Recurrent MiscarriageGreen‐top Guideline No. 17

In the 2018 Cochrane meta-analysis, subgroup analysis showed a significantly more pronounced effect in women with three or more versus two or more prior miscarriages.

“with subgroup analysis showing a significantly more pronounced effect in women with three or more versus two or more prior miscarriages.196”

• cites [196] 196. Haas DM, Hathaway TJ, Ramsey PS. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiol- ogy. Cochrane Database Syst Rev. 2018;10:CD003511. sourceDisputed

  In “Trials with placebo controls,” the review reports no evidence of a difference between the prior-miscarriage subgroups (interaction test P = 0.15). Although the estimated reduction was larger in the three-or-more group, the review does not find that the difference was statistically significant. (LLM, conf=0.94)

  Checked by a reasoning model — may be wrong.

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A systematic review reported miscarriage rates of 11.3%, 17.0%, 28.0%, 39.6%, 47.2% and 63.9% for women with no, one, two or three, four, five and six previous miscarriages respectively.

“A systematic review has reported the miscarriage rates to be 11.3%, 17.0%, 28.0%, 39.6%, 47.2% and 63.9% for women with no, one, two or three, four, five and six previous miscarriages respectively.19”

• cites [19] 19. Coomarasamy A, Devall AJ, Brosens JJ, Quenby S, Stephenson MD, Sierra S, et al. Micronized vaginal progesterone to prevent miscar- riage: a critical evaluation of randomized evidence. Am J Obstet Gynecol. 2020;223(2):167-76. sourcePartly supported

  The Discussion’s “Target populations for progesterone therapy” section says miscarriage risk rises with the number of previous miscarriages, and its Figure 8 caption describes a systematic review of miscarriage outcomes by number of prior losses. The text available in our copy does not give the six quoted percentages, so their values and correspondence to the stated groups cannot be verified. (LLM, conf=0.83)

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Primary versus secondary recurrent miscarriage did not result in a significantly different future prognosis.

“In two studies, primary versus secondary (those with a previous live birth) recurrent miscarriage did not result in a significantly different future prognosis.20,21”

• cites [20] 20. Brigham SA, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod. 1999;14(11):2868-71. sourceNot checked — no full text of the source
• cites [21] 21. Clifford K, Rai R, Regan L. Future pregnancy outcome in un- explained recurrent first trimester miscarriage. Hum Reprod. 1997;12(2):387-9. sourceSupported

A meta-analysis reported increased miscarriage rates for men aged over 40 years, although far less pronounced than the effect of increased maternal age.

“A meta-analysis has also reported increased miscarriage rates for men aged over 40 years, although far less pronounced when compared with the effect of increased maternal age.18”

• cites [18] 18. du Fossé NA, van der Hoorn MP, van Lith JMM, le Cessie S, Lashley EELO. Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis. Hum Reprod Update. 2020;26(5):650-69. sourceSupported

Compared with white Europeans, the odds of a sporadic miscarriage were increased in Black African and Black Caribbean women.

“A large observational study found that compared with white Europeans, the odds of a sporadic miscarriage were increased in Black African and Black Caribbean women.22”

• cites [22] 22. Oliver-Williams CT, Steer PJ. Racial variation in the number of spon- taneous abortions before a first successful pregnancy, and effects on subsequent pregnancies. Int J Gynaecol Obstet. 2015;129(3):207-12. sourceSupported

In the meta-analysis of Ng et al. (2021), women with a BMI below 19 and above 25 kg/m2 were at higher odds of recurrent miscarriage.

“In the meta-analysis of Ng et al. (2021) women with a BMI below 19 and above 25 kg/m 2 were at higher odds of recurrent miscarriage.31”

• cites [31] 31. Ng KYB, Cherian G, Kermack AJ, Bailey S, Macklon N, Sunkara SK, et al. Systematic review and meta-analysis of female lifestyle factors and risk of recurrent pregnancy loss. Sci Rep. 2021;11(1):7081. sourcePartly supported

  The Results (Underweight; Overweight and obesity, page not available) report higher odds of recurrent pregnancy loss in the general population for underweight women and women with BMI >25 kg/m². The paper does not give a BMI <19 cutoff for the pooled underweight finding, so that precise threshold is unsupported. It also finds no increased odds of a further miscarriage among underweight women who already have recurrent pregnancy loss. (LLM, conf=0.85)

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Preliminary studies do not suggest an additional value or sensitivity in diagnosis associated with the use of clinical assays of other aPL.

“preliminary studies do not suggest an additional value or sensitivity in diagnosis associated with their use.40”

• cites [40] 40. Tebo AE, Jaskowski TD, Hill HR, Branch DW. Clinical relevance of multiple antibody specificity testing in anti-phospholipid syndrome and recurrent pregnancy loss. Clin Exp Immunol. 2008;154(3):332-8. sourcePartly supported

  The Discussion says routine testing of the non-recommended aPL assays lacks clinical utility and that their overall combined sensitivity was not significantly higher than standard tests. The Results, however, report significantly higher sensitivity for these assays in the recurrent pregnancy loss group, although this came with lower specificity. The unqualified claim of no additional sensitivity therefore overstates the findings. (LLM, conf=0.86)

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There is some evidence for an association between increased caffeine intake and sporadic miscarriage.

