Making miscarriage matter

Miscarriage, defined as the loss of a pregnancy before viability, affects more than 10% of women. Although the effect differs between women, it can have major physical and psychological effects. Providing effective personalised care is important. Reliable information on the effectiveness of interventions used to manage miscarriage is therefore essential. “Imagine if the entire edifice of knowledge in medicine was built upon a falsehood”, said Richard Horton in 2019.1Horton R Offline: The gravy train of systematic reviews.Lancet. 2019; 3941790Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar He singled out Cochrane as one of the organisations contributing to better health outcomes for everyone by summarising evidence: “Cochrane's claims are big: trusted evidence, informed decisions, better health. But what if the astonishing energy, commitment, and productivity of the systematic review community are poisoning rather than nourishing medical practice?”1Horton R Offline: The gravy train of systematic reviews.Lancet. 2019; 3941790Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Published in April, 2021, the Lancet Series on miscarriage reports practice recommendations for the management of miscarriage.2Quenby S Gallos ID Dhillon-Smith RK et al.Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss.Lancet. 2021; 397: 1658-1667Summary Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 3Coomarasamy A Gallos ID Papadopoulou A et al.Sporadic miscarriage: evidence to provide effective care.Lancet. 2021; 397: 1668-1674Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 4Coomarasamy A Dhillon-Smith RK Papadopoulou A et al.Recurrent miscarriage: evidence to accelerate action.Lancet. 2021; 397: 1675-1682Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar In this three-paper Series, Siobhan Quenby, Arri Coomarasamy, and colleagues used literature reviews to inform a UK-wide consensus conference held in December, 2019, but they did not assess the individual studies. Progesterone treatment is a cornerstone in the management of recurrent miscarriage, and the authors recommend that “micronised progesterone can be considered for asymptomatic women with recurrent miscarriage, and is likely to be more effective in women with a high number of previous miscarriages”.4Coomarasamy A Dhillon-Smith RK Papadopoulou A et al.Recurrent miscarriage: evidence to accelerate action.Lancet. 2021; 397: 1675-1682Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar This recommendation is based on a 2019 Cochrane review by David Haas and colleagues5Haas DM Hathaway TJ Ramsey PS Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology.Cochrane Database Syst Rev. 2019; 11CD003511Google Scholar with ten studies (1684 women) reporting a reduced risk of miscarriage (relative risk [RR] 0·73, 95% CI 0·54–1·00) in unselected women with recurrent miscarriage, and in women with at least three previous miscarriages (four studies including 1334 women; RR 0·59, 95% CI 0·34–1·01).5Haas DM Hathaway TJ Ramsey PS Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology.Cochrane Database Syst Rev. 2019; 11CD003511Google Scholar The Cochrane review was updated in 2019 to exclude a study in 700 women that had been retracted by the journal following concerns about the accuracy and reliability of the trial data.6Journal of Maternal-Fetal and Neonatal MedicineStatement of retraction: peri-conceptional progesterone treatment in women with unexplained recurrent miscarriage: a randomized double-blind placebo-controlled trial.J Matern Fetal Neonatal Med. 2020; 331073Crossref PubMed Scopus (0) Google Scholar Can the other studies in the Cochrane review be trusted? A study by Ashok Kumar and colleagues7Kumar A Begum N Prasad S Aggarwal S Sharma S Oral dydrogesterone treatment during early pregnancy to prevent recurrent pregnancy loss and its role in modulation of cytokine production: a double-blind, randomized, parallel, placebo-controlled trial.Fertil Steril. 2014; 102: 1357-1363Summary Full Text Full Text PDF PubMed Scopus (54) Google Scholar that contributes 13% of the weight reports a large and significant benefit of progestorone in recurrent miscarriage. (RR 0·41; 95% CI 0·22–0·78). However, the weighted mean baseline values of the subgroups do not add up to comparable baseline values for the study population as a whole (appendix).7Kumar A Begum N Prasad S Aggarwal S Sharma S Oral dydrogesterone treatment during early pregnancy to prevent recurrent pregnancy loss and its role in modulation of cytokine production: a double-blind, randomized, parallel, placebo-controlled trial.Fertil Steril. 2014; 102: 1357-1363Summary Full Text Full Text PDF PubMed Scopus (54) Google Scholar Another study that reports a large significant benefit from progesterone (RR 0·46, 95% CI 0·23, 0–93; 12% of the weight) was a single author study that randomly allocated 180 women according to the day of the week the women attended the clinic.8El-Zibdeh MY Dydrogesterone in the reduction of recurrent spontaneous abortion.J Steroid Biochem Mol Biol. 2005; 97: 431-434Crossref PubMed Scopus (71) Google Scholar The third study in this domain that reports a positive (albeit non-significant) effect of progesterone, is extracted from a retrospective trial registration of a study that was never published.9Agarwal N Role of inflammatory markers in recurrent pregnancy loss and effect of oral micronized therapy on these cases.http://ctri.nic.in/Clinicaltrials/pmaindet2.php?%20trialid=14740Date: Sept 16, 2016Date accessed: April 28, 2021Google Scholar Without these studies, the estimated treatment effect of progesterone becomes much less convincing (RR 0·95, 95% CI 0·79–1·13), as also becomes apparent from the updated Cochrane review that was published in April, 2021.10Devall AJ Papadopoulou A Podesek M et al.Progestogens for preventing miscarriage: a network meta-analysis.Cochrane Database Syst Rev. 2021; 4CD013792PubMed Google Scholar Although this Correspondence does not allow an extensive assessment of studies on thyroxine, aspirin, or heparin, we are concerned that the integrity of a large part of the studies underlying these reviews might not be any better. Women with miscarriage are vulnerable and deserve dedicated care and evidence-based treatment. The reliability of studies included in systematic reviews deserves greater attention. We can no longer take everything on trust. BWM is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). BWM reports consultancy fees for ObsEva, Merck, and Guerbet. All other authors declare no competing interests. Download .pdf (.37 MB) Help with pdf files Supplementary appendix Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy lossMiscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5–18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3–11·4%), two miscarriages is 1·9% (1·8–2·1%), and three or more miscarriages is 0·7% (0·5–0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. Full-Text PDF Sporadic miscarriage: evidence to provide effective careThe physical and psychological effect of miscarriage is commonly underappreciated. The journey from diagnosis of miscarriage, through clinical management, to supportive aftercare can be challenging for women, their partners, and caregivers. Diagnostic challenges can lead to delayed or ineffective care and increased anxiety. Inaccurate diagnosis of a miscarriage can result in the unintended termination of a wanted pregnancy. Uncertainty about the therapeutic effects of interventions can lead to suboptimal care, with variations across facilities and countries. Full-Text PDF Recurrent miscarriage: evidence to accelerate actionWomen who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. Full-Text PDF