Published in UAB Insight, Fall 2004

CME Exam Coming Soon!

ABSTRACT: Recognizing that premature delivery has multiple etiologies should lead to specific therapies aimed at underlying pathologies.

CME OBJECTIVE: The reader will discover what is known about different etiologies for premature delivery and appropriate approaches to decrease morbidity and mortality.
William W. Andrews, PhD, MD, no conflicts of interest.

About 12% of the 4 million live births in the United States each year are complicated by preterm delivery. The March of Dimes identifies prematurity as the number one health problem among American infants.

Advances in technology and neonatal intensive care management have improved survival among preterm infants, yet morbidity, including long-term neurological handicap, is essentially unchanged, explains UAB Professor of Obstetrics and Gynecology William W. Andrews, PhD, MD.

"In addition to continued morbidity, preterm delivery rates have risen 27% since 1981. Increased use of assisted reproductive technologies and subsequent multiple gestations contribute to the rise, but do not wholly account for it," he says.

Morbidity and Risk Factors

Half of preterm births are caused by spontaneous onset of premature labor; one third by spontaneous premature rupture of membranes; and the remainder are "indicated" births in which the obstetrician intervenes because of a specified indication, such as fetal compromise or preeclampsia.

"Preterm births cause 75% of perinatal mortality and about 50% of all long-term neurological handicaps," Andrews says. "The subset of babies born before 32 weeks gestation — 10% to 20% of preterm deliveries — experience 80% of all perinatal morbidity and mortality." More than 98% of infants born at 32 to 35 weeks survive and few have long-term deficits, the March of Dimes reports.

African American women are twice as likely as other American women to deliver premature or low-birth-weight infants. Other risk factors include prior preterm delivery, maternal weight <110 lbs., multiple gestations, bleeding, and concurrent sexually transmitted disease.

"Asymptomatic upper genital tract infection also is strongly associated with prematurity; women who have a spontaneous preterm birth are three times as likely to have bacteria in their upper genital tract, compared with those whose babies are delivered for a specified indication," he says. "And, inflammatory mediators, such as cytokines and metalloproteinase, are risk markers found much more frequently in spontaneous preterm births than in indicated births."

Upper genital tract bacterial colonization or infection also corresponds to younger gestational age at birth. "Up to 75% of women who deliver before 30 weeks gestation have upper genital tract bacterial colonization, making these infections a substantial risk factor for the group of babies born earliest who experience the greatest morbidity and mortality," he says, noting that among this group of infants, even a small increase in gestational age can translate into substantial improvements in survival.

Preventing Preterm Birth

"Trials investigating perinatal antibiotics for infections associated with preterm delivery have produced mixed results," Andrews says. "Some showed no benefit and suggested adverse effects, but others found prophylactic antibiotics increased gestational age and produced modest improvements in outcomes."

Andrews and colleagues theorized that in earlier trials perinatal antibiotics were administered too late in pregnancy to improve outcomes. Consequently, UAB investigators designed a trial testing efficacy of antibiotics administered in the period between pregnancies, which could potentially prevent initial ascension of bacteria into the upper genital tract.

Investigators randomized 241 women with prior spontaneous preterm births (<34 weeks gestation) to two 1 g doses of oral azithromycin 4 days apart plus 750 mg of sustained-release metronidazole for 7 days or placebo. The regimen was repeated every 4 months until participants became pregnant.

Of the 124 women who became pregnant during the 7-year study, 59 were taking antibiotics. "Participants in the antibiotic group and placebo group had equivalent risk factors and interpregnancy intervals and no significant differences in maternal age, ethnicity, tobacco use, marital status, or days between last treatment and subsequent conception," he says.

Negative Results

The study, which was presented at the 2004 meeting of the Society of Maternal-Fetal Medicine and won the March of Dimes Award for Excellence in Research on Prematurity, showed women treated with antibiotics had neither lower preterm birth rates nor lower frequency of miscarriage.

"Although not statistically significant, one of the most striking results was a 2.4 week earlier mean gestational age of delivery in the antibiotic group," he says. Additionally, there was a statistically significant difference in birth weights; babies born to women taking antibiotics weighed an average of 500 g less than those born to women taking placebo.

Andrews stresses that while this study demonstrates no benefit from interpregnancy antibiotics and the possibility of harm in certain women, neither physicians nor their pregnant patients should avoid antibiotics when needed.