“Similarly, there is some evidence for an association between increased caffeine intake and sporadic miscarriage.27”

• cites [27] 27. Chen LW, Wu Y, Neelakantan N, Chong MF, Pan A, van Dam RM. Maternal caffeine intake during pregnancy and risk of pregnancy loss: a categorical and dose-response meta-analysis of prospective studies. Public Health Nutr. 2016;19(7):1233-44. sourcePartly supported

  The Conclusions (p. 10) associate higher maternal caffeine intake with greater pregnancy-loss risk, and the Results (p. 7) say the conclusion remained the same after excluding studies involving stillbirth. The paper does not distinguish sporadic from recurrent miscarriage, so it supports the association with miscarriage generally but not that specific qualifier. (LLM, conf=0.83)

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Approximately 50% of sporadic miscarriages are a result of fetal chromosome anomalies (pooled prevalence 49.7%; 95% CI 34.9-64.6%).

“A review reported that approximately 50% of sporadic miscarriages are a result of fetal chromosome anomalies (pooled prevalence 49.7%; 95% CI 34.9-64.6%).”

• cites [52] 52. Zhu X, Li J, Zhu Y, Wang W, Wu X, Yang Y, et al. Application of chromosomal microarray analysis in products of miscarriage. Mol Cytogenet. 2018;11:44. sourcePartly supported

  The Results (Subject features and general findings; page unavailable) report genetic abnormalities in 55.3% (224/405) of the miscarriage samples, broadly supporting the ‘approximately 50%’ statement. This is a study of its own samples, not a review reporting a pooled prevalence; our copy does not report 49.7% or the stated 95% confidence interval. (LLM, conf=0.89)

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Miscarriages following assisted reproductive treatment have rates of cytogenetic anomalies similar to sporadic miscarriages (56.8% versus 53.6%; OR 1.11, 95% CI 0.71-1.73).

“A study has shown that miscarriages following assisted reproductive treatment have rates of cytogenetic anomalies similar to sporadic miscarriages (56.8% versus 53.6%; OR 1.11, 95% CI 0.71-1.73).52”

• cites [52] 52. Zhu X, Li J, Zhu Y, Wang W, Wu X, Yang Y, et al. Application of chromosomal microarray analysis in products of miscarriage. Mol Cytogenet. 2018;11:44. sourcePartly supported

  The Results (Genetic findings in subgroups) find no significant difference between assisted-reproduction and natural-conception samples, with an adjusted OR of 1.110 (95% CI 0.713–1.726). But the claim reverses the rates: 56.8% is for natural conception and 53.6% for assisted reproduction. The paper calls the comparator natural conception, not sporadic miscarriage. (LLM, conf=0.90)

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Among fetal chromosome anomalies in sporadic miscarriage, in descending order of frequency were trisomy (51.9%), polyploidy (18.8%), monosomy (15.2%), structural anomalies (6.5%), and others (7.6%).

“Among those with anomalies, in descending order of frequency were: trisomy (51.9%); polyploidy (18.8%); monosomy (15.2%); structural anomalies (6.5%); and others (7.6%).52”

• cites [52] 52. Zhu X, Li J, Zhu Y, Wang W, Wu X, Yang Y, et al. Application of chromosomal microarray analysis in products of miscarriage. Mol Cytogenet. 2018;11:44. sourcePartly supported

  The Results, ‘Subject features and general findings’ (page unavailable), support trisomies as prominent among the abnormalities, but do not report the claimed distribution. They report 224 abnormal samples, including 77.2% single aneuploidies and 7.1% CNVs; Table 2 lists 13 straightforward triploidies, not polyploidy at 18.8%. The cited paper therefore does not support the five percentages attributed to it for sporadic miscarriage. (LLM, conf=0.84)

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The risk of sporadic second trimester miscarriage was not significantly increased in women with didelphys (RR 1.71, 95% CI 0.63-4.59) and unicornuate uteri (RR 2.27, 95% CI 0.64-7.96) versus normal controls.

“The risk of sporadic second trimester miscarriage was not significantly increased in women with didelphys (RR 1.71, 95% CI 0.63-4.59;four studies) and unicornuate uteri (RR 2.27, 95% CI 0.64-7.96;four studies) versus normal controls.62”

• cites [62] 62. Venetis CA, Papadopoulos SP, Campo R, Gordts S, Tarlatzis BC, Grimbizis GF. Clinical implications of congenital uterine anoma- lies: a meta-analysis of comparative studies. Reprod Biomed Online. 2014;29(6):665-83. sourceSupported

In a large meta-analysis of a general obstetric population, no increase in risk of miscarriage was found in women with myomas (11.5% versus 8.0%; RR 1.16, 95% CI 0.80-1.52).

“In a large meta-analysis of a general obstetric population, including 1394 women with myomas and 20 435 without, no increase in risk of miscarriage was found (11.5% versus 8.0%; RR 1.16, 95% CI 0.80-1.52).67”

• cites [67] 67. Sundermann AC, Velez Edwards DR, Bray MJ, Jones SH, Latham SM, Hartmann KE. Leiomyomas in Pregnancy and Spontaneous Abortion: A Systematic Review and Meta-analysis. Obstet Gynecol. 2017;130(5):1065-72. sourceSupported

The commonest congenital uterine anomalies across all populations appear to be canalisation defects (septate) followed by unification defects (bicornuate and unicornuate).

