NIHR Signal Little or no benefit from progesterone to prevent preterm birth

Published on 20 September 2016

In this trial, vaginal progesterone given to women at high risk of preterm delivery did not reduce the risk of premature birth compared to a placebo. The consequences for the baby in the first 28 days of life, and children at two years’ old, were also similar when looked at as a whole.

Many different outcomes were looked at and this can provide a confusing picture. There appear slightly fewer deaths or brain injury around birth with progesterone. At two years childhood brain function was no different between groups, and there was no other significant harms in children’s development long term. There was an unexplained and non-significant suggestion of an increase in infant deaths at two years with progesterone.

Previous research has suggested that progesterone can prevent premature birth and that, with women’s consent, it could be offered as an option to women at risk. This trial, by far the largest of its kind on the subject, suggests the balance of risk and benefit is not simple. Discussions regarding a woman’s preferences should now include the probability of the lack of long term benefits.

Little or no benefit from progesterone to prevent preterm birth

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Why was this study needed?

In the UK, about 8 babies in every 100 are born prematurely (before the 37th week of pregnancy). Risk factors include a previous premature birth and a short cervix.

Premature birth is the biggest single cause of death and serious complications in the first 28 days of life, and the risk of mortality increases the earlier a baby is born. Babies who survive have increased rates of disability, in particular neurodevelopmental problems.

Previous research suggested that progesterone treatment can delay the early onset of labour, although whether it is associated with effects on a child’s health after birth was uncertain. By delaying birth, progesterone may reduce the risk of impairment; or it may prolong the unborn baby’s exposure to harmful conditions in the womb.

The NIHR-funded study (OPPTIMUM) looked at whether progesterone reduced premature births and associated deaths and complications. It also looked at the treatment effects on children’s cognitive function at two years.

What did this study do?

This was a randomised controlled trial involving 1,228 pregnant women at risk of giving birth prematurely. After assessing eligibility, 618 women were randomly assigned to daily treatment with vaginal progesterone (200mg daily) taken from around 24 weeks until 34 weeks of pregnancy and 610 to an inactive placebo treatment. The trial looked at whether progesterone had any effect on:

  • Babies dying in the womb or being born before 34 weeks;
  • Any of death, brain injury or chronic infant lung disease in the first 28 days of life;
  • The children’s scores in a standardised test of brain function at two years of age.

These were the main outcomes specified for the trial, though the researchers separately analysed the individual components of these outcomes and a range of other outcomes of interest. This many outcomes can increase the risk of finding significant differences by chance and the researchers corrected for this in their analysis. This was a large high quality trial, carried out at several centres in the UK to rigorous standards, so its findings are reliable.

What did it find?

The trial found that progesterone compared with giving placebo treatment had:

  • No effect on the risk of premature birth or of babies dying in the womb (adjusted odds ratio [OR] 0.86, 95% confidence interval [CI] 0.61 to 1.22).
  • No effect on the combined risk of death, brain injury and lung disease in the first 28 days of life (adjusted OR 0.62; CI 0.38 to 1.03). When analysed separately, progesterone was associated with significantly lower rates of death in the first 28 days, with 1 out of 600 in the progesterone group compared to 6 out of 597 in the placebo group (unadjusted OR 0.17; CI 0.06 to 0.49). Less brain injury was also associated with progesterone, occurring in 18 out of 584 babies in the progesterone group, compared with 34 out of 574 babies in the placebo group (unadjusted OR 0.50; CI 0.31 to 0.84).
  • No effect on childhood brain development at two years (difference in mean cognitive score -0.48; CI -2.77 to 1.81).
  • There was no statistically significant difference in number of deaths up to two years of age, though there were 20 deaths amongst 500 children in the progesterone group and 16 deaths amongst 509 in the placebo group (OR 1.28; CI 0.66 to 2.51).

What does current guidance say on this issue?

NICE guidance from 2015 recommends that vaginal progesterone or a stitch to close the cervix is offered to women with a history of preterm birth and a cervix length of less than 25mm according to ultrasound scan at between 16 and 24 weeks. NICE recommend that vaginal progesterone is also offered to women who have a shortened cervix at this stage of pregnancy without a history of preterm birth. In each case, it is recommended that the benefits and risks of treatment are discussed with the woman and her preferences taken into account.

