Maternal-Fetal Medicine Units (MFMU) Network 

 In 1986, the NICHD convened the first MFMU Network, consisting of seven sites; after four competitive recompetitions, the Network currently funds 14 sites. Like the NRN, the scientific partnership between the PPB, the funded maternalfetal medicine divisions, and the data-coordinating center has also become a strong force in the obstetric research community; Network staff present regularly at national and international scientific meetings.

Evaluations of Common Medical Practices
A Spirit of Trans-NIH Collaboration

Evaluations of Common Medical Practices

The MFMU Network continues to rise to the challenge of designing programs and treatments for the prevention of preterm births using evidence-based medical practices. Based on the scientific literature and the rapidly growing practice in the obstetric community of using prophylactic antibiotics during pregnancy for the prevention of poor birth outcomes, the MFMU Network designed a randomized, double-blind clinical trial to evaluate this practice. The hypothesis for this study was derived from earlier randomized studies that showed a benefit to treating asymptomatic bacterial vaginosis in women with a history of prior preterm birth, as well as studies that correlated bacterial vaginosis in pregnancy with LBW babies. This study evaluated whether treatment of asymptomatic bacterial vaginosis in low-risk women reduced the risk of preterm delivery. Almost 2,000 women in the Network were assigned to receive either an antibiotic or a placebo at 16 to 23 weeks' gestation, and again at 24 to 29 weeks' gestation. The primary outcome was delivery before 37 weeks' gestation. Surprisingly, there was no difference in the rate of preterm birth between the two groups; preterm delivery occurred in about 12 percent of pregnancies in each group (N Engl J Med 2000; 342:534-40). Although the results of the study were negative, the findings were important for the obstetric community in that mass screening for bacterial vaginosis in pregnancy could not be recommended. These findings also support the growing body of evidence that preterm birth is a multifactorial problem.

A study of mid-trimester endovaginal sonography in women at high risk for spontaneous preterm delivery further examined this multifactorial basis by evaluating the contribution of cervical length, as measured by ultrasound in the second trimester, to preterm labor. The study concluded that cervical length at 16 to 18 weeks' gestation predicted spontaneous preterm delivery at less than 35 weeks' gestation in women with a prior early spontaneous delivery (JAMA 2001; 286:1340-1348). Thus, sonographic evaluation of the cervix identifies women at increased risk for preterm birth and may identify a subgroup of patients eligible for an intervention.

The MFMU Network also builds upon information obtained from its own studies. For example, an MFMU Network study designed to identify predictive factors for spontaneous preterm birth found that fetal fibronectin (FFN) was a promising biological marker. To elucidate this relationship, 13 Network sites conducted a randomized trial of antibiotic treatment in women who were FFNpositive (n=700) for reducing preterm births. Treatment of asymptomatic women with a positive cervical/vaginal FFN test between 21 and 25 weeks' gestational age with metronidazole plus erythromycin did not decrease the risk of spontaneous preterm delivery (Am J Obstet Gynecol 2000; 183:469-75). 

 In part due to an ongoing trial in the MFMU Network that was evaluating repeat courses of antenatal corticosteroids, in March 2000, the NIH convened a consensus development conference Antenatal Corticosteroid Revisited: Repeat Courses. Its purpose was to review research on repeat courses of antenatal corticosteroid therapy. The panel concluded that the available data was inadequate to recommend the repeated use of antenatal corticosteroid therapy for women at risk of preterm birth (http://consensus.nih.gov/2000/2000AntenatalCorticosteroidsRevisted112html.htm). This consensus conference changed the practice patterns of many obstetricians regarding the use of antenatal corticosteroids. Further, the conclusion supported the continuation of the Network's ongoing, randomized, placebo-controlled trial of women at less than 32 weeks' gestation who were at risk for spontaneous preterm delivery (n=2,400) and remained pregnant more than one week following initial corticosteroid therapy. Following the recommendation of the DSMC, the NICHD halted the trial after enrollment of approximately 450 patients due to safety concerns suggesting lower birth weight in the treatment group, slow recruitment, and no evidence of efficacy. The findings indicate that routine weekly repetition of antenatal steroids to women at high risk for preterm birth, in order to assure maximum exposure to all preterm neonates, cannot be justified. Furthermore, exposure to weekly courses of steroids decreased birth weight and increased the risk of small-for-gestational-age neonates.

