase glucose uptake in skeletal muscle in postreceptor effect (increased glucose disposal);
do not stimulate insulin secretion and release; do not cause hypoglycemia; side effects include gastrointestinal
(GI) upset; not associated with weight gain; placental transfer may be beneficial; currently recommended as first-line
therapy for newly diagnosed type 2 diabetes; cardioprotective effect; α-glucosidase inhibitors—eg, acarbose; little GI
tract absorption; prevent absorption of glucose from upper GI tract, thereby decreasing postprandial glucose levels; taken
with each meal; do not cause hypoglycemia; do not require endogenous insulin; associated flatulence limits compliance;
thiazolidinediones (TZDs)—rosiglitazone and pioglitazone; peroxisome proliferative activated receptor-gamma
(PPARγ) agonists; regulate transcription of insulin-responsive genes; improve insulin sensitivity of muscle and adipose
tissue; prevent β-cell apoptosis; associated with weight gain and edema (contraindicated in congestive heart failure);
monitor liver function; placental transfer; no pregnancy data; incretin mimetics—glucagon-like peptide 1 (GLIP-1) and
glucose-dependent insulinotropic polypeptide (GIP); potentiate glucose-dependent insulin secretion; inhibit glucagon secretion;
decrease fasting glucose and postprandial glucose; administered by subcutaneous (SC) injection
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| Placental transfer: sulfonylurea—insulin secretagogue; risk of crossing placenta and stimulating fetal insulin secretion;
can result in fetal hyperinsulinemia and diabetic fetopathy; human placental models show minimal transport of glyburide;
maximum glyburide binding to albumin occurs below expected lower albumin level associated with pregnancy;
glyburide and metformin similarly decrease glucose (glyburide best for nonobese women, metformin better for obese
women with insulin resistance); metformin may reduce fetal hyperinsulinism; may affect in utero programming;
acarbose—not effective, but likely good adjunct; no harm to infant; teratogenesis—meta-analysis of metformin
showed no increase in teratogenicity; may have protective effect; in control group, pooled malformation rate 7.2%),
whereas in metformin group, rate 1.7%
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| Comparison of glyburide and insulin (Langer et al): study shows no difference in outcome (as measured by, eg,
LGA, macrosomia, cord-serum insulin concentration, hypoglycemia, intravenous (IV) glucose or perinatal mortality);
concluded oral medication provided same outcome as insulin therapy; 4% of glyburide group had to go on insulin; subsequent
investigation found more LGA infants and macrosomia among women on higher doses of glyburide, but no
difference in PI or morbidity; more randomized trials needed; 15% to 20% failure rate in other studies; concern about
more macrosomia and hypoglycemia with oral medications; no long-term monitoring of children involved in studies
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| Clinical trial with metformin: metformin used for treatment of PCOS, during embryogenesis, and throughout pregnancy;
some reports of normalized first trimester loss and normalized rates of GDM (studies not well-designed); long-
term follow-up of children in trials showed normal growth and motor-social development; metformin in gestational diabetes
(MiG) study—no hypoglycemia or weight gain with metformin; improves insulin resistance; ≈50% placental
transfer; expected to enhance actions of fetal insulin, decreasing fetus’ response to diabetes, and to avoid hyperinsulinemia
related to maternal diabetes; possible (not proven) positive influence on reducing risk for diabetes later in mother and
reducing risk for obesity in offspring; MiG hypothesis—compared to insulin, metformin results in similar perinatal outcomes,
improved markers of insulin sensitivity in mother and infant, and improved treatment acceptability; primary outcome
measures—composite of neonatal morbidity score, hypoglycemia, respiratory distress, phototherapy, birth
trauma, low Apgar scores, and prematurity; composite outcome estimate 30%; 750 women necessary to show insulin not
better than metformin; secondary outcome measures—neonatal anthropometric measurements, cord blood insulin, maternal
glucose control, hypertensive complications, postpartum glucose tolerance, and patient’s amenability to treatment;
publication of study results pending; expected long-term follow-up of women and children exposed to metformin; composite
outcome of neonatal morbidity 32% with metformin vs 32.2% with insulin
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| Clinical trials with acarbose: 6 women with GDM treated with acarbose had normalization of glucose levels and
healthy infants; in another study, 19 women randomized to acarbose, and failure rate of 42% seen; possible role as adjunctive
therapy
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| Summary: GDM carries significant long-term risks (eg, maternal type 2 diabetes, obesity and metabolic syndrome in offspring);
by 11 yr of age, LGA offspring of mother with GDM has >3-fold higher risk for metabolic syndrome than average-for-gestational-age
offspring; breast-feeding cuts risk by 50%
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| MANAGEMENT OF THE DIABETIC PATIENT IN LABOR —Gayle Olson, MD, Associate Professor, Department of
OB/GYN Maternal Fetal Medicine, University of Texas Medical Branch, Galveston
