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Giants in Obstetrics and Gynecology Series: a profile of Robert L. Goldenberg, MD

  • Roberto Romero
    Correspondence
    Corresponding author: Roberto Romero, MD, DMedSci.
    Affiliations
    Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Detroit, MI
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      Dr Robert L. Goldenberg, a preeminent figure in Obstetrics and Gynecology, has improved the understanding of syndromes responsible for maternal and perinatal morbidity and mortality, with a particular emphasis on the circumstances responsible for preterm birth, fetal growth restriction, and fetal death. He has a keen interest in the social determinants of health and disease, especially in the southern United States and in low- and middle-income countries. His work has provided important insight into the prediction of spontaneous preterm birth; the role of antenatal steroids in inducing fetal maturity; and the determinants of fetal death, fetal growth restriction, and virtually every other “great obstetrical syndrome.”
      Dr Goldenberg possesses the talent to identify important healthcare issues and to formulate testable hypotheses as well as the leadership to assemble teams that can address critical questions requiring multicenter participation. For his many contributions to the field of Obstetrics and Gynecology, Dr Goldenberg is herein recognized as a “Giant in Obstetrics and Gynecology.”

      Early Life

      Robert was born in New York City in 1943 and lived there until the age of 12 when his family moved to Florida. His father, a musician and a fur coat manufacturer, then purchased a large chicken farm that, at its peak, housed more than 100,000 egg-laying hens. Robert spent time working on the farm, which, he said, put him in touch with nature and helped pay for college.
      Both medicine and history were early interests for Robert. As an undergraduate student pursuing a Bachelor of Science degree at Columbia University in New York, he was torn between the two paths (Figure 1). He told me about a conversation with his parents when he was 14 years old, in which he said he liked that medicine combined his interest in science with the ability to help people. He made the final decision to follow medicine only after he was accepted into Duke University’s School of Medicine; however, the two disciplines remained complementary for Robert throughout his career.
      Figure thumbnail gr2
      Figure 1Portrait of a young Robert Goldenberg
      Romero. A profile of Robert L. Goldenberg, MD. Am J Obstet Gynecol 2021.
      Robert recalled that his interview for medical school at Duke University “had nothing to do with medicine and everything to do with Chinese history . . . a great deal of my life has been influenced by history.” Robert told me that, as an undergraduate, he was fascinated by the post-Civil War Reconstruction era in the South, which sparked a lifelong interest in justice, equity, and diversity and was an important factor in his later move to Alabama.

      Internship, Residency, and Fellowship

      After graduating from medical school, Robert completed a one-year medical internship at Duke University; in 1969, he returned to Columbia University and later transferred to Yale University for his residency in Obstetrics and Gynecology (Figure 2). He credits Dr Charles B. Hammond, Chair of the Department of Obstetrics and Gynecology at Duke University Medical Center, for his mentorship during his time at Duke. Robert had a short flirtation with pediatrics; however, he decided that delving into fetal life might be more interesting and challenging.
      Figure thumbnail gr3
      Figure 2Portrait of Robert at his Yale residency graduation in 1974
      The portrait shows Robert in the second row, sixth from left. The people at his right are Charlotte Houde (Director of Nurse Midwifery) and Drs Leon Speroff and John Hobbins.
      Romero. A profile of Robert L. Goldenberg, MD. Am J Obstet Gynecol 2021.
      After one year at Columbia University, Robert took a detour and began a Fellowship in Reproductive Endocrinology at the National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) in Bethesda, Maryland.
      Robert remembers feeling uneasy when he started at the NICHD. He had a particularly demanding supervisor, who “clearly expected a level of knowledge and work that, at the beginning, I didn’t think I could ever attain.” With mentors and role models, Robert found his groove, telling me that he learned valuable lessons about the collection and analysis of data, the conduct of research, and the importance of hard work and open, honest communication. Robert recalled another mentor, Dr Griff Ross, who was particularly inspiring and taught him to appreciate the challenges and rewards of research: “He made me feel that I could make a meaningful contribution to medicine and science.”
      At the NICHD, he also met Dr Judith Vaitukaitis (another “Giant in Obstetrics and Gynecology”
      • Romero R.
      Giants in Obstetrics and Gynecology Series: a profile of Judith Vaitukaitis, MD, who made possible the early detection of pregnancy.
      ) while she worked with Dr Glenn Braunstein on the development of a radioimmunoassay for the beta-subunit of human chorionic gonadotropin. The impetus for this work was to develop a biomarker for choriocarcinoma, a malignant tumor derived from the trophoblast.
      • Harvey R.A.
      • Mitchell H.D.
      • Stenman U.H.
      • et al.
      Differences in total human chorionic gonadotropin immunoassay analytical specificity and ability to measure human chorionic gonadotropin in gestational trophoblastic disease and germ cell tumors.
      However, an unexpected development was the importance of the assay for the early detection of pregnancy. Robert had firsthand involvement with patients diagnosed with choriocarcinoma who were referred to the NIH because they had not responded to treatment elsewhere. “In research, you have to learn how to deal with unexpected findings,” Robert commented.
      After leaving the NICHD, Robert continued his Obstetrics and Gynecology residency at the Yale University School of Medicine, where he worked with Dr Robert H. Glass, Director of the Yale Infertility Clinic. Subsequently, Dr Nathan Kase (another “Giant in Obstetrics and Gynecology”
      • Romero R.
      Giants in Obstetrics and Gynecology Series: a profile of Nathan Kase, MD.
      ), the Chair of Obstetrics and Gynecology, asked Robert to assume leadership of the Clinic. He was appointed Assistant Professor for Obstetrics and Gynecology and served as Director of the Yale Infertility Clinic from 1974 to 1976.