“The commonest anomalies across all populations appear to be the canalisation defects (i.e. the septate variety) followed by the unification defects (i.e. the bicornuate and unicornuate variety).61”

• cites [61] 61. Chan YY, Jayaprakasan K, Zamora J, Thornton JG, Raine-Fenning N, Coomarasamy A. The prevalence of congenital uterine anom- alies in unselected and high-risk populations: a systematic review. Hum Reprod Update. 2011;17(6):761-71. sourcePartly supported

  The Conclusion says canalization defects are the most common anomaly in the high-risk groups, but the arcuate uterus is most prevalent in the unselected population. The Discussion (Distribution of congenital uterine anomalies) also includes uterus didelphys among unification defects. Thus, the claimed ranking does not hold across all populations. (LLM, conf=0.88)

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In a population with recurrent miscarriage, the overall rate of subsequent miscarriage (first or second trimester) remained significantly increased 1.13 (1.06-1.22) compared with women with unexplained recurrent miscarriage.

“the overall rate of subsequent miscarriage (first or second trimester) remained significantly increased 1.13 (1.06-1.22)compared with women with unexplained recurrent miscarriage.62”

• cites [62] 62. Venetis CA, Papadopoulos SP, Campo R, Gordts S, Tarlatzis BC, Grimbizis GF. Clinical implications of congenital uterine anoma- lies: a meta-analysis of comparative studies. Reprod Biomed Online. 2014;29(6):665-83. sourcePartly supported

  Table 2 reports a significantly increased combined first- and second-trimester miscarriage risk in women with congenital uterine anomalies who had experienced recurrent miscarriages (RR 1.13, 95% CI 1.06–1.22). The study descriptions list comparison groups with recurrent miscarriage and a normal uterus, but do not establish that all comparison cases were unexplained. (LLM, conf=0.84)

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The risk of sporadic first trimester miscarriage was not significantly increased in women with arcuate (RR 1.22, 95% CI 0.87-1.72), didelphys (RR 1.13, 95% CI 0.45-2.86) and unicornuate uteri (RR 1.38, 95% CI 0.83-2.28) versus normal controls.

“a meta-analysis has shown that the risk of sporadic first trimester miscarriage was not significantly increased in women with arcuate (RR 1.22, 95% CI 0.87-1.72;six studies), didelphys (RR 1.13, 95% CI 0.45-2.86;four studies) and unicornuate uteri (RR 1.38, 95% CI 0.83-2.28;five studies) versus normal controls.62”

• cites [62] 62. Venetis CA, Papadopoulos SP, Campo R, Gordts S, Tarlatzis BC, Grimbizis GF. Clinical implications of congenital uterine anoma- lies: a meta-analysis of comparative studies. Reprod Biomed Online. 2014;29(6):665-83. sourceSupported

Causes of second trimester miscarriage appear to overlap with the causes of first trimester miscarriage on one end of the spectrum and causes of preterm birth on the other end.

“Causes of second trimester miscarriage appear to overlap with the causes of first trimester miscarriage on one end of the spectrum and causes of preterm birth on the other end of the spectrum.”

• cites [75] 75. Sneider K, Christiansen OB, Sundtoft IB, Langhoff-Roos J. Recurrence of second trimester miscarriage and extreme preterm delivery at 16-27 weeks of gestation with a focus on cervical insuf- ficiency and prophylactic cerclage. Acta Obstet Gynecol Scand. 2016;95(12):1383-90. sourceSupported

Women with intrauterine adhesions and endometrial thickness less than 5 mm have higher sporadic miscarriage rates versus women with endometrial thickness of more than 5 mm (50% versus 8.3%; P < 0.001).

“Small cohort studies have, however, suggested that women with intrauterine adhesions and endometrial thickness less than 5 mm have higher sporadic miscarriage rates versus women with endometrial thickness of more than 5 mm (50% versus 8.3%; P < 0.001).74”

• cites [74] 74. Baradwan S, Shafi D, Baradwan A, Bashir MS, Al-Jaroudi D. The effect of endometrial thickness on pregnancy outcome in patients with Asherman's syndrome post-hysteroscopic adhesiolysis. Int J Womens Health. 2018;10:77-82. sourcePartly supported

  The Results report miscarriages in 50% of pregnancies in group A versus 8.3% in group B (P<0.001). The Subjects and methods define group A as endometrial thickness ≤5 mm, not <5 mm, and the Results do not classify the miscarriages as sporadic. (LLM, conf=0.88)

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With newer molecular techniques a further 5-7% submicroscopic variants may also be detected.

“It is worth noting that with newer molecular techniques a further 5-7% submicroscopic variants may also be detected.52,54”

• cites [52] 52. Zhu X, Li J, Zhu Y, Wang W, Wu X, Yang Y, et al. Application of chromosomal microarray analysis in products of miscarriage. Mol Cytogenet. 2018;11:44. sourcePartly supported

  The Background (page unavailable) says chromosomal microarray analysis can detect submicroscopic copy-number variants and reports an additional 5.7–13% yield in karyotypically normal products of conception. That supports the possibility of further detection, but the cited range is not 5–7% and applies specifically to those specimens. The paper’s own 7.1% figure is a share of abnormal findings, not an additional detection rate for all specimens. (LLM, conf=0.85)

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• cites [54] 54. van den Berg MM, van Maarle MC, van Wely M, Goddijn M. Genetics of early miscarriage. Biochim Biophys Acta. 2012; 1822(12):1951-9. sourceNot checked — no full text of the source

All the latest classifications on uterine anomalies (ESHRE/ESGE, CUME and ASRM) consider the arcuate uterus to be a normal variant with no clinical implications.