"Women with legitimate medical indications can and should take antibiotics before or during pregnancy. This study shows 'shotgun' elimination of genital tract bacteria does not prevent or reduce preterm birth, but use of antibiotics in selected patients for preventing preterm birth requires further study," he says.

"Prematurity was once considered a homogenous condition, but we now understand it is a heterogenous problem with multiple etiologies. For example, we may not have found the subset of at-risk women who can benefit from antibiotics, but efforts are underway to identify markers of risk that can better pinpoint those individuals."

Progesterone

Other strategies for preventing prematurity also are being studied. According to Andrews, a synthetic progesterone is the most promising.

"Twenty years ago, 17 alpha-hydroxy-progesterone caproate (17P) was used to prevent preterm birth, but its benefit was debated, and it fell out of favor," he says, adding that a recent study published in The New England Journal of Medicine (2003;348:2379-2385) revived interest in progesterone for prevention of prematurity. Researchers halted the study early when results showed significant protection against recurrent premature delivery for all groups of at-risk women taking 17P.

Investigators randomized 463 women at 16 to 20 weeks gestation to either weekly 250 mg injections of 17P or placebo. Participants were given injections until week 36 of gestation. Progesterone substantially reduced rates of preterm delivery before 37 weeks (36.3% for 17P group vs 54.9% for placebo group), before 35 weeks (20.6% vs 30.7%), and before 32 weeks (11.4% vs 19.6%). 17P treatment also improved neonatal outcomes, reducing incidence of necrotizing enterocolitis, intraventricular hemorrhage, and the need for supplemental oxygen.

A recent South American study (Am J Obstet Gynecol. 2003;1884:419-424) investigating progesterone suppositories for prevention of preterm birth showed similar benefits; treatment reduced premature delivery rates by about half.

"Preliminary results are encouraging, but there are concerns," Andrews says. "The progesterone formulation used in recent studies is not commercially available in the US. A compounding pharmacy can supply the injectable form, but Medicaid does not cover cost — about $130 for a 10-week supply — placing it out of reach for some lower-income women who may be at greater risk."

An opinion issued by the American College of Obstetricians and Gynecologists (Obstet Gynecol. 2003;102:115-116) cites progesterone's potential benefits but calls for further study and cautions physicians to restrict use to pregnant women with a documented history of spontaneous preterm birth.

"FDA approval of 17P for preterm delivery prevention depends on more study of efficacy and long-term safety," he explains. "The FDA is wary of approving a synthetic steroid hormone for broad use that could be associated with disastrous problems, such as those that occurred with DES in the 1960s." Long-term followup of children of women treated with 17P is also ongoing at centers around the country.

UAB is currently recruiting participants for a trial of weekly progesterone injections versus placebo in women pregnant with twins or triplets between 16 and 21 weeks gestation. The trial is sponsored by the National Institutes of Child Health and Human Development's Maternal-Fetal Medicine Units Network.

UAB Professor of obstetrics and gynecology Dwight J. Rouse, MD, is coprincipal investigator, along with Steve N. Caritis, MD, professor of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, 1 of 12 participating centers.

Andrews suggests physicians consider progesterone therapy in women with prior preterm birth.

Cervical Sonography

"Measuring cervical length to predict preterm birth is controversial," Andrews says. "Certain cervical measurements, such as funneling and cervical shortening, are strongly associated risk factors for prematurity. Because we do not yet understand the mechanism of cervical shortening, optimal management is unclear. Some hypothesize an intrinsic mechanical abnormality causes cervical dilation without contraction, but that does not appear true for all patients."

Andrews notes numerous etiologies, including inflammation or infection, could cause premature cervical remodeling, and thus an incompetent cervix, and that effective intervention must be tailored to the condition's underlying cause. "Cerclage is often used to treat cervical incompetence, but benefits are unclear. If, for example, the patient has an infection, closing the cervix could result in a concealed abscess that would increase preterm birth risk, not decrease it.

"We are identifying many useful markers of prematurity risk. The challenge is to understand what to do with that information," he concludes. "Once scientists recognized cancer as a disease with multiple causes, treatment and outcomes improved dramatically. Understanding that prematurity also has many causes can lead to specifically targeted interventions and similar successes."

For more information:
Dr. William Andrews
1.800.UAB.MIST
mailto:mist@uabmc.edu