In addition, Network researchers recently released findings from a groundbreaking trial that identified a therapy for the prevention of recurrent preterm birth. They studied 463 women who had a previous preterm delivery and were, therefore, considered at high risk for recurrent preterm delivery. This randomized, double-masked, clinical trial compared the effects of weekly treatment of 17 Alpha-hydroxyprogesterone caproate (17P) versus placebo injections on preventing preterm birth in women at high risk for preterm birth. Importantly, the trial showed that showed that 17P treatment reduced preterm birth by 34 percent in this population. Women who received weekly 17P injections starting at 16 to 20 weeks' gestation had a significantly reduced risk of preterm delivery before 37, 35, or 32 weeks' gestation when compared to women who received placebo injections. Further, among those who did deliver preterm, infants of women treated with 17P had significantly lower rates of severe complications. Treatment was equally effective in African American and non-African American subjects (an important consideration because the preterm birth rate is two-fold higher in African Americans) and showed benefit in preventing spontaneous and indicated preterm births. 17P is the first successful treatment demonstrated to reduce the risk of recurrent preterm delivery in a subset of high-risk women and to improve neonatal outcomes for infants born to these women (N Engl J Med 2003; 348:2379-85). Further studies to determine whether this treatment can be used for other populations of pregnant women at high risk for preterm delivery, such as those with multiple gestations and women with short cervical length, are currently being planned.

The rate of cesarean delivery has risen dramatically over the past two decades; in fact, cesarean delivery currently ranks as the most commonly performed surgical procedure. A substantial portion of women who undergo a cesarean delivery have a history of a previous cesarean delivery, but some women who have had a previous cesarean deliver their infants vaginally. Evidence about the risks and benefits of vaginal birth after cesarean (VBAC) that would assist the obstetrician in counseling women with a history of a prior cesarean delivery is not current and is generally derived from small studies. The MFMU Network thus chose to use its large patient population to study the outcomes of VBAC, including information on complications, fetal injury, and contributing factors. The MFMU Cesarean Registry, completed in December 2002, includes observational data on more than 52,000 primary and repeat cesarean deliveries and more than 18,000 VBAC deliveries. This landmark study provided the largest resource of information on cesarean deliveries collected in a standardized, prospective fashion by trained study personnel. The study found that women who attempted trial labor had significantly higher rates of maternal morbidity (i.e., uterine rupture, endometritis, and transfusion) and neonatal complications (i.e., hypoxic-ischemic encephalopathy) compared with women undergoing an elective repeat cesarean delivery.

In another study, the Fetal Pulse Oximetry (FOX) trial, the Network is studying the utility of fetal pulse oximeter during labor under an Investigational Device Exemption through the FDA. The goal of this randomized, controlled trial is to determine if fetal pulse oximetry during labor affects the overall cesarean delivery rate, or the rate of cesarean delivery for fetal distress, in women with a singleton gestation who experience labor at more than 36 weeks' gestation. Current recruitment is approximately 3,000 patients; researchers anticipate that the sample size of 10,000 will be enrolled prior to the start of the next Network cycle (April 2006).

To address the question of the benefit of screening and treatment for GDM, the MFMU Network is conducting a randomized clinical trial to test the hypothesis that daily self blood glucose monitoring and diet therapy reduces neonatal morbidity in women with mild GDM. The primary outcome composite includes hypoglycemia, hyperinsulinemia, hyperbilirubinemia, birth trauma, death, or stillbirth.

A Spirit of Trans-NIH Collaboration

As the PPB-supported MFMU Network has grown and developed, additional expertise and funding for large studies has come from other NIH Institutes. The first of these trans-NIH collaborations, with the NHLBI, set out to address the growing numbers of pregnant women with asthma and the lack of evidence-based information about how best to treat them. This observational study of 3,000 pregnant women with mild and moderate asthma was completed in March 2000. The study found that, except for an increased incidence of discharge diagnoses of neonatal sepsis, asthma and its contemporary management were not associated with adverse perinatal outcomes (Obstet Gynecol 2004; 103:5-12).

Nested within this observational study, the MFMU Network conducted a randomized trial of theophylline versus inhaled steroids to treat moderate asthma during pregnancy. The objective was to determine if prolonged anti-inflammatory therapy with inhaled corticosteroids would result in better control of moderate asthma during pregnancy. Despite its greater anti-inflammatory effects, beclomethasone treatment of persistent asthma resulted in similar rates of asthma exacerbations requiring intervention and similar pregnancy outcomes as treatment with theophylline (Am J Obstet Gynecol 2004; 190:737-44).