“all the latest classifications on uterine anomalies (ESHRE/ European Society for Gynaecological Endoscopy [ESGE], Congenital Uterine Malformation by Experts [CUME] and ASRM) consider the arcuate uterus to be a normal variant with no clinical implications”

• cites [64] 64. Grimbizis GF, Gordts S, Di Spiezio SA, Brucker S, De Angelis C, Gergolet M, et al. The ESHRE/ESGE consensus on the classifica- tion of female genital tract congenital anomalies. Hum Reprod. 2013;28(8):2032-44. sourcePartly supported

  In “Definitions: uterine main classes and sub-classes,” the paper includes some small fundal indentations in the normal-uterus class U0. But it also places minor cavity deformities in U1c, and “Consensus development” says the clinical value of this variant needs further research—not that it has no clinical implications. This ESHRE/ESGE paper does not establish what CUME and ASRM classify. (LLM, conf=0.87)

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• cites [65] 65. Ludwin A, Martins WP, Nastri CO, Ludwin I, Coelho Neto MA, Leitao VM, et al. Congenital Uterine Malformation by Experts (CUME): better criteria for distinguishing between nor- mal/arcuate and septate uterus? Ultrasound Obstet Gynecol. 2018;51(1):101-9. sourceNot checked — no full text of the source
• cites [66] 66. Pfeifer SM, Attaran M, Goldstein J, Lindheim SR, Petrozza JC, Rackow BW, et al. ASRM mullerian anomalies classification 2021. Fertil Steril. 2021;116(5):1238-52. sourceNot checked — no full text of the source

Cervical insufficiency, along with infection and congenital uterine anomalies, appear to be main contributors of second trimester miscarriage.

“Cervical insufficiency, along with infection and congenital uterine anomalies appear to be main contributors of second trimester miscarriage.75”

• cites [75] 75. Sneider K, Christiansen OB, Sundtoft IB, Langhoff-Roos J. Recurrence of second trimester miscarriage and extreme preterm delivery at 16-27 weeks of gestation with a focus on cervical insuf- ficiency and prophylactic cerclage. Acta Obstet Gynecol Scand. 2016;95(12):1383-90. sourcePartly supported

  The Introduction (page unavailable) lists cervical insufficiency, congenital uterine anomalies and infection as conditions that may be associated with second-trimester miscarriage. It also lists fetal and placental anomalies and says the cause remains unexplained in at least 50% of cases; it does not establish the three named conditions as the main contributors. The Discussion (page unavailable) further describes infection’s causal role as inconclusive. (LLM, conf=0.86)

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A small randomised controlled trial of 48 women with recurrent miscarriage and hyperprolactinaemia showed significant differences in live birth between bromocriptine and no bromocriptine (85.7% versus 52.4% respectively, P < 0.05).

“A small randomised controlled trial (RCT) of 48 women with recurrent miscarriage and hyperprolactinaemia were randomised into bromocriptine versus no bromocriptine, showing significant differences in live birth (85.7% versus 52.4% respectively, P < 0.05).94”

• cites [94] 94. Hirahara F, Andoh N, Sawai K, Hirabuki T, Uemura T, Minaguchi H. Hyperprolactinemic recurrent miscarriage and results of random- ized bromocriptine treatment trials. Fertil Steril. 1998;70(2):246-52. sourcePartly supported

  The Selection of Subjects section reports that 48 women were randomized, but only 24 had hyperprolactinemia; the other 24 had occult hyperprolactinemia. The Randomized Bromocriptine Treatment Trials section reports the cited live-birth rates and P < .05, but those rates are among the 21 women who conceived in each group, not all 48 randomized women. (LLM, conf=0.88)

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The incidence of subclinical hypothyroidism (TSH more than 2.5 mIU/l) has been reported to be raised in a small observational study of women with recurrent miscarriage.

“the incidence of subclinical hypothyroidism (SCH) (on this occasion defined as TSH more than 2.5 mIU/l) has been reported to be raised in a small observational study of women with recurrent miscarriage, 85”

• cites [85] 85. Bernardi LA, Cohen RN, Stephenson MD. Impact of subclinical hy- pothyroidism in women with recurrent early pregnancy loss. Fertil Steril. 2013;100(5):1326-31. sourceSupported

The presence of thyroid antibodies is associated with an increased risk of recurrent miscarriage.

“Two systematic reviews and meta-analyses reported that the presence of thyroid antibodies was associated with an increased risk of recurrent miscarriage.87,88”

• cites [87] 87. van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2011;17(5):605-19. sourceNot checked — no full text of the source
• cites [88] 88. Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ. 2011;342:d2616. sourceSupported

Data from a meta-analysis on sporadic miscarriages suggests an association between subclinical hypothyroidism and miscarriage.

“while data from a meta-analysis on sporadic miscarriages also suggests an association.86”

• cites [86] 86. Zhang Y, Wang H, Pan X, Teng W, Shan Z. Patients with subclinical hypothyroidism before 20 weeks of pregnancy have a higher risk of miscarriage: A systematic review and meta-analysis. PloS one. 2017;12(4):e0175708. sourcePartly supported

  The Results (section 2; page not provided) report a significant association between untreated subclinical hypothyroidism and miscarriage (RR 1.90, 95% CI 1.59–2.27). The inclusion criteria define miscarriage as the outcome but do not restrict it to sporadic rather than recurrent miscarriage, so the ‘sporadic’ qualifier is not established by this paper. (LLM, conf=0.84)

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The presence of bacterial vaginosis in the first trimester of pregnancy has been reported as a risk factor for miscarriage and preterm birth.