Most of the evidence considered by NICE was of low or moderate quality. NICE concluded that further research should be undertaken which compares vaginal progesterone with a cervical stitch and with both treatments used together. This is one further piece of the evidence that will need to be considered in guidance on this topic.

What are the implications?

The results from this high quality trial differ from the findings of previous studies and could be included in any discussion with women about the benefits and risks of treatment. Whereas previous meta-analyses of smaller, low quality studies had suggested that progesterone reduced the risk of preterm birth in high risk women, this study did not. However, it did find that progesterone may reduce the risk of death or brain injury within the first 28 days of life. But this is a secondary finding of the study, benefit is not seen at two years and any mechanism is unclear when there was no reduction in pre-term births.

This is one of the few studies to report on possible longer term effects of progesterone on children.  For women and clinicians discussing this, the research suggests that there is no clear benefit to prescribing progesterone.

Citation and Funding

Norman JE, Marlow N, Messow CM, et al; OPPTIMUM study group. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet. 2016;387(10033):2106-16.

This project was funded by Efficacy and Mechanism Evaluation (EME) Programme, a National Institute for Health Research (NIHR) and Medical Research Council (MRC) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.

Bibliography

Mol BW, Daly M, Dodd JM. Progestogens and preterm birth—not the hoped for panacea? Lancet. 2016;387(10033):2066-8.

National Institute of Child Health and Human Development. What are the risk factors for preterm labor and birth?. Bethesda (MD): National Institute of Child Health and Human Development; 2013.

NICE. Preterm labour and birth. NG25. London: National Institute for Health and Care Excellence; 2015.

Why was this study needed?

In the UK, about 8 babies in every 100 are born prematurely (before the 37th week of pregnancy). Risk factors include a previous premature birth and a short cervix.

Premature birth is the biggest single cause of death and serious complications in the first 28 days of life, and the risk of mortality increases the earlier a baby is born. Babies who survive have increased rates of disability, in particular neurodevelopmental problems.

Previous research suggested that progesterone treatment can delay the early onset of labour, although whether it is associated with effects on a child’s health after birth was uncertain. By delaying birth, progesterone may reduce the risk of impairment; or it may prolong the unborn baby’s exposure to harmful conditions in the womb.

The NIHR-funded study (OPPTIMUM) looked at whether progesterone reduced premature births and associated deaths and complications. It also looked at the treatment effects on children’s cognitive function at two years.

What did this study do?

This was a randomised controlled trial involving 1,228 pregnant women at risk of giving birth prematurely. After assessing eligibility, 618 women were randomly assigned to daily treatment with vaginal progesterone (200mg daily) taken from around 24 weeks until 34 weeks of pregnancy and 610 to an inactive placebo treatment. The trial looked at whether progesterone had any effect on:

  • Babies dying in the womb or being born before 34 weeks;
  • Any of death, brain injury or chronic infant lung disease in the first 28 days of life;
  • The children’s scores in a standardised test of brain function at two years of age.

These were the main outcomes specified for the trial, though the researchers separately analysed the individual components of these outcomes and a range of other outcomes of interest. This many outcomes can increase the risk of finding significant differences by chance and the researchers corrected for this in their analysis. This was a large high quality trial, carried out at several centres in the UK to rigorous standards, so its findings are reliable.

What did it find?

The trial found that progesterone compared with giving placebo treatment had:

  • No effect on the risk of premature birth or of babies dying in the womb (adjusted odds ratio [OR] 0.86, 95% confidence interval [CI] 0.61 to 1.22).
  • No effect on the combined risk of death, brain injury and lung disease in the first 28 days of life (adjusted OR 0.62; CI 0.38 to 1.03). When analysed separately, progesterone was associated with significantly lower rates of death in the first 28 days, with 1 out of 600 in the progesterone group compared to 6 out of 597 in the placebo group (unadjusted OR 0.17; CI 0.06 to 0.49). Less brain injury was also associated with progesterone, occurring in 18 out of 584 babies in the progesterone group, compared with 34 out of 574 babies in the placebo group (unadjusted OR 0.50; CI 0.31 to 0.84).
  • No effect on childhood brain development at two years (difference in mean cognitive score -0.48; CI -2.77 to 1.81).
  • There was no statistically significant difference in number of deaths up to two years of age, though there were 20 deaths amongst 500 children in the progesterone group and 16 deaths amongst 509 in the placebo group (OR 1.28; CI 0.66 to 2.51).