      Iatrogenic Prematurity and Mode of Delivery of the Preterm Breech Fetus

      In 1960, Yale-New Haven Hospital, under the leadership of Dr Louis Gluck (who later developed the lecithin-to-sphingomyelin ratio to assess the likelihood of respiratory distress syndrome [RDS]), created one of the first newborn intensive care units (NICU) in the United States, largely devoted to the care of preterm neonates and, in particular, the treatment of RDS. An astute resident, Robert noticed that a major factor leading to RDS was the erroneous assignment of gestational age by physicians, leading to untimely and unwarranted termination of pregnancy. He set out to define and quantitate the magnitude of iatrogenic prematurity by examining 100 consecutive cases of RDS. He reported that 15% of cases were clearly attributable to erroneous decisions and that another 18% could have an iatrogenic component as well. Robert argued in favor of documenting fetal lung maturity or fetal maturity with ultrasound biometry before each elective cesarean delivery or induction of labor.
      • Goldenberg R.L.
      • Nelson K.
      Iatrogenic respiratory distress syndrome. An analysis of obstetric events preceding delivery of infants who develop respiratory distress syndrome.
      In a separate study, he focused on the neonatal outcome of preterm breech deliveries.
      • Goldenberg R.L.
      • Nelson K.G.
      The premature breech.
      ,
      • Goldenberg R.L.
      • Nelson K.G.
      The unanticipated breech presentation in labor.
      At the time, it was well known that breech infants delivered vaginally at term had higher perinatal morbidity and mortality rates than those born via cesarean delivery; however, the outcome of breech delivery of preterm babies was unknown. To address this question, Robert conducted a study and reported the result of outcomes of births <2500 g according to the mode of delivery: he found that morbidity and mortality were greater in preterm breech infants delivered vaginally than in those delivered surgically. He proposed that serious consideration should be given to delivering all preterm breech infants by cesarean section when childbirth was anticipated.
      • Goldenberg R.L.
      • Nelson K.G.
      The premature breech.
      This influential study has shaped the standard of obstetrical care for the last 40 years.
      Improvements in neonatal care during the 1970s increased the likelihood of survival of preterm neonates and lowered the gestational age at which an infant is considered viable. However, these advances posed important medical dilemmas—namely, when to monitor, when to indicate cesarean delivery, and when to resuscitate a distressed preterm fetus. Robert advocated in a point-of-view article, published in The Lancet, that intense fetal surveillance, intervention, and the active involvement of prospective parents in the decision-making process may be indicated at an earlier gestational age than current practice dictated.
      • Iams J.D.
      • Romero R.
      • Culhane J.F.
      • Goldenberg R.L.
      Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth.
      The medical issues surrounding optimal care of patients at risk of periviable birth remain important.

      From Connecticut to Alabama

      As part of his role as a faculty physician at Yale University, Robert had a small obstetrical practice in which he said he often provided “unconventional obstetrical care, such as water births.” He described himself as “a bit of a rebel, maybe a hippie. I had long, long hair and a beard, and I didn’t wear the traditional white lab coats—I thought the white coats would distance me from my patients.” His support of midwifery programs and other forms of alternative care for pregnant women distanced him from the Department’s priorities at the time, and he began to seek other opportunities.
      Dr Charles E. Flowers, Jr., Chair of Obstetrics and Gynecology at the University of Alabama at Birmingham School of Medicine, was interested in improving healthcare for women and newborns. He and Robert had crossed paths at several medical meetings: while speaking, they found they had much in common. Dr Flowers wanted to initiate a midwifery program at Alabama and asked Robert if he would be willing to help. Robert accepted a position, and Dr Flowers became one of Robert’s most important mentors: “Dr Flowers was an exceptionally good doctor who had a vision of how care should be given, who should give it, and the quality of care people should receive.” Dr Flowers’ goal was to provide all women in Alabama the best care possible and to train his residents to do the same, without regard to income, race, social standing, or any other characteristic.

      Perinatal Mortality in Alabama

      Concerning Alabama in the 1970s, Robert believed that, in many locations, medical care for women fell well below acceptable standards. He saw more cases of maternal mortality during his first two months in Alabama than he had witnessed anywhere else. However, he soon found that he did not have enough influence from his position in the Department of Obstetrics and Gynecology to make a difference. Consequently, when the position of Director for the Bureau of Maternal and Child Health in the Alabama Department of Public Health became available in 1977, Robert applied and was appointed. Despite his clear differences with Mr George Wallace, Alabama’s governor at the time and a staunch segregationist, Robert told me that they were able to work together on the common goal of “making things better for those who were less well off.”
      Governor Wallace declared that reduction of the maternal and infant mortality rates was a priority of his administration. Robert led the group that standardized prenatal care services across Alabama’s county health departments and established a statewide referral system that gave mothers and their children access to facilities that were otherwise unavailable to them. The system implemented in Alabama was, in part, based on a publication by Dr Irwin Merkatz, from Case Western University in Cleveland, Ohio, and Dr Kenneth G. Johnson, from the Mount Sinai School of Medicine in New York.
      • Merkatz I.R.
      • Johnson K.G.
      Regionalization of perinatal care for the United States.
      Robert also realized that data were essential to inform policy and clinical care; therefore, he spearheaded the creation and implementation of a countywide obstetrical computerized system in 1978. In addition to making prenatal data from health department clinics available at the time of delivery, the information system was used to obtain and transfer health data, and it provided the basis for many important contributions in both Obstetrics and Neonatology.
      • Wirtschafter D.D.
      • Blackwell W.C.
      • Goldenberg R.L.
      • et al.
      A county-wide obstetrical automated medical record system.
      In 1980, Alabama saw a 50% reduction in its infant mortality rate—and was no longer listed among the states with the worst infant mortality rate in the country. Robert reported improvements in neonatal mortality in the state, which he attributed to improved access and quality of medical care through the regionalization of perinatal services.
      • Goldenberg R.L.
      • Humphrey J.L.
      • Hale C.B.
      • Boyd B.W.
      • Wayne J.B.
      Neonatal deaths in Alabama, 1970-1980: an analysis of birth weight- and race-specific neonatal mortality rates.
      Robert told me that “building a regionalized system of care was a rewarding experience,” and he later replicated these efforts in Zambia.