“The presence of bacterial vaginosis in the first trimester of pregnancy has been reported as a risk factor for miscarriage and preterm birth.112”

• cites [112] 112. Hay PE, Lamont RF, Taylor-Robinson D, Morgan DJ, Ison C, Pearson J. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ. 1994;308(6924):295-8. sourcePartly supported

  The Abstract reports that bacterial vaginosis detected early in pregnancy was associated with preterm delivery and late miscarriage. However, the relevant analysis included women recruited before 16 weeks, rather than isolating the first trimester, and assessed late miscarriage (16–24 weeks), not miscarriage generally. (LLM, conf=0.86)

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A high quality meta-analysis of RCTs showed that the only treatment or treatment combination that led to a significant increase in the live birth rate in women with recurrent miscarriage and APS was aspirin with unfractionated heparin (UFH) infusion.

“A high quality meta-analysis of RCTs assessed pregnancy outcomes for women with recurrent miscarriage and APS who were treated with aspirin, steroids, intravenous globulin and heparin.It showed that the only treatment or treatment combination that lead to a significant increase in the live birth rate was aspirin with unfractionated heparin (UFH) infusion.163”

• cites [163] 163. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent mis- carriage for women with antiphospholipid antibody or lupus antico- agulant. Cochrane Database Syst Rev. 2005(2):CD002859, 2012. sourcePartly supported

  The Main results and Heparin sections report that, among the interventions examined, only unfractionated heparin combined with aspirin significantly reduced pregnancy loss compared with aspirin alone, supporting the live-birth finding. However, the paper does not describe UFH as an infusion, and its Main results say the quality of the included trials was not high. Page numbers are unavailable in our copy. (LLM, conf=0.85)

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Systematic screening and subsequent treatment for bacterial vaginosis in women with low-risk pregnancies showed no evidence of risk reduction of late miscarriage or spontaneous very preterm birth.

“The PREMEVA multicentre double-blind RCT of 84 530 pregnant women screened for bacterial vaginosis.Systematic screening and subsequent treatment for bacterial vaginosis in women with low-risk pregnancies showed no evidence of risk reduction of late miscarriage or spontaneous very preterm birth.152”

• cites [152] 152. Subtil D, Brabant G, Tilloy E, Devos P, Canis F, Fruchart A, et al. Early clindamycin for bacterial vaginosis in pregnancy (PREMEVA): a multicentre, double-blind, randomised controlled trial. Lancet. 2018;392(10160):2171-9. sourceSupported

A 2015 Bayesian network meta-analysis confirmed the findings on aspirin and UFH for recurrent miscarriage and APS.

“A 2015 Bayesian network meta-analysis also confirmed the above findings.165”

• cites [165] 165. Zhang T, Ye X, Zhu T, Xiao X, Liu Y, Wei X, et al. Antithrombotic Treatment for Recurrent Miscarriage: Bayesian Network Meta- Analysis and Systematic Review. Medicine (Baltimore). 2015; 94(45): e1732. sourceSupported

Studies on sporadic miscarriage have shown associations with smoking, alcohol and caffeine.

“Studies on sporadic miscarriage have shown associations with smoking, 25,158 alcohol 26,159 and caffeine.27,160,161”

• cites [25] 25. Nielsen A, Hannibal CG, Lindekilde BE, Tolstrup J, Frederiksen K, Munk C, et al. Maternal smoking predicts the risk of spontaneous abortion. Acta Obstet Gynecol Scand. 2006;85(9):1057-65. sourceNot checked — no full text of the source
• cites [158] 158. Mishra GD, Dobson AJ, Schofield MJ. Cigarette smoking, men- strual symptoms and miscarriage among young women. Aust N Z J Public Health. 2000;24(4):413-20. sourceNot checked — no full text of the source
• cites [26] 26. Kesmodel U, Wisborg K, Olsen SF, Henriksen TB, Secher NJ. Moderate alcohol intake in pregnancy and the risk of spontaneous abortion. Alcohol Alcohol. 2002;37(1):87-92. sourceNot checked — no full text of the source
• cites [159] 159. Harlap S, Shiono PH. Alcohol, smoking, and incidence of spon- taneous abortions in the first and second trimester. Lancet. 1980;2(8187):173-6. sourceNot checked — no full text of the source
• cites [27] 27. Chen LW, Wu Y, Neelakantan N, Chong MF, Pan A, van Dam RM. Maternal caffeine intake during pregnancy and risk of pregnancy loss: a categorical and dose-response meta-analysis of prospective studies. Public Health Nutr. 2016;19(7):1233-44. sourceSupported
• cites [160] 160. Weng X, Odouli R, Li DK. Maternal caffeine consumption during pregnancy and the risk of miscarriage: a prospective cohort study. Am J Obstet Gynecol. 2008;198(3):279:e1-8. sourceNot checked — no full text of the source
• cites [161] 161. Tolstrup JS, Kjaer SK, Munk C, Madsen LB, Ottesen B, Bergholt T, et al. Does caffeine and alcohol intake before pregnancy pre- dict the occurrence of spontaneous abortion? Hum Reprod. 2003;18(12):2704-10. sourceSupported

Meta-analyses have reported a significant association between thyroid peroxidase (TPO) antibodies, thyroid dysfunction and recurrent miscarriage.

“Meta-analyses have reported a significant association between TPO antibodies, thyroid dysfunction and recurrent miscarriage.87,88”

• cites [87] 87. van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2011;17(5):605-19. sourceNot checked — no full text of the source
• cites [88] 88. Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ. 2011;342:d2616. sourcePartly supported

  The Results (Thyroid autoantibodies and miscarriage; page not available) report a significant overall association, and all included studies tested for TPO antibodies. But the recurrent-miscarriage subgroup did not reach statistical significance (P=0.06). The Discussion (Association of thyroid autoantibodies with adverse pregnancy outcomes; page not available) describes the finding in women with normal thyroid function, so it does not establish the claimed association with thyroid dysfunction. (LLM, conf=0.90)

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Prospective observational studies have suggested a higher subsequent miscarriage rate in women with recurrent miscarriage and untreated chronic endometritis versus no endometritis or treated endometritis.