What does current guidance say on this issue?

NICE guidance from 2015 recommends that vaginal progesterone or a stitch to close the cervix is offered to women with a history of preterm birth and a cervix length of less than 25mm according to ultrasound scan at between 16 and 24 weeks. NICE recommend that vaginal progesterone is also offered to women who have a shortened cervix at this stage of pregnancy without a history of preterm birth. In each case, it is recommended that the benefits and risks of treatment are discussed with the woman and her preferences taken into account.

Most of the evidence considered by NICE was of low or moderate quality. NICE concluded that further research should be undertaken which compares vaginal progesterone with a cervical stitch and with both treatments used together. This is one further piece of the evidence that will need to be considered in guidance on this topic.

What are the implications?

The results from this high quality trial differ from the findings of previous studies and could be included in any discussion with women about the benefits and risks of treatment. Whereas previous meta-analyses of smaller, low quality studies had suggested that progesterone reduced the risk of preterm birth in high risk women, this study did not. However, it did find that progesterone may reduce the risk of death or brain injury within the first 28 days of life. But this is a secondary finding of the study, benefit is not seen at two years and any mechanism is unclear when there was no reduction in pre-term births.

This is one of the few studies to report on possible longer term effects of progesterone on children.  For women and clinicians discussing this, the research suggests that there is no clear benefit to prescribing progesterone.

Citation and Funding

Norman JE, Marlow N, Messow CM, et al; OPPTIMUM study group. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet. 2016;387(10033):2106-16.

This project was funded by Efficacy and Mechanism Evaluation (EME) Programme, a National Institute for Health Research (NIHR) and Medical Research Council (MRC) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.

Bibliography

Mol BW, Daly M, Dodd JM. Progestogens and preterm birth—not the hoped for panacea? Lancet. 2016;387(10033):2066-8.

National Institute of Child Health and Human Development. What are the risk factors for preterm labor and birth?. Bethesda (MD): National Institute of Child Health and Human Development; 2013.

NICE. Preterm labour and birth. NG25. London: National Institute for Health and Care Excellence; 2015.

Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial

Published on 23 February 2016

Norman, J, Marlow, M, Messow, C, Shennan, A, Bennett, Thornton, S, Robson, S, McConnachie, A, Petrou, S, Sebire, N, Lavender, T, Whyte, S, Norrie, J

The Lancet , 2016

Background Progesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on the child. Methods We did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22–24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com, number ISRCTN14568373. Findings Between Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, 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), nor on the childhood outcome (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). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0·27). Interpretation Vaginal 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. Funding Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.

Expert commentary

No naturally occurring human progestogen deficiency state exists, but drugs with this action - natural progesterone in the UK, synthetic medroxyprogesterone acetate in the US - are widely prescribed to prevent pre-term birth. Last year NICE concluded, on the basis of “moderate-to-low quality” evidence, that prophylactic progesterone should be offered to women, with or without a history of pre-term birth, who also had a short cervix. They also recommended that further research should include baby follow-up. The large OPPTIMUM trial of progesterone or placebo has now followed-up babies for two years. By then more babies had died, and more survivors moderately or severely neurologically impaired in the progesterone group. The differences did not reach conventional levels of statistical significance but OPPTIMUM is much higher quality than previous trials. This study offers no support for progesterone; NICE may wish to revise its guidance.

Jim Thornton, Professor of Obstetrics & Gynaecology, University of Nottingham; Head of Service for Obstetrics, Gynaecology and Neonatology, Nottingham University Hospitals NHS Trust