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| Adverse outcomes: increase with maternal age, duration of diabetes, worsening glycemic control, comorbidities (eg,
obesity, hypertension), preeclampsia, preterm birth, stillbirth, and fetal overgrowth (macrosomia); postpartum hypoglycemia;
timing of delivery—early delivery considered because of increased risk for stillbirth (more prevalent in patients
with overt diabetes and poor glucose control), fetal overgrowth (evidence does not support early delivery for baby believed
to be big), and neonatal hypoglycemia; stillbirth—defined as death of fetus at age >20 wk gestation; affects
gravidas with type 1 and 2 diabetes mellitus; not increased for patients with GDM; rate in Denmark 18 per 1000 pregnancies,
in Scotland 25 per 1000 births, in United States 5.9 per 1000 births, and in nondiabetic United States population 4.0
per 1000 births; hyperglycemia, congenital anomalies, and infection play role; significant portion unexplained; antenatal
testing important; antenatal testing and delivery—majority of patients delivered at 38 wk; patients not diet-controlled,
poorly controlled, or with pregestational diabetes monitored 2 times per week, beginning at 32 wk or earlier; begin surveillance
sooner and increase intensity as severity of diabetes increases
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| Estimating fetal weight within 10%: data comparing methods—accuracy of maternal perception 70%, Leopold’s
maneuvers 66%, and ultrasonography (US) 42%; another study showed Leopold’s maneuvers and US equivalent; new
techniques for estimating fetal weight—humeral soft tissue; SC soft tissue (eg, midcalf, midthigh); cheek-to-cheek diameter;
cardiac interventricular septum; 3-dimensional US; magnetic resonance imaging (MRI); cord diameter; abdominal
circumference; methods generally ≥10% inaccurate; birth weight >4500 g—brachial plexus injury increased in
proportion to increase in birth weight; 5% to 6% rate of shoulder dystocia (SD); incidence of brachial plexus injury
≈0.8%; retrospective study of >29,000 women showed SD increased with birth weight and black ethnicity; occiput posterior
appeared protective (among women delivering vaginally); macrosomia defined as 4500 g for diabetic woman;
delivery—consider prelabor cesarean delivery; assess delivery history; clinical pelvimetry; watch progression of labor
(eg, prolonged second stage, arrest of descent)
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| Fetal lung maturity (FLM): reference range >70 mg/g for diabetic patient; lamellar body count ≈50,000 corresponds
most closely to presence of phosphatidylglycerol (PG); corticosteroids—significant impact on glucose control; require
increase in insulin dose; can be accomplished via insulin drip, but not necessary; one study showed patients receiving
>25% of daily insulin dose on day 1 before starting corticosteroids and increasing slightly until day 5; pay close attention
to glucose; in past, what was thought to be delayed lung maturity may have been issue of dating; no differences found in
amniotic fluid markers when comparing pregnancies of well-controlled diabetics to normal pregnancies; delay in PG in
poorly controlled diabetic pregnancy; 1998 comparison of amniotic fluid markers confirms previous findings; studies
suggest FLM not delayed in well-controlled diabetic pregnancy; exercise caution with poorly controlled diabetics; recommendations
for testing—amniocentesis may not be necessary at >38 wk in well-dated, well controlled diabetic pregnancy;
may still be recommended for those with poorly dated pregnancy, unconfirmed date, poor glucose control, or
inadequate prenatal care
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| Induction: study of induction vs expectant management—class B diabetics induced at 38 wk; majority delivered at 39
wk; majority of patients in expectant group delivered at 40 wk; decreased incidence of macrosomia in diabetic group; SD
occurred only in expectant management group; no increase in cesarean deliveries; study concluded no advantage to delaying
delivery; cesarean delivery for macrosomia—increased risk for postpartum infection; increased risk for wound
complications; decreased risk for postpartum hemorrhage; intrapartum glycemic control—consider when inducing diabetic
patient; intermediate insulin given at bedtime; discontinue morning insulin; continue infusion of 5% dextrose in
lactated Ringer’s (D5LR), 5% dextrose in normal saline (D5NS) and/or insulin as needed; maintain glucose level at ≈100
mg/dL; check glucose hourly; regular insulin infusion tailored to glucose values; alternative therapy—36 women in labor
randomized to insulin infusion or alternating glucose vs nonglucose fluids; study found no difference in mean intrapartum
blood glucose
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| Postpartum management: type 1 diabetes—may require small amount of insulin for 24 to 72 hr postpartum; sliding
scale when patient’s status nothing by mouth; postpartum doses reduced by one-third to one-half of predelivery doses;
0.6 U/kg in divided doses when patient allowed to ingest substances by mouth; fasting and postprandial goals—100
and 150 mg/dL; detail glucose monitoring before discharge; nutrition consultation necessary before discharge; type 2
diabetes—may not require medical therapy; oral agents if needed; GDM quickly normalized; cease monitoring when