“Prospective observational studies have suggested a higher subsequent miscarriage rate in women with recurrent miscarriage and untreated chronic endometritis versus no endometritis or treated endometritis, 153,154 however welldesigned prospective RCTs are lacking.”

• cites [153] 153. McQueen DB, Perfetto CO, Hazard FK, Lathi RB. Pregnancy out- comes in women with chronic endometritis and recurrent preg- nancy loss. Fertil Steril. 2015;104(4):927-31. sourceNot checked — no full text of the source
• cites [154] 154. Cicinelli E, Matteo M, Tinelli R, Pinto V, Marinaccio M, Indraccolo U, et al. Chronic endometritis due to common bacteria is prev- alent in women with recurrent miscarriage as confirmed by im- proved pregnancy outcome after antibiotic treatment. Reprod Sci. 2014;21(5):640-7. sourcePartly supported

  The Results (page not specified) report more successful pregnancies after antibiotics when chronic endometritis resolved than when it persisted, supporting an association with better reproductive outcomes. But the Abstract describes a retrospective analysis, and the Results compare treated women whose endometritis resolved or persisted—not untreated women or women without endometritis. They do not establish the claimed higher subsequent miscarriage rate. (LLM, conf=0.88)

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There are no adverse fetal outcomes reported in the meta-analysis of RCTs of low dose aspirin for the prevention of pre-eclampsia in pregnancy.

“There are no adverse fetal outcomes reported in the metaanalysis of RCTs of low dose aspirin for the prevention of pre-eclampsia in pregnancy.169”

• cites [169] sourcePartly supported

  The Authors’ conclusions (in the Background passage; page unavailable) report fewer fetal or neonatal deaths and fewer small-for-gestational-age babies with low-dose aspirin. The review also reports no clear increase in neonatal bleeding, but it does report and assess adverse fetal outcomes rather than finding that none occurred. The claim is supported if it means no increased fetal harm was identified, but its unqualified wording overstates the findings. (LLM, conf=0.84)

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Aspirin plus unfractionated heparin significantly reduced the miscarriage rate by 54% compared with aspirin alone (RR 0.46, 95% CI 0.29-0.71).

“This treatment combination significantly reduced the miscarriage rate by 54% (aspirin plus UFH versus aspirin alone RR 0.46, 95% CI 0.29-0.71).”

• cites [163] 163. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent mis- carriage for women with antiphospholipid antibody or lupus antico- agulant. Cochrane Database Syst Rev. 2005(2):CD002859, 2012. sourceSupported

A meta-analysis of prospectively collected data in a recurrent miscarriage population has shown an association between BMI and subsequent miscarriage.

“A meta-analysis of prospectively collected data in a recurrent miscarriage has shown an association between BMI and subsequent miscarriage.31,157”

• cites [31] 31. Ng KYB, Cherian G, Kermack AJ, Bailey S, Macklon N, Sunkara SK, et al. Systematic review and meta-analysis of female lifestyle factors and risk of recurrent pregnancy loss. Sci Rep. 2021;11(1):7081. sourcePartly supported

  The Results (Overweight and obesity; page unavailable) report a meta-analysis finding higher odds of a further miscarriage among women with recurrent pregnancy loss and BMI > 25 or > 30. The paper describes the included studies as observational but does not establish that the data were prospectively collected. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [157] 157. Metwally M, Saravelos SH, Ledger WL, Li TC. Body mass index and risk of miscarriage in women with recurrent miscarriage. Fertil Steril. 2010;94(1):290-5. sourceNot checked — no full text of the source

There were insufficient data to perform a subgroup analysis of women with recurrent miscarriage, TPO antibodies and SCH in the TABLET study.

“However, there were insufficient data to perform a subgroup analysis of women with recurrent miscarriage, TPO antibodies and SCH.192”

• cites [192] 192. Dhillon-Smith RK, Middleton LJ, Sunner KK, Cheed V, Baker K, Farrell- Carver S, et al. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. N Engl J Med. 2019;380(14):1316-25. sourceCould not verify

  Statistical Analysis (p. 5) describes separate subgroup analyses by number of previous miscarriages and baseline thyrotropin concentration. Neither that passage nor the Outcomes table (p. 9) says there were insufficient data for a combined subgroup of women with recurrent miscarriage, TPO antibodies, and subclinical hypothyroidism; searches for that subgroup and for subclinical hypothyroidism found no such statement. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

A case-control trial involving 89 couples who underwent genetic counselling demonstrated similar cumulative live birth rates between those attempting natural conception (67.6%) and those undergoing IVF/ICSI and PGD (65.4%).

“A case-control trial involving 89 couples who underwent genetic counselling (of which 52 elected to attempt natural conception and 37 chose to undergo IVF/ICSI and PGD) demonstrated similar cumulative live birth rates (67.6% and 65.4%, respectively) between the two groups.”