The NHBLI also provided funding to the MFMU Network to conduct the Combined Antioxidant and Preeclampsia Prediction Study (CAPPS) for the prediction and prevention of preeclampsia. This randomized, controlled trial is designed to determine if antioxidants (vitamins C and E) can prevent preeclampsia in low-risk women (n=10,000). In addition, the observational component of the trial is designed to identify markers that may predict preeclampsia. Initiated in 2003, CAPPS is just getting under way.

The MFMU Network is collaborating with the NINDS on a randomized trial of the beneficial effects of antenatal exposure to magnesium sulfate for the prevention of cerebral palsy. This trial is based on case-control studies that identified magnesium sulfate as protective against the development of cerebral palsy. This double-blind, randomized trial involves more than 2,000 women at high risk of delivering very preterm (less than 32 weeks of gestation, a major risk factor for cerebral palsy). All of the children will be followed for two years with the primary outcome of developmental tests at age two correlating with the diagnosis of cerebral palsy. Recruitment into the trial is expected to end in May 2004, with data expected by fall of 2006.

The NIH ORWH has also supported the MFMU Network, specifically in funding studies of pharmacokinetics in recognition of the widespread use of medications during pregnancy that are not studied for such use. Pregnant women are often excluded from clinical trials, resulting in product labeling that does not address pregnancy dosage, safety, or efficacy; as a result, providers often prescribe drugs off-label. These funds were an attempt to address the common clinical practice of off-label drug administration. ORWH support was distributed to MFMU Network sites that submitted proposals for pharmacokinetic studies of certain drugs in pregnancy.

In addition, the ORWH supported the MFMU Network's Factor V Leiden study, conducted to determine the incidence of pregnancy-related thromboembolism in women carrying the Factor V Leiden mutation, a genetic factor that has been associated with an increased risk for thromboembolic events. Initially, this study was proposed as an interventional trial of heparin versus placebo in women with the Factor V Leiden mutation, but Network researchers felt that baseline data for the mutation's effect on risk for a thromboembolic event in pregnancy was needed before an interventional trial was undertaken. In this prospective, observational, multicenter study, 5,188 low-risk nulliparous pregnant women were enrolled and tested for the mutation. The trial showed that the Factor V Leiden mutation did not increase risk of thromboembolic events or adverse pregnancy outcomes. The interventional trial was not undertaken, then, and this population of low-risk nulliparous women with the Factor V Leiden mutation does not require prophylactic treatment in pregnancy.

The June 2003 issue (Volume 27) of Seminars in Perinatalogy was devoted exclusively to the MFMU Network, highlighting its history, trials, findings, and impact in the field in the following articles:

• Meis P, Spong C, and Thom EA (Eds). Introduction. (183-4)
• Goldenberg RL, Iams JD, Mercer BM, Meis, P, Moawad A, Das A, Copper R, and Johnson F for the NICHD MFMU Network. What we have learned about the predictors of preterm birth. (185-193)
• Iams JD and Owen J for the NICHD MFMU Network. What we have learned about cervical ultrasound. (194-203)
• Iams JD for the NICHD MFMU Network. What we have learned about uterine contractions and preterm birth. The HUAM Prediction Study. (204-211)
• Carey JC and Klebanoff MD for the NICHD MFMU Network. What we have learned about vaginal infections and preterm birth. (212-216)
• Mercer BM, Goldenberg RL, Das AF, Thurnau GR, Bendon RW, Miodovnik M, Ramsey RD, and Rabello YA for the NICHD MFMU Network. What we have learned regarding antibiotic therapy for the reduction of infant morbidity after preterm premature rupture of the membranes. (217-230)
• Andrews WW and Goldenberg RL for the NICHD MFMU Network. What we have learned from an antibiotic trial in fetal fibronectin positive women. (231-238)
• Sibai BM, Caritis S, and Hauth J for the NICHD MFMU Network. What we have learned about preeclampsia. (239-246)
• Iams JD and Mercer BM for the NICHD MFMU Network. What we have learned about antenatal prediction of neonatal morbidity and mortality. (247-252)
• Thom E and Rouse D for the NICHD MFMU Network. What we have learned about conducting randomized controlled trials in the NICHD MFMU Network. (253-260)

The MFMU Network will be recompeted in 2006; more information on the MFMU Network is available at http://www.bsc.gwu.edu/mfmu/.

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