      From Public Health in Alabama to Leadership in the Department of Obstetrics and Gynecology

      Robert had always been interested in the intersection between Public Health and Obstetrics, and he used the tools of epidemiology to make important contributions to our discipline. He was determined to bring together the knowledge he acquired in Public Health to Obstetrics and Gynecology; therefore, he had a dual appointment as Professor of Obstetrics and Gynecology and of Public Health at the University of Alabama.
      In 1995, when he was appointed Chair of the Department of Obstetrics and Gynecology, Robert stated that his goal was to build a research-intensive department while simultaneously continuing Dr Flowers’ goal of training excellent physicians for Alabama and providing the best possible care for women and their infants. “After five years, at the end of my time as Chair, we had one of the leading research departments for obstetrics and gynecology in the country,” he told me, “and the Department was near the top in terms of grant funding and publications—that culture of excellence persists in the Department to this day. One of my favorite bits of recognition was being named the ‘Charles E. Flowers Professor.’”

      The March of Dimes Prevention of Prematurity Project

      Given that preterm birth was responsible for 70% of neonatal deaths in the 1980s, considerable interest was shown in the possibility that pharmacologic inhibition of uterine contractility may prolong gestation and reduce the rate of preterm delivery.
      • Creasy R.K.
      • Golbus M.S.
      • Laros Jr., R.K.
      • Parer J.T.
      • Roberts J.M.
      Oral ritodrine maintenance in the treatment of preterm labor.
      Many thought that tocolysis had not achieved a substantial impact in reducing the rate of preterm deliveries because therapeutic intervention had been initiated too late once labor had been well established. Previously, in the late 1970s, Dr Robert Creasy (University of California, San Francisco [UCSF]), Dr Graham Liggins (University of Auckland, New Zealand), and Ms Beverly Gummer, NZRN, proposed a system for predicting spontaneous preterm birth with the hope that early intervention would reduce the rate of preterm birth.
      • Creasy R.K.
      • Gummer B.A.
      • Liggins G.C.
      System for predicting spontaneous preterm birth.
      Their proposal questioned whether the rate of prematurity could be reduced by identifying patients at risk, monitoring for early signs of preterm labor (ie, increased uterine contractility), and implementing a program of bed rest, early tocolysis, and other interventions designed to improve health during pregnancy.
      • Creasy R.K.
      • Gummer B.A.
      • Liggins G.C.
      System for predicting spontaneous preterm birth.
      The March of Dimes supported the implementation of a multicenter randomized clinical trial (RCT) to determine whether enhanced prenatal care could reduce the rate of preterm birth compared to the standard of care. The trial included the UCSF, Ohio State University, Vanderbilt University, Northwestern University, and the University of Alabama, where Robert was the principal investigator. The results of the overall study and those at the University of Alabama did not indicate benefits, although there was some heterogeneity among the centers.
      • Goldenberg R.L.
      • Davis R.O.
      • Copper R.L.
      • Corliss D.K.
      • Andrews J.B.
      • Carpenter A.H.
      The Alabama preterm birth prevention project.
      ,
      • Copper R.L.
      • Goldenberg R.L.
      • Creasy R.K.
      • et al.
      A multicenter study of preterm birth weight and gestational age-specific neonatal mortality.
      Robert said that one of the lessons learned from this experience was that screening alone without an effective intervention was not useful and, in some cases, may cause harm.

      Antimicrobial Agents Reduce the Rate of Preterm Birth in Women with Bacterial Vaginosis

      In the 1980s, the role of ascending intra-amniotic infection as a cause of preterm labor gained momentum among researchers after the demonstration that microorganisms were present in the amniotic cavity in a fraction of patients with preterm labor or delivery.
      • Romero R.
      • Mazor M.
      Infection and preterm labor.
      This finding strengthened the known association between acute histologic chorioamnionitis and spontaneous preterm labor. The NICHD sponsored the Vaginal Infection in Pregnancy Study, a large multicenter study, to determine whether colonizations of the lower genital tract with certain microorganisms was associated with spontaneous preterm birth and whether treatment with antimicrobial agents could reduce the rate of preterm birth.
      • Regan J.A.
      • Klebanoff M.A.
      • Nugent R.P.
      The epidemiology of group B streptococcal colonization in pregnancy. Vaginal Infections and Prematurity Study Group.
      • Klebanoff M.A.
      • Regan J.A.
      • Rao A.V.
      • et al.
      Outcome of the Vaginal Infections and Prematurity Study: results of a clinical trial of erythromycin among pregnant women colonized with group B streptococci.
      • Regan J.A.
      • Klebanoff M.A.
      • Nugent R.P.
      • et al.
      Colonization with group B streptococci in pregnancy and adverse outcome. VIP Study Group.
      • Carey J.C.
      • Blackwelder W.C.
      • Nugent R.P.
      • et al.
      Antepartum cultures for Ureaplasma urealyticum are not useful in predicting pregnancy outcome. The Vaginal Infections and Prematurity Study Group.
      • Meis P.J.
      • Goldenberg R.L.
      • Mercer B.
      • et al.
      The Preterm Prediction Study: significance of vaginal infections. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      • Cotch M.F.
      • Pastorek 2nd, J.G.
      • Nugent R.P.
      • Yerg D.E.
      • Martin D.H.
      • Eschenbach D.A.
      Demographic and behavioral predictors of Trichomonas vaginalis infection among pregnant women. The Vaginal Infections and Prematurity Study Group.
      • Eschenbach D.A.
      • Nugent R.P.
      • Rao A.V.
      • et al.
      A randomized placebo-controlled trial of erythromycin for the treatment of Ureaplasma urealyticum to prevent premature delivery. The Vaginal Infections and Prematurity Study Group.
      • Hillier S.L.
      • Nugent R.P.
      • Eschenbach D.A.
      • et al.
      Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. The Vaginal Infections and Prematurity Study Group.
      • Hillier S.L.
      • Krohn M.A.
      • Nugent R.P.
      • Gibbs R.S.
      Characteristics of three vaginal flora patterns assessed by Gram stain among pregnant women. Vaginal Infections and Prematurity Study Group.
      The investigators concluded that bacterial vaginosis was a risk factor for spontaneous preterm birth; however, the presence of any particular microorganism, including group B streptococcus
      • Regan J.A.
      • Klebanoff M.A.
      • Nugent R.P.
      The epidemiology of group B streptococcal colonization in pregnancy. Vaginal Infections and Prematurity Study Group.
      and Ureaplasma urealyticum,
      • Carey J.C.
      • Blackwelder W.C.
      • Nugent R.P.
      • et al.
      Antepartum cultures for Ureaplasma urealyticum are not useful in predicting pregnancy outcome. The Vaginal Infections and Prematurity Study Group.
      was not. Treatment with erythromycin in patients who had genital mycoplasmas detected in the lower genital tract also yielded negative results.
      • Eschenbach D.A.
      • Nugent R.P.
      • Rao A.V.
      • et al.
      A randomized placebo-controlled trial of erythromycin for the treatment of Ureaplasma urealyticum to prevent premature delivery. The Vaginal Infections and Prematurity Study Group.
      Robert used data from that study to explore the prevalence of various bacterial colonization by ethnicity.
      • Goldenberg R.L.
      • Klebanoff M.A.
      • Nugent R.
      • Krohn M.A.
      • Hillier S.
      • Andrews W.W.
      Bacterial colonization of the vagina during pregnancy in four ethnic groups. Vaginal Infections and Prematurity Study Group.
      The University of Alabama was composed of an outstanding group of obstetricians, gynecologists, and specialists in maternal-fetal medicine and microbiologists that included Dr Gail H. Cassell, a leading authority on the microbiology of genital mycoplasmas; Dr John C. Hauth, Professor and later Chair of the Department of Obstetrics and Gynecology; and Dr William W. Andrews, also later Chair of the Department.
      In 1995, the team reported the results of an RCT, finding that the administration of metronidazole and erythromycin reduced the rate of preterm delivery at <37 weeks of gestation in high-risk women who presented with bacterial vaginosis (rate of preterm delivery, 31% with treatment vs 49% with placebo; P=.006).
      • Hauth J.C.
      • Goldenberg R.L.
      • Andrews W.W.
      • DuBard M.B.
      • Copper R.L.
      Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis.
      Interestingly, the antimicrobial agents were not effective in preventing preterm birth in patients without bacterial vaginosis, and such treatment did not reduce the rate of preterm delivery at <32 weeks of gestation. The rate of preterm delivery at <34 weeks of gestation was higher in women treated with antimicrobial agents who did not have bacterial vaginosis than in women in the placebo group (13.4% vs 4.8%; P=.02). These promising results led to a subsequent study in which patients with asymptomatic bacterial vaginosis were randomized to metronidazole or placebo to prevent preterm birth: unexpectedly, this intervention was not effective.
      • Carey J.C.
      • Klebanoff M.A.
      • Hauth J.C.
      • et al.
      Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.
      The University of Alabama was one of the participating centers, and Robert told me that there were several possible explanations for the results, including a false-positive result of a smaller trial and the difficulties in maintaining quality in the conduct of the large multicenter trials.
      That same year, Robert published a paper in the American Journal of Obstetrics & Gynecology (AJOG) that compared concentrations of amniotic fluid interleukin (IL)-6 in women with preterm labor to that of women in the control group. The paper concluded that IL-6 levels were significantly higher in patients with intra-amniotic infection and in those with microbial invasion of the chorionic membranes than in those with sterile amniotic fluid without bacteria in the chorioamniotic membranes.
      • Andrews W.W.
      • Hauth J.C.
      • Goldenberg R.L.
      • Gomez R.
      • Romero R.
      • Cassell G.H.
      Amniotic fluid interleukin-6: correlation with upper genital tract microbial colonization and gestational age in women delivered after spontaneous labor versus indicated delivery.
      This finding strengthened the role of intra-amniotic infection in spontaneous preterm labor and IL-6 as a marker for intra-amniotic inflammation.

      The Prematurity Prevention Study

      In 1986, the NICHD established the Maternal-Fetal Medicine Units (MFMU) Network with several goals, including strengthening research on the prediction and prevention of preterm birth and improving the quality of evidence that informed obstetrical care in the United States. During the second term of the Network, the University of Alabama at Birmingham joined the group, and Robert served as an investigator. He proposed and led the Prematurity Prevention Study, which examined the roles of obstetrical history, bacterial vaginosis, fetal fibronectin, cervical length, and other biomarkers in the prediction of preterm birth.
      • Iams J.D.
      • Goldenberg R.L.
      • Mercer B.M.
      • et al.
      The Preterm Prediction Study: recurrence risk of spontaneous preterm birth. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      ,
      • Goldenberg R.L.
      • Iams J.D.
      • Mercer B.M.
      • et al.
      The Preterm Prediction Study: toward a multiple-marker test for spontaneous preterm birth.
      This observational study was one of the best investments in terms of scientific productivity and understanding of the risk factors for preterm birth—the observations served as the basis for subsequent RCTs.
      • Goldenberg R.L.
      • Klebanoff M.
      • Carey J.C.
      • Macpherson C.
      Metronidazole treatment of women with a positive fetal fibronectin test result.
      The most reliable information about the prediction of spontaneous preterm birth, that is, fetal fibronectin, sonographic cervical length, and bacterial vaginosis, emerged from this important study.
      • Iams J.D.
      • Goldenberg R.L.
      • Mercer B.M.
      • et al.
      The Preterm Prediction Study: recurrence risk of spontaneous preterm birth. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      ,
      • Goldenberg R.L.
      • Thom E.
      • Moawad A.H.
      • Johnson F.
      • Roberts J.
      • Caritis S.N.
      The preterm prediction study: fetal fibronectin, bacterial vaginosis, and peripartum infection. NICHD Maternal Fetal Medicine Units Network.
      • Goldenberg R.L.
      • Mercer B.M.
      • Meis P.J.
      • Copper R.L.
      • Das A.
      • McNellis D.
      The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. NICHD Maternal Fetal Medicine Units Network.
      • Goldenberg R.L.
      • Mercer B.M.
      • Iams J.D.
      • et al.
      The Preterm Prediction Study: patterns of cervicovaginal fetal fibronectin as predictors of spontaneous preterm delivery. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      • Goldenberg R.L.
      • Iams J.D.
      • Mercer B.M.
      • et al.
      The Preterm Prediction Study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network.
      • Goldenberg R.L.
      • Iams J.D.
      • Das A.
      • et al.
      The Preterm Prediction Study: sequential cervical length and fetal fibronectin testing for the prediction of spontaneous preterm birth. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      • Mercer B.M.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The Preterm Prediction Study: prediction of preterm premature rupture of membranes through clinical findings and ancillary testing. The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.