• cites [182] 182. Ikuma S, Sato T, Sugiura-Ogasawara M, Nagayoshi M, Tanaka A, Takeda S. Preimplantation Genetic Diagnosis and Natural Conception: A Comparison of Live Birth Rates in Patients with Recurrent Pregnancy Loss Associated with Translocation. PloS one. 2015;10(6):e0129958. 183. 104. Iews M, Tan J, Taskin O, Alfaraj S, AbdelHafez FF, Abdellah AH, et al. Does preimplantation genetic diagnosis improve reproductive outcome in couples with recurrent pregnancy loss owing to struc- tural chromosomal rearrangement? A systematic review Reprod Biomed Online. 2018;36(6):677-85. sourcePartly supported

  The Abstract (Methods and Findings) confirms that 52 patients chose natural conception and 37 chose PGD after genetic counseling. Table 4 in the Results reports similar cumulative live birth rates, but the citing sentence reverses them: 67.6% was for PGD and 65.4% for natural conception. (LLM, conf=0.94)

  Experimental — accuracy not yet measured

The RCTs included in the meta-analyses of progestogen supplementation differ.

“Caution should be exercised when interpreting the results of these meta-analyses due to differences in the RCTs included in the analyses.199,200”

• cites [199] sourcePartly supported

  The Discussion (p. 7) describes methodological differences among trials pooled in a Cochrane analysis: only two of four used a placebo. It does not compare the sets of RCTs included in different meta-analyses, so it does not establish the stated reason for caution about those analyses. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [200] 200. Kumar A, Begum N, Prasad S, Aggarwal S, Sharma S. Oral dydro- gesterone 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(5):1357-63 e3. sourceNot checked — no full text of the source

In the updated meta-analysis, subgroup analysis did not show significant differences between women with three or more versus two or more prior miscarriages.

“A subgroup analysis on this occasion did not show significant differences between women with three or more versus two or more prior miscarriages.198”

• cites [198] 198. Haas DM, Hathaway TJ, Ramsey PS. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiol- ogy. Cochrane Database Syst Rev. 2019;11:CD003511. 199. 105. Coomarasamy A, Williams H, Truchanowicz E, Seed PT, Small R, Quenby S, et al. A Randomized Trial of Progesterone in Women with Recurrent Miscarriages. N Engl J Med. 2015;373(22):2141-8. sourceSupported

A 2018 Cochrane meta-analysis reported that progestogen supplementation compared with placebo/controls reduces the number of miscarriages (RR 0.69, 95% CI 0.51-0.92; 11 trials, 2359 women; moderate-quality evidence).

“A meta-analysis of the Cochrane collaboration in 2018 reported a reduction in the number of miscarriages for women given progestogen supplementation compared with placebo/ controls (RR 0.69, 95% CI 0.51-0.92,11 trials, 2359 women, moderate-quality evidence)”

• cites [196] 196. Haas DM, Hathaway TJ, Ramsey PS. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiol- ogy. Cochrane Database Syst Rev. 2018;10:CD003511. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Another observational trial has shown miscarriage rates to be similar in hypothyroid women receiving thyroxine and euthyroid women with TPO antibodies receiving thyroxine.

“Another observational trial has shown miscarriage rates to be similar in hypothyroid women receiving thyroxine and euthyroid women with TPO antibodies receiving thyroxine.194”

• cites [194] 194. Lata K, Dutta P, Sridhar S, Rohilla M, Srinivasan A, Prashad GR, et al. Thyroid autoimmunity and obstetric outcomes in women with recurrent miscarriage: a case-control study. Endocr Connect. 2013;2(2):118-24. sourceSupported

The updated meta-analysis concluded that there may still be a reduction in the number of miscarriages for women given progestogen supplementation compared with placebo/controls (RR 0.73, 95% CI 0.54-1.00; ten trials, 1684 women; moderate-quality evidence).

“The updated meta-analysis concluded that there may still be a reduction in the number of miscarriages for women given progestogen supplementation compared with placebo/controls (RR 0.73, 95% CI 0.54-1.00,ten trials, 1684 women, moderate-quality evidence)”

• cites [198] 198. Haas DM, Hathaway TJ, Ramsey PS. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiol- ogy. Cochrane Database Syst Rev. 2019;11:CD003511. 199. 105. Coomarasamy A, Williams H, Truchanowicz E, Seed PT, Small R, Quenby S, et al. A Randomized Trial of Progesterone in Women with Recurrent Miscarriages. N Engl J Med. 2015;373(22):2141-8. sourceSupported

Extrapolated data from the Cochrane review of women undergoing hysteroscopic myomectomy prior to assisted reproduction did not find a significant reduction in miscarriage rates compared with expectant management (OR 1.54, 95% CI 0.47-5.00; P = 0.47, 94 women; very low quality evidence).

“However, extrapolated data from the Cochrane review of women undergoing hysteroscopic myomectomy prior to assisted reproduction did not find a significant reduction in miscarriage rates compared with expectant management (OR 1.54, 95% CI 0.47-5.00;P = 0.47, 94 women; very lowquality evidence).190”

• cites [190] 190. Bosteels J, van Wessel S, Weyers S, Broekmans FJ, D'Hooghe TM, Bongers MY, et al. Hysteroscopy for treating subfertility associ- ated with suspected major uterine cavity abnormalities. Cochrane Database Syst Rev. 2018;12:CD009461. sourcePartly supported

  The review’s “Adverse events: miscarriage” section reports the stated odds ratio, confidence interval, P value and sample size, and finds insufficient evidence of a difference from expectant management. Its “Quality of the evidence” section grades the myomectomy trial as very low quality. However, the reported comparison concerns women with otherwise unexplained subfertility and a submucous fibroid; the review does not describe these 94 women as undergoing myomectomy prior to assisted reproduction. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

One RCT found that hysteroscopic septum resection did not improve the reproductive outcomes of women with a septate uterus.