fasting blood glucose <100 mg/dL; marked fasting hyperglycemia may require insulin; diagnosis of diabetes should not
be made postoperatively or if patient recovering from infection; benefits of breast-feeding—for mother, increases energy
expenditure and lowers blood glucose; long-lasting effects inconclusive; for infant, provides protection against extremes
of nutrition; appears to lower risk for obesity, hypertension, diabetes, and cardiovascular disease; 6-wk
postpartum testing—2-hr 75-g oral glucose tolerance test; only 37% of women with GDM during pregnancy received
postpartum testing (median time from discharge to testing 428 days); 94% received postpartum Papanicolaou (Pap) test
(median time from discharge to testing 49 days)
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| ELECTIVE PRIMARY CESAREAN DELIVERY —Marjorie Meyer, MD, Associate Professor of Obstetrics and Gynecology,
and Medical Director, Birthing Center, University of Vermont College of Medicine, Burlington
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| Factors influencing increase in cesarean delivery rates: fear of body changes; fear of long-term sequelae of
vaginal delivery; increased risk for primary cesarean delivery; convenience and control
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| Data from National Institutes on Health (NIH) consensus conference on maternal request for cesarean
delivery: no level 1 evidence (randomized controlled trial); strong evidence that primary cesarean delivery associated
with increased risk for hemorrhage and increased length of hospital stay
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| Maternal outcomes: weak evidence favoring vaginal birth—infection, anesthetic complications, subsequent placenta
previa, and breast-feeding; weak evidence favoring cesarean delivery—urinary incontinence; surgical and traumatic
complications; maternal outcomes with weak evidence for either mode of delivery—anorectal function
(misconception that cesarean delivery protects pelvic floor); sexual function, pelvic organ prolapse, subsequent stillbirth,
and maternal mortality
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| Neonatal outcomes: moderate evidence favoring planned vaginal delivery—respiratory morbidity; weak evidence
favoring planned vaginal delivery—iatrogenic prematurity; neonatal length of stay; weak evidence favoring planned
cesarean delivery—fetal mortality (assuming waiting for spontaneous labor until 42 wk); hypoxic ischemic encephalopathy
and intracranial hemorrhage; birth injury and laceration; neonatal infection
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| Patient-specific factors: age; future childbearing plans; obesity; assessment of gestational age; psychologic factors;
risk associated with primary cesarean delivery increased from ≈0.5% to 2% from 1998 to 2003; increased rate of rehospitalization
after primary cesarean delivery; 2-fold increased risk for rehospitalization within 30 days, and 70% increased
risk for rest of year (rehospitalization primarily due to infection); increased cost and length of stay with primary cesarean
delivery vs vaginal birth; more (70%) neonatal intensive care unit (NICU) admissions and pulmonary disorders (2-fold increased
risk; Apgar scores slightly improved, but Apgar score not good long-term outcome parameter)
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| Summary: moderate evidence that primary cesarean delivery increases maternal rehospitalization, length of stay, neonatal
respiratory complications, and maternal risk, especially after multiple cesarean deliveries; weak evidence that primary
vaginal delivery increases risk for long-term urinary incontinence or sexual dysfunction; recommendations—decision
for primary cesarean delivery acceptable within ethical boundaries; importance of considering family size and escalating
risk with multiple cesarean deliveries cannot be overstated; placenta previa life-threatening complication of multiple cesarean
deliveries, even when diagnosed antenatally
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Suggested Reading
American College of Obstetricians and Gynecologists Committee on Practice Bulletins—Obstetrics.
ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 30, September 2001 (replaces
Technical Bulletin Number 200, December 1994). Gestational Diabetes. Obstet Gynecol 98:525, 2001; American College of
Obstetricians and Gynecologists. ACOG Committee Opinion No. 394, December 2007. Cesarean delivery on maternal request.
Obstet Gynecol 110:1501, 2007; Bertini AM et al: Perinatal outcomes and the use of oral hypoglycemic agents. J Perinat
Med 33:519, 2005; Kjos SL et al: Insulin-requiring diabetes in pregnancy: a randomized trial of active induction of labor and
expectant management. Am J Obstet Gynecol 169:611, 1993; Langer O et al: A comparison of glyburide and insulin in
women with gestational diabetes mellitus. N Engl J Med 343:1134, 2000; Mathiesen ER et al: Insulin dose during glucocorticoid
treatment for fetal lung maturation in diabetic pregnancy: test of an algorithm. Acta Obstet Gynecol Scand 81:835, 2002; National
Institutes of Health State-of-the Science Conference Statement. Cesarean Delivery on Maternal request. Obstet Gynecol
107:1836, 2006; Piper JM et al: Does maternal diabetes delay fetal pulmonary maturity? Am J Obstet Gynecol 168(3 pt
1):783, 1993; Rowan JA et al: Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 358:2003,
2008.
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