      Fetal Death

      While Robert was the Director for Maternal and Child Health in Alabama, he focused on pregnancy outcomes and noticed very little literature regarding fetal death. He had begun to collect information on stillbirth and published a paper in 1987 that looked at the rate of fetal death in Alabama between 1974 and 1983.
      • Goldenberg R.L.
      • Foster J.M.
      • Cutter G.R.
      • Nelson K.G.
      Fetal deaths in Alabama, 1974-1983: a birth weight-specific analysis.
      In 2003, the NICHD established the Stillbirth Collaborative Research Network, a multicenter network that Robert was asked to chair. Through this Network, Robert became even more heavily involved in studying different aspects of fetal death.
      The Lancet published a series entitled “Stillbirths 2011,” which highlighted global rates and causes of stillbirth and explored cost-effective interventions to prevent this adverse outcome (including maternal and neonatal deaths).
      • Copper R.L.
      • Goldenberg R.L.
      • Creasy R.K.
      • et al.
      A multicenter study of preterm birth weight and gestational age-specific neonatal mortality.
      The series included eight comments from professional organizations and parent groups, two issue articles, and six series papers, which recommended key actions that, if implemented, could halve the rate of stillbirths by 2020. Robert contributed a paper that looked ahead to 2020
      • Goldenberg R.L.
      • McClure E.M.
      • Bhutta Z.A.
      • et al.
      Stillbirths: the vision for 2020.
      and co-authored a paper analyzing different interventions and their cost-effectiveness.
      • Bhutta Z.A.
      • Yakoob M.Y.
      • Lawn J.E.
      • et al.
      Stillbirths: what difference can we make and at what cost?.
      In addition, he organized the series with other investigators and The Lancet, and he credits the journal for increasing public health interest and research in fetal death and for placing the condition at the forefront of pregnancy outcome research.
      The Lancet ran a follow-up series in 2016 that offered a roadmap to end preventable stillbirths by 2030.
      • Horton R.
      • Samarasekera U.
      Stillbirths: ending an epidemic of grief.
      The second series was composed of four series comments and five series papers, of which Robert co-authored two papers as part of the journal’s “Ending Preventable Stillbirths Series” study group: both looked at the progress in addressing stillbirth and actions still to be taken to reduce the outcome in the United States and globally.
      • Frøen J.F.
      • Friberg I.K.
      • Lawn J.E.
      • et al.
      Stillbirths: progress and unfinished business.
      ,
      • Flenady V.
      • Wojcieszek A.M.
      • Middleton P.
      • et al.
      Stillbirths: recall to action in high-income countries.
      Beginning in the early 2000s, Robert analyzed data from the US stillbirth networks, and, more recently, expanded his research of the condition to low-income settings. He has published numerous papers on the possible causes and treatments for stillbirth in low- and middle-income countries, including the epidemiology of stillbirth,
      • McClure E.M.
      • Pasha O.
      • Goudar S.S.
      • et al.
      Epidemiology of stillbirth in low-middle income countries: a Global Network Study.
      the use of antenatal corticosteroids to prevent stillbirth,
      • Goldenberg R.L.
      • Thorsten V.R.
      • Althabe F.
      • et al.
      The Global Network Antenatal Corticosteroids Trial: impact on stillbirth.
      the impact of clinical interventions to reduce stillbirths,
      • Urdaneta M.L.
      • Krehbiel R.
      Cultural heterogeneity of Mexican-Americans and its implications for the treatment of diabetes mellitus type II.
      and the probable causes of stillbirth.
      • McClure E.M.
      • Garces A.
      • Saleem S.
      • et al.
      Global Network for Women’s and Children’s Health Research: probable causes of stillbirth in low- and middle-income countries using a prospectively defined classification system.
      For more than 20 years, Robert has collaborated with Dr Elizabeth McClure, a perinatal epidemiologist at the Research Triangle Institute and the University of North Carolina, who is also interested in pregnancy outcomes. Like Robert, she is a member of the Global Network for Women’s and Children’s Health Research. The multicountry research network hosts study sites in India, Pakistan, Guatemala, Kenya, Zambia, Bangladesh, and the Democratic Republic of the Congo. Dr McClure first acted as a project coordinator and is now the principal investigator of its data center. When their association began, Robert was her supervisor. He has enjoyed the slow transition of their roles over the years until Dr McClure became the boss, Robert told me. He observed that she “has been the perfect person to work with. She has written many of the papers I’m an author on, and many of them started with her ideas.”
      “My primary research site in the Global Network is at Aga Khan University in Karachi, Pakistan, a world-class institution. Sarah Saleem, in the Department of Community Health Sciences and head of the Pakistan Global Network site, has been a real friend and wonderful collaborator for more than 20 years (Figure 3). Relationships like these, with people all over the world, in large part based on a commitment to improving the health of women and children in resource-limited countries, have in the past and continue to give my life real meaning,” Robert said.
      Figure thumbnail gr4
      Figure 3Robert’s presentation to the Pakistan Obstetrics and Gynecology Society, 2018
      From left to right, the portrait shows Drs Sarah Saleem, Robert Goldenberg, Elizabeth McClure, Sadiah Ahsan Pal, Naila Siddiqui, and Sonia Naqvi.
      Romero. A profile of Robert L. Goldenberg, MD. Am J Obstet Gynecol 2021.
      Currently, Robert and Dr McClure are conducting a large study of fetal death in India and Pakistan. Funded by the Bill and Melinda Gates Foundation, their team has undertaken a relatively unexplored area: their goal is to understand why fetal death occurs, how many are associated with various infections, and which other causes of fetal death in those settings could be likely (Figure 4). Robert believes it is an area they can focus their skills and resources on to make a significant contribution toward further comprehension of this particular pregnancy outcome.
      Figure thumbnail gr5
      Figure 4Robert with the research team in Pakistan, 2018
      In the front row, from left to right, the portrait shows Drs Sarah Saleem, Robert Goldenberg, Elizabeth McClure, and Rozina Karmaliani.
      Romero. A profile of Robert L. Goldenberg, MD. Am J Obstet Gynecol 2021.

      Randomized Clinical Trials to Clarify Management Issues in Obstetrics and Maternal-Fetal Medicine

      While reviewing the obstetrical literature, it became clear to Robert that important data on effective interventions could be gained through randomized trials by contrast with historic data. Information about which intervention was better, or whether an intervention worked at all, could not be retrieved from historic data alone. Self-taught in the organization and oversight of an RCT, Robert reviewed widely used interventions in clinical practice, such as bed rest, to acquire supportive data to determine whether a given intervention had a measurable impact and whether it was reasonable to continue.
      Drs Bill Andrews, John Hauth, Robert, and later Alan Tita became convinced that infection, especially in the membranes, was an important cause of not only prematurity but also of postcesarean delivery infection, among other conditions. They collaborated with Dr Cassell, from the Department of Microbiology at the University of Alabama at Birmingham, to better understand the issues surrounding Ureaplasma species in particular: they found that the extended use of wide-spectrum prophylactic antibiotic treatment in women undergoing cesarean delivery at term shortened hospital stays and reduced the frequency of postcesarean disease, endometritis, and wound infections.
      • Andrews W.W.
      • Hauth J.C.
      • Cliver S.P.
      • Savage K.
      • Goldenberg R.L.
      Randomized clinical trial of extended spectrum antibiotic prophylaxis with coverage for Ureaplasma urealyticum to reduce post-cesarean delivery endometritis.
      In the 1990s, when much less was known about HIV, Robert thought that many cases of HIV transmission between the mother and fetus were associated with histologic chorioamnionitis. After the trial in Alabama showed positive pregnancy outcomes with the use of erythromycin and metronidazole, he thought that it may be possible to reduce the rate of mother-to-child HIV transmission if the risk of chorioamnionitis could be reduced by using these agents.
      At that time, funding for HIV-related research was easier to procure than for prematurity research, so Robert designed a combined study. Working with the HIV Prevention Trials Network, he served as the principal investigator for a large, multisite, randomized trial in Africa to assess the efficacy of antibiotics in reducing chorioamnionitis and its associated mother-to-child HIV transmission. Women across four sites—two in Malawi, one in Tanzania, and one in Zambia—were randomized to the antibiotic intervention, and occurrences of chorioamnionitis and HIV transmission were measured. The trial indicated that antibiotics did not decrease cases of chorioamnionitis or reduce mother-to-child transmission of HIV.
      • Taha T.E.
      • Brown E.R.
      • Hoffman I.F.
      • et al.
      A phase III clinical trial of antibiotics to reduce chorioamnionitis-related perinatal HIV-1 transmission.
      Robert told me that he finds great satisfaction in the design and implementation of RCTs: “I would rather learn about pregnancy, stillbirth, neonatal mortality, and other pregnancy outcomes more than anything else. I can’t believe how lucky I am to be able to still work in the area that I love. I don’t think that many people can say that as they get into their 60s and 70s, to be able to continue to make an impact, to learn new things.” Moreover, he emphasized, the most important factor in having a successful trial is to be a good and fair collaborator.

      Reducing Maternal-Fetal Mortality and Preeclampsia in Low-Income Countries

      Nearly 20 years ago, Robert began to unite his love of travel and his passion for medical research. He has continued to work with researchers globally to understand maternal, fetal, and neonatal mortality and which interventions might best mitigate these pregnancy outcomes among women in low-income countries. He collaborated with a team in Colombia, South America, to improve mortality rates; he spent a month in Armenia to gain an understanding of its infant mortality trends and to teach in clinics; and he acted as a consultant to the government of Egypt, addressing the infant mortality rate and which factors impacted this outcome across the country. In doing so, he fulfilled a commitment to be of service in international settings, and he has developed many close friendships and relationships with international colleagues and investigators.
      Robert worked extensively in Zambia for many years, and in 2001, while working with Dr Moses Sinkala, now deceased, of Zambia and Drs Sten Vermund and Jeffrey Stringer of the United States, he established the Center for Infectious Disease Research in Zambia (CIDRZ)—a collaboration between the University of Alabama at Birmingham, the University of Zambia School of Medicine, and the Zambian Government. At that time, nearly 30% of pregnant women in Zambia were HIV-positive, and the CIDRZ quickly had 200,000 HIV-positive patients under its care. The work by the CIDRZ had an important role in Zambia’s decline in HIV-related mortality, especially among newborns. Robert considers this as one of his most fulfilling contributions. In addition, he and the other CIDRZ leaders adapted the computerized obstetrical records program that he had developed in Alabama and implemented it citywide in Lusaka, Zambia. The system, covering 23 clinics and a few hospitals, is still in use and captures most births occurring in Lusaka.
      However, transferring an intervention between high-income and low-income countries may not always succeed, and Robert examined this phenomenon. He reviewed the changing rates of eclampsia and maternal death over time to understand which interventions could benefit women in low-income countries. This endeavor also came from his interest in history, and he conducted a literature review in Medline, PubMed, and the Cochrane Database for the years 1900–2010, evaluating preeclampsia- and eclampsia-associated maternal mortality in high-income countries and the effective interventions.
      Subsequently, the review
      • Goldenberg R.L.
      • McClure E.M.
      • Macguire E.R.
      • Kamath B.D.
      • Jobe A.H.
      Lessons for low-income regions following the reduction in hypertension-related maternal mortality in high-income countries.
      reported a decline in maternal mortality associated with preeclampsia and eclampsia and a 90% reduction in cases of eclampsia in high-income countries between 1940 and 1970, at a time before magnesium sulfate was used as an intervention among patients in the United States.
      • Goldenberg R.L.
      • McClure E.M.
      • Macguire E.R.
      • Kamath B.D.
      • Jobe A.H.
      Lessons for low-income regions following the reduction in hypertension-related maternal mortality in high-income countries.
      During that era, the most important common interventions in use were prenatal care for hypertension, proteinuria screening, and increased access to hospital care for the timely induction of labor or cesarean delivery in severe cases. Robert concluded that a “substantial reduction in preeclampsia- and eclampsia-related mortality could be made by following these same steps in low-income countries and that magnesium sulfate, [although] it may somewhat reduce mortality, should not be the cornerstone of maternal mortality reduction programs.”