“The trial found that hysteroscopic septum resection did not improve the reproductive outcomes of women with a septate uterus.186”

• cites [186] 186. Rikken JFW, Kowalik CR, Emanuel MH, Bongers MY, Spinder T, Jansen FW, et al. Septum resection versus expectant management in women with a septate uterus: an international multicentre open- label randomized controlled trial. Hum Reprod. 2021;36(5):1260-7. sourceSupported

Meta-analyses have shown no significant benefit of immunotherapy (e.g., paternal cell immunisation, third-party donor leucocytes, trophoblast membranes, IVIg) over placebo in preventing further miscarriage in women with unexplained recurrent miscarriage.

“A Cochrane systematic review and meta-analysis has shown that the use of various forms of immunotherapy, including paternal cell immunisation, third-party donor leucocytes, trophoblast membranes and IVIg, in women with unexplained recurrent miscarriage provides no significant beneficial effect over placebo in preventing further miscarriage.203”

• cites [203] 203. Wong LF, Porter TF, Scott JR. Immunotherapy for recurrent mis- carriage. Cochrane Database Syst Rev. 2014;2014(10):CD000112. sourceSupported

The prognosis for a successful future pregnancy with supportive care alone in women with unexplained recurrent miscarriage is in the region of 75%.

“These women and their partners can be reassured that the prognosis for a successful future pregnancy with supportive care alone is in the region of 75%.20,21”

• cites [20] 20. Brigham SA, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod. 1999;14(11):2868-71. sourceNot checked — no full text of the source
• cites [21] 21. Clifford K, Rai R, Regan L. Future pregnancy outcome in un- explained recurrent first trimester miscarriage. Hum Reprod. 1997;12(2):387-9. sourceSupported

Several observational studies have suggested that attendance at a dedicated early pregnancy clinic has a beneficial effect on pregnancy outcomes.

“However, data from several non-randomised studies have suggested that attendance at a dedicated early pregnancy clinic has a beneficial effect, 20,21,208,209”

• cites [20] 20. Brigham SA, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod. 1999;14(11):2868-71. sourceNot checked — no full text of the source
• cites [21] 21. Clifford K, Rai R, Regan L. Future pregnancy outcome in un- explained recurrent first trimester miscarriage. Hum Reprod. 1997;12(2):387-9. sourceSupported
• cites [208] 208. Liddell HS, Pattison NS, Zanderigo A. Recurrent miscarriage-- outcome after supportive care in early pregnancy. Aust N Z J Obstet Gynaecol. 1991;31(4):320-2, Recurrent Miscarriage -Outcome After Supportive Care in Early Pregnancy. sourceNot checked — no full text of the source

RCTs and meta-analyses in the IVF/ICSI context have failed to show a reduction in miscarriage rates with endometrial scratch/injury.

“although to date RCTs and meta-analyses in this patient group have failed to show a reduction in miscarriage rates.205,206”

• cites [205] 205. Nastri CO, Lensen SF, Gibreel A, Raine-Fenning N, Ferriani RA, Bhattacharya S, Martins W Endometrial injury in women undergo- ing assisted reproductive techniques. Cochrane Database Syst Rev. 2015;3:CD009517. sourceSupported
• cites [206] 206. Lensen S, Osavlyuk D, Armstrong S, Stadelmann C, Hennes A, Napier E, et al. A Randomized Trial of Endometrial Scratching be- fore In Vitro Fertilization. N Engl J Med. 2019;380(4):325-34. sourceSupported

An association of miscarriage with anxiety, depression, post-traumatic stress disorder, and suicide has been shown.

“as an association of miscarriage with anxiety, depression, post-traumatic stress disorder, and suicide has been shown.11”

• cites [11] 11. Coomarasamy A, Gallos ID, Papadopoulou A, Dhillon-Smith RK, Al-Memar M, Brewin J, et al. Sporadic miscarriage: evidence to pro- vide effective care. Lancet. 2021;397(10285):1668-74. sourcePartly supported

  The Summary (p. 3) describes miscarriage’s psychological impact and says diagnostic delays can increase anxiety. A cited study’s title in the references (p. 23) mentions posttraumatic stress and depression following miscarriage, but this paper’s retrieved passages do not report those associations as findings or address suicide. The full four-outcome claim is therefore not supported by our copy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

A review and critical evaluation of the PROMISE and PRISM trials concluded that women with a history of miscarriage who present with bleeding in early pregnancy may benefit from progesterone.

“A review and critical evaluation of the PROMISE and PRISM trials concluded that women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of progesterone.19”

• cites [19] 19. Coomarasamy A, Devall AJ, Brosens JJ, Quenby S, Stephenson MD, Sierra S, et al. Micronized vaginal progesterone to prevent miscar- riage: a critical evaluation of randomized evidence. Am J Obstet Gynecol. 2020;223(2):167-76. sourceSupported

Unlike sporadic miscarriage, recurrent miscarriage tends to occur even if the fetus has no chromosomal anomalies.

“iii) unlike sporadic miscarriage, recurrent miscarriage tends to occur even if the fetus has no chromosomal anomalies.5”

• cites [5] 5. Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368(9535): 601-11. sourceNot checked — no full text of the source

Recurrent miscarriage is a distinct clinical entity rather than just three incidental sporadic miscarriages occurring by chance.

“Several features suggest that recurrent miscarriage is a distinct clinical entity rather than just three incidental sporadic miscarriages occurring by chance:”

• cites [5] 5. Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368(9535): 601-11. sourceNot checked — no full text of the source

Sporadic miscarriage is often the result of random fetal chromosomal anomalies.

“Sporadic miscarriage (occurring most commonