An investigator’s odyssey into preterm birth prevention PAUL MEIS, PROFESSOR EMERITUS OF OBSTETRICS AND GYNECOLOGY AND MATERNAL FETAL MEDICINE, UK
.................................................................................................................................................................. had a long-standing interest Iinhave preterm birth dating back to the 1980s, when our group attempted a regional programme to reduce the problem in North Carolina (Moore et al. J Perinatol 1986;6:216–20). By the end of the decade I was disappointed in the results of this and many other published efforts to reduce preterm birth rates. It was at this time that I learned, through a meta-analysis published in BJOG (Keirse BJOG 1990;97:149–154), of the interest in progesterone to prevent preterm birth. In his comments Kierse stated that treatment with 17 a-hydroxyprogesterone caproate (17P) may reduce the occurrence of preterm birth, but that ‘. . . further well controlled research would be needed before it is recommended for clinical practice’. The opportunity to participate in large clinical trials arose when our centre was successful in joining the Maternal Fetal Medicine Units Network, a group of 15 academic obstetrical centres organised by the US National Institutes of Health (NIH) to conduct clinical research. When I first proposed a trial of 17P to prevent preterm delivery in women at risk to the network’s
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Steering Committee, the idea was greeted with much skepticism. As the placenta produces large quantities of progesterone during gestation, why would the addition of a bit more make a difference? Over time, however, I was able to convince my co-investigators to develop a trial protocol, with the BJOG meta-analysis as underpinning evidence. After much preparatory work we began enrolling subjects: women with a history of a prior spontaneous preterm delivery. At that time, the 17P drug for injection was available from only one generic drug manufacturer. We began enrollment into the trial, but after 150 subjects had been enrolled we were informed that the US Food and Drug Administration (FDA) had closed down the drug manufacturer, and that all drugs had been recalled. We were now without a source for our study drug. After considering our options, we chose to commission the supplier of our placebo compound, a research pharmacy, to produce our study drug as well, and began recruitment anew. Recruitment then progressed well
towards our goal of 500 women; however, when 463 subjects had been enrolled and randomised to 17P treatment or placebo, we were notified by the Data Safety and Monitoring Committee for the study that enrollment should be stopped. Their analysis indicated that the outcome of pregnancies for women receiving 17P was significantly better than for the placebo group, and that placebo treatment was inappropriate. Thus, in 2003 our historic paper published the results of the pregnancies of these 463 women (Meis et al. New Engl J Med 2003;348:2379–2385). Although not all trials of 17P have shown certainty in benefit in preventing other causes of preterm delivery, the journey initiated with a BJOG paper has set the scene for the continuation of improvement in the outcome of pregnancies through multicentre studies.
Disclosure of interests The author has no conflicts of interest regarding drugs or any commercial products. &
ª 2014 Royal College of Obstetricians and Gynaecologists
Copyright of BJOG: An International Journal of Obstetrics & Gynaecology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
.................................................................................................................................................................. had a long-standing interest Iinhave preterm birth dating back to the 1980s, when our group attempted a regional programme to reduce the problem in North Carolina (Moore et al. J Perinatol 1986;6:216–20). By the end of the decade I was disappointed in the results of this and many other published efforts to reduce preterm birth rates. It was at this time that I learned, through a meta-analysis published in BJOG (Keirse BJOG 1990;97:149–154), of the interest in progesterone to prevent preterm birth. In his comments Kierse stated that treatment with 17 a-hydroxyprogesterone caproate (17P) may reduce the occurrence of preterm birth, but that ‘. . . further well controlled research would be needed before it is recommended for clinical practice’. The opportunity to participate in large clinical trials arose when our centre was successful in joining the Maternal Fetal Medicine Units Network, a group of 15 academic obstetrical centres organised by the US National Institutes of Health (NIH) to conduct clinical research. When I first proposed a trial of 17P to prevent preterm delivery in women at risk to the network’s
40
Steering Committee, the idea was greeted with much skepticism. As the placenta produces large quantities of progesterone during gestation, why would the addition of a bit more make a difference? Over time, however, I was able to convince my co-investigators to develop a trial protocol, with the BJOG meta-analysis as underpinning evidence. After much preparatory work we began enrolling subjects: women with a history of a prior spontaneous preterm delivery. At that time, the 17P drug for injection was available from only one generic drug manufacturer. We began enrollment into the trial, but after 150 subjects had been enrolled we were informed that the US Food and Drug Administration (FDA) had closed down the drug manufacturer, and that all drugs had been recalled. We were now without a source for our study drug. After considering our options, we chose to commission the supplier of our placebo compound, a research pharmacy, to produce our study drug as well, and began recruitment anew. Recruitment then progressed well
towards our goal of 500 women; however, when 463 subjects had been enrolled and randomised to 17P treatment or placebo, we were notified by the Data Safety and Monitoring Committee for the study that enrollment should be stopped. Their analysis indicated that the outcome of pregnancies for women receiving 17P was significantly better than for the placebo group, and that placebo treatment was inappropriate. Thus, in 2003 our historic paper published the results of the pregnancies of these 463 women (Meis et al. New Engl J Med 2003;348:2379–2385). Although not all trials of 17P have shown certainty in benefit in preventing other causes of preterm delivery, the journey initiated with a BJOG paper has set the scene for the continuation of improvement in the outcome of pregnancies through multicentre studies.
Disclosure of interests The author has no conflicts of interest regarding drugs or any commercial products. &
ª 2014 Royal College of Obstetricians and Gynaecologists
Copyright of BJOG: An International Journal of Obstetrics & Gynaecology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