      Working with the Bill and Melinda Gates Foundation

      The Bill and Melinda Gates Foundation took an interest in the work in low- and middle-income countries, and it provided funding to build models for what might reduce maternal mortality, stillbirths, and neonatal mortality. Robert, working with Dr McClure of the Research Triangle Institute, assembled a group of investigators to perform the studies. The research team examined interventions that might have had an important impact on preeclampsia-related maternal mortality and especially on maternal seizures.
      • Goldenberg R.L.
      • Jones B.
      • Griffin J.B.
      • et al.
      Reducing maternal mortality from preeclampsia and eclampsia in low-resource countries—what should work?.
      Interestingly, magnesium sulfate showed evidence of efficacy when included in the model. However, the key elements in improving outcomes were early diagnosis, transfer of the patient to the hospital, and expeditious delivery. Robert concluded that an emphasis on magnesium sulfate often took resources away from other effective components of care (Global Health: Science and Practice).

      Antenatal Steroid Usage in Low- and Middle-Income Countries

      The use of steroids to induce fetal lung maturity and thus improve outcomes after preterm delivery is now well established in the United States and other developed countries. However, as late as 1993, the use of corticosteroids to induce fetal lung maturity was rare in the United States, despite extensive evidence of effectiveness. Robert emphasized this discordance and ultimately participated in the NIH consensus conference, which recommended widespread use. He explored ways to encourage appropriate steroid use and documented increasing use after the conference. He frequently worked with Dr Alan Jobe to better understand the issues involved in steroid use. Many physicians have observed that this intervention—widely considered to be the most effective treatment in perinatal medicine—is underutilized in low-income settings.
      Drs Fernando Althabe and Jose Belizan, from the Institute for Clinical Effectiveness and Health Policy, in Buenos Aires, Argentina, were interested in expanding the use of antenatal corticosteroids in low-income settings, especially for at-home births. However, in addition to studying how to expand their use, Robert and others proposed that the effectiveness of corticosteroids should be tested in low-income settings before implementation. This concept was part of the genesis for a population-based, multifaceted strategy to implement antenatal corticosteroid treatment vs standard of care in low- to middle-income countries. The study of an antenatal corticosteroid treatment clustered randomized trial was carried out by the Global Network of the NICHD: it found that although antenatal steroid use could be increased at the population level, such use in mothers of low-birthweight infants did not decrease neonatal mortality but revealed an excess of 3.5 neonatal deaths and increased the risk of maternal infection for every 1000 women exposed to this strategy.
      • Althabe F.
      • Belizán J.M.
      • McClure E.M.
      • et al.
      A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomised trial.
      However, a subsequent study has shown that antenatal glucocorticoid steroids, when used in facilities offering advanced NICU care, are also effective in low- and middle-income countries, and this raises the issue of the complexity of the design, execution, and interpretation of RCTs in different parts of the world.
      • Oladapo O.T.
      • Vogel J.P.
      • et al.
      WHO ACTION Trials Collaborators
      Antenatal dexamethasone for early preterm birth in low-resource countries.

      Routine Ultrasound in Low-Income Countries

      Ultrasound, an integral part of antenatal care in high-income countries, improves gestational age dating, reduces the number of postdate pregnancies, improves the diagnosis of twins and malpresentations, and detects congenital anomalies. The question of whether the use of obstetrical ultrasound during prenatal care can reduce maternal-fetal or neonatal mortality in low-income countries was one that Robert was interested in answering for some time.
      As part of the NICHD Global Network, Robert conducted a clustered RCT in five low-income countries (Guatemala, Pakistan, the Democratic Republic of Congo, Kenya, and Zambia) to determine whether the implementation of a protocol for two ultrasounds during antenatal care and referral for complications would reduce the primary outcome—a composite of maternal mortality, maternal near-miss mortality, fetal death, and neonatal mortality (Figure 5).
      • Goldenberg R.L.
      • Nathan R.O.
      • Swanson D.
      • et al.
      Routine antenatal ultrasound in low- and middle-income countries: first look—a cluster randomised trial.
      The work, made possible through the support of the Gates Foundation and General Electric, also garnered interest from the World Health Organization and the US Agency for International Development. Robert credits Dr McClure for her contributions to the design of the study, which introduced ultrasound in 60 communities among the five countries. There was no measurable difference in maternal mortality, fetal mortality, or neonatal mortality. Robert noted it as an example of introducing an intervention used extensively in high-income countries into different settings without evidence of change. Furthermore, he added that one lesson gained from the study was that treatments available through the referrals at the study sites were inadequate. Pregnancy complications were more accurately diagnosed with the use of ultrasound, but this did not change the treatment options or care that women received in response to the diagnosis.
      Figure thumbnail gr6
      Figure 5Robert's visit to Guatemala to set up an ultrasound trial, 2014
      From Guatemala, bottom left to right: Marta Lidia Aguilar, psychologist and Global Network Registry supervisor; Dr Jose Eduardo Cano, obstetrician-gynecologist for the National Reproductive Health Program; Dr Ana Garces, Global Network Senior Investigator; and Ms Oralia Rufina Garcia, health post- auxiliary nurse. From the United States, top left to right: Dr Robert Goldenberg; David Swanson (now deceased) who was a public health analyst at the University of Washington; and Dr Elizabeth McClure, a senior research epidemiologist at RTI (Research Triangle Institute) International.
      Romero. A profile of Robert L. Goldenberg, MD. Am J Obstet Gynecol 2021.

