Progestogens and preterm birth—not the hoped for panacea?
Authors: Ben W J Mol, Mandy Daly, Jodie M Dodd
Journal: The Lancet (2016)

Preterm birth is the most common cause of neonatal morbidity and mortality globally, affecting about 15 million children every year.1Blencowe H Cousens S Oestergaard MZ et al.National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications.Lancet. 2012; 379: 2162-2172Summary Full Text Full Text PDF PubMed Scopus (2901) Google Scholar Of children born preterm, an estimated 2·4 million (15·6%) are born extremely preterm (before 28 weeks gestation) or very preterm (before 32 weeks gestation).1Blencowe H Cousens S Oestergaard MZ et al.National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications.Lancet. 2012; 379: 2162-2172Summary Full Text Full Text PDF PubMed Scopus (2901) Google Scholar Furthermore, some 1 million children every year die as a consequence of preterm birth or its complications.1Blencowe H Cousens S Oestergaard MZ et al.National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications.Lancet. 2012; 379: 2162-2172Summary Full Text Full Text PDF PubMed Scopus (2901) Google Scholar In 2014, the Preterm Birth Priority Setting Partnership in the UK identified prediction and prevention of preterm birth as the top research priority in this area.2Duley L Uhm S Oliver S Top 15 UK research priorities for preterm birth, on behalf of the Preterm Birth Priority Setting Partnership Steering Group.Lancet. 2014; 383: 2041-2042Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar Progesterone has been considered a promising therapeutic agent to prevent preterm birth. Having been assessed in several small, randomised trials in the 1960s and 1970s, a meta-analysis by Keirse3Keirse MJ Progestogen administration in pregnancy may prevent preterm delivery.Br J Obstet Gynaecol. 1990; 97: 149-154Crossref PubMed Scopus (219) Google Scholar identified a reduction in the occurrence of preterm birth after antenatal use of progesterone. This finding inspired others to undertake new randomised trials, and in 2003, both Meis and colleagues4Meis PJ Klebanoff M Thom E et al.National Institute of Child Health and Human Development Maternal-Fetal Medicine Units NetworkPrevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1266) Google Scholar and Da Fonseca and colleagues5Da Fonseca EB Bittar RE Carvalho MH Zugaib M Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.Am J Obstet Gynecol. 2003; 188: 419-424Summary Full Text Full Text PDF PubMed Scopus (638) Google Scholar reported a reduction of preterm birth in women with previous preterm birth after treatment with 17α-hydroxyprogesterone caproate and vaginal progesterone, respectively. Subsequent meta-analysis (incorporating both intramuscular and vaginal preparations) confirmed that progestogens could prolong pregnancy, and were associated with a reduction in short-term neonatal mortality and morbidity.6Dodd JM Jones L Flenady V Cincotta R Crowther CA Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth.Cochrane Database Systemat Rev. 2013; 7 (CD004947.)PubMed Google Scholar However, it remains uncertain whether this approach is associated with improvements in long-term outcomes for children. Whereas longer duration of pregnancy is often related to better neonatal outcomes, a longer stay in a hazardous uterine environment might be harmful.7Alfirevic Z Tocolytics: do they actually work?.BMJ. 2012; 345: e6531Crossref PubMed Scopus (9) Google Scholar In The Lancet, Jane Norman and colleagues8Norman JE Marlow N Messow C-M et al.for the OPPTIMUM study groupVaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial.Lancet. 2016; (published online Feb 23.)http://dx.doi.org/10.1016/S0140-6736(16)00350-0Google Scholar report the effect of vaginal progesterone (200 mg daily taken from 22–24 to 34 weeks of gestation) in 1228 women at increased risk for preterm birth on early child development at 2 years of age. They did a randomised, multicentre, placebo-controlled study using rigorous standards, including an assessment of maternal compliance with medication, an unbiased assessment of outcomes, and used a sample size larger than all of the previously published studies combined. The authors report three primary family-centred outcomes, an obstetric outcome (fetal death or delivery before 34 weeks and 0 days of gestation), a neonatal outcome (composite of death, bronchopulmonary dysplasia, and brain injury), and a childhood outcome (Bayley-III cognitive composite score), reflecting the fact that the effect of the intervention is through the prolongation of pregnancy, with an anticipated benefit in improved neonatal and child health. Progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0·86, 95% CI 0·61–1·22) or neonatal outcome (OR 0·62, 0·38–1·03). Although the OPPTIMUM study itself shows no difference on the primary obstetric and neonatal outcome, all obstetric and neonatal outcomes showed a reduction in the occurrence of unwanted neonatal outcomes after the administration of progesterone (neonatal death, unadjusted OR 0·17, 95% CI 0·06–0·49; brain injury on ultrasound 0·50, 0·31–0·84). However, there was no identifiable improvement in child development when assessed at 2 years of age (cognitive score, progesterone group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means −0·48, 95% CI −2·77 to 1·81). It will be important to incorporate these findings into subsequent updates of the Cochrane Systematic Reviews on this topic. First, the results from OPPTIMUM highlight the importance of perinatal trials to routinely follow up maternal and child participants after birth. As shown by Norman and colleagues, the risk–benefit ratio of any perinatal intervention might vary considerably according to effects on the woman and her infant, both immediately after birth and extending into childhood, as has been shown with the use of antibiotics for women in spontaneous preterm labour, or the effects of multiple doses of corticosteroids.9Kenyon S Pike K Jones DR et al.Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial.Lancet. 2008; 372: 1319-1327Summary Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 10Wapner RJ Sorokin Y Mele L et al.Long-term outcomes after repeat doses of antenatal corticosteroids.N Engl J Med. 2007; 357: 1190-1198Crossref PubMed Scopus (247) Google Scholar It could be assumed that when an intervention does not influence the mechanism it aims to improve—for example prolongation of pregnancy—it does not work. However, the opposite is not guaranteed: successful short-term improvements in health do not necessarily correlate with improvements in longer-term health outcomes. Although this might be a message that complicates the lives not only of researchers, but also of research funders, it is an important reality. Researchers should consider the long-term effects for both neonates and their families; every study of a perinatal intervention that shows short-term benefits should ideally include longer-term follow-up of participants to assess potential benefits and harms. Second, careful consideration of the interpretation of the 2-year outcome is needed. It is interesting that the better neonatal outcome of vaginal progesterone does not translate to any benefit in terms of longer-term child health. Although there might be associations between short-term morbidity and longer-term health, the lack of observed effect could reflect both the impact of a multitude of postnatal factors (eg, socioeconomic factors, attention to the child) on child development, as well as the relative imprecision of the Bayley-III cognitive scale, meaning that more subtle developmental variations might go undetected.11Anderson PJ De Luca CR Hutchinson E Roberts G Doyle LW Victorian Infant Collaborative GroupUnderestimation of developmental delay by the new Bayley-III scale.Arch Pediatr Adolesc Med. 2010; 164: 352-356Crossref PubMed Scopus (369) Google Scholar Third, since OPPTIMUM also indicates that at 2 years of age no harm is to be anticipated from progesterone, the decision to use progesterone or not also becomes an issue of shared decision making. The most important short-term perinatal outcome for preterm birth, neonatal death, occurred in one of the children in the progesterone group compared with six in the placebo group (unadjusted OR 0·17, 95% CI 0·06–0·49). Similarly, a meta-analysis had already indicated that progesterone reduced the risk of perinatal mortality in women with a history of spontaneous preterm birth (risk ratio [RR] 0·50, 95% CI 0·33–0·75) and in women with an ultrasound-identified short cervix (RR 0·74, 95% CI 0·42–1·29).6Dodd JM Jones L Flenady V Cincotta R Crowther CA Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth.Cochrane Database Systemat Rev. 2013; 7 (CD004947.)PubMed Google Scholar Obviously, for parents who have suffered the loss of a child due to prematurity the decision to use progesterone in a subsequent pregnancy might be influenced by this information. This decision should be weighed against the fact that in Norman and colleagues' study8Norman JE Marlow N Messow C-M et al.for the OPPTIMUM study groupVaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial.Lancet. 2016; (published online Feb 23.)http://dx.doi.org/10.1016/S0140-6736(16)00350-0Google Scholar the difference in neonatal death rate was not seen in the death rate at the age of 2 years (hazard ratio 1·28, 95% CI 0·66–2·51). Future use of standardised outcomes can prevent the variety of outcomes that have been used in the studies done thus far,12van 't Hooft J Duffy JM Daly M et al.Global Obstetrics Network (GONet)A core outcome set for evaluation of interventions to prevent preterm birth.Obstet Gynecol. 2016; 127: 49-58Crossref PubMed Scopus (136) Google Scholar and individual patient data meta-analysis of progestogens to prevent preterm birth will allow a better assessment of treatment benefits, particularly for subgroups of women. The OPPTIMUM study is a step forward in the understanding of progesterone as a treatment in women at risk for preterm birth. The study also highlights the importance for perinatal trialists to incorporate at the outset an undertaking to continue to assess longer-term outcomes, to use standardised outcomes, and to integrate the obtained results. This can best be achieved in a global collaboration of those working on this topic. BWJM is a member of the advisory board of ObsEva, Switzerland, and payments from this role go to his institute. MD and JMD declare no competing interests. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trialVaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age. Full-Text PDF Open Access