      Aspirin to Prevent Preeclampsia

      Meta-analyses and systematic reviews of trials of low-dose aspirin (60–150 mg/day) in pregnant women for the prevention of preeclampsia had shown that those who take aspirin had a lower rate of preterm birth and preeclampsia, an effect that seemed to be enhanced when aspirin was initiated at <16 weeks of gestation.
      • Wright D.
      • Rolnik D.L.
      • Syngelaki A.
      • et al.
      Aspirin for evidence-based preeclampsia prevention trial: effect of aspirin on length of stay in the neonatal intensive care unit.
      ,
      • Rolnik D.L.
      • Nicolaides K.H.
      • Poon L.C.
      Prevention of preeclampsia with aspirin.
      However, this beneficial effect had not been tested by a trial in which the primary endpoint was preterm birth and aspirin initiated in the first trimester of pregnancy. Such a trial was undertaken by seven community sites in six countries, led by Drs Matt Hoffman, Robert Silver, and Richard Derman of the United States and Dr Shiva Goudar of India. The findings of the study were published recently, showing that when low-dose aspirin was initiated between 6 0/7 and 13 6/7 weeks of gestation, there was a reduced incidence of preterm delivery and reduced perinatal mortality before 37 weeks of gestation.
      • Hoffman M.K.
      • Goudar S.S.
      • Kodkany B.S.
      • et al.
      Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (aspirin): a randomised, double-blind, placebo-controlled trial.
      Robert believes in the study’s importance: the low cost and proven tolerability of aspirin make it readily available and safe to use worldwide.

      Professional Endeavors and Awards

      Among more than 750 articles in publication, Robert has several citation classics that cover seminal topics in our field: “Epidemiology and causes of preterm birth,”
      • Goldenberg R.L.
      • Culhane J.F.
      • Iams J.D.
      • Romero R.
      Epidemiology and causes of preterm birth.
      “Intrauterine infection and preterm delivery,”
      • Goldenberg R.L.
      • Hauth J.C.
      • Andrews W.W.
      Intrauterine infection and preterm delivery.
      “The length of the cervix and the risk of spontaneous premature delivery,”
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network.
      and “Prevention of premature birth,”
      • Goldenberg R.L.
      • Rouse D.J.
      Prevention of premature birth.
      among others.
      However, publications are but one part of Robert’s story. He has served as an advisor to the US Congress, the NIH study sections and consensus conferences, the United Cerebral Palsy Research Advisory Council, the state of Alabama, the Bill and Melinda Gates Foundation, and the World Health Organization.
      As an investigator, Robert has been a leader in the MFMU Network and the Global Network, and he is the chair of the Stillbirth Network. His contributions have been recognized by many, and he is the recipient of a Lifetime Achievement Award from the Society of Maternal-Fetal Medicine. Many institutions take great pride in their association with Robert, who received the Duke University Medical Alumnus Award (Figure 6), a Distinguished Faculty Award from the University of Alabama, the Joseph Butterfield Award from the NICHD, and the International Stillbirth Alliance Distinguished Researcher Award.
      Figure thumbnail gr7
      Figure 6Robert receiving the Duke University Distinguished Medical Alumnus Award, 2012
      From left to right, the portrait shows Drs Nancy Andrews (dean), Robert Goldenberg, and Victor Dzau (chancellor).
      Romero. A profile of Robert L. Goldenberg, MD. Am J Obstet Gynecol 2021.

      Personal Life

      Robert noted that the COVID-19-related lockdown has been a mixed blessing. Given the travel restrictions, he has been unable to visit his grandchildren, 11-year-old Ava and 8-year-old Joseph, who live in San Francisco. However, as the children were at home for most of the year, Robert set aside an hour each day to “chat” with them via video conference. Even better, a reunion with his family is in the works: “Now that I’ve gotten my vaccine, I am planning an in-person visit to see the kids and my son David and daughter-in-law Sarah in the very near future. My son Matthew, who lives nearby, is a frequent companion” (Figure 7).
      Figure thumbnail gr8
      Figure 7Robert’s birthday in 1991 with his children David, Matthew, and Kira
      Romero. A profile of Robert L. Goldenberg, MD. Am J Obstet Gynecol 2021.
      Fitness and recreation have always been important to Robert. He played baseball and football in his youth, and he rowed crew and played football while at Columbia. He took up running and completed more than 10 marathons. Robert also told me that he enjoys solitary activities, such as bird-watching, because it leaves him with his thoughts (Figure 8).
      Figure thumbnail gr9
      Figure 8Robert in Mongolia learning to hunt with eagles, 2010
      Romero. A profile of Robert L. Goldenberg, MD. Am J Obstet Gynecol 2021.
      Robert is an avid reader of nonfiction—among his favorites is The Discoverers: A History of Man’s Search to Know His World and Himself by Daniel Boorstein. Another favorite is Jared Diamond’s Guns, Germs, and Steel: The Fates of Human Societies, which emphasizes the importance of environmental factors and, in particular, the development of societies and cultures beyond genetic factors. He recently read The Soul of America: The Battle for Our Better Angels by Jon Meacham, a chronicle of the struggles and divisions throughout US history, including slavery, post-Civil War repression, and persistent racism, with a hopeful recounting of how leaders and activists have repeatedly helped to turn the tide: “It brought me back to what I was interested in trying to understand in college. There’s a straight line that leads from the South’s loss in the Civil War to the racism that we see now.”

      Reflections

      Despite his extraordinary success as an academic leader, physician, and scientist, Robert told me that at the age of 50, his career was still a “work in progress.” At that point, his interest in improved care of women in low-income countries led him to work on issues related to global health: “I felt particularly proud to build systems of care and research infrastructures—that is the most rewarding thing in which I’ve been involved.”
      Throughout his career, Robert has enjoyed mentoring and working with young investigators in developing countries: particularly, the process of proposing a hypothesis, generating data, testing it, and molding the findings into a manuscript.
      For Robert, the secret to remaining engaged in the field beyond the traditional retirement age is to like what you do: “I enjoy other hobbies—but the major way I like to spend my time is working on pregnancy-related research.” Furthermore, Robert said that he never stops asking questions, never accepts that what has been done is always the best thing, and always seeks to determine how things can be improved.
      For his many contributions to obstetrics and maternal-fetal medicine, the AJOG recognizes Dr Robert Goldenberg as a “Giant in Obstetrics and Gynecology.”

      Acknowledgments

      This profile is based on conversations with Dr Robert Goldenberg that took place between 2019 and 2021. I would like to thank Mss Andrea Bernard, Rebecca Hudson, and Maureen McGerty for their contributions to this profile.
      Dr Goldenberg has reviewed and approved this profile.

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        Metronidazole treatment of women with a positive fetal fibronectin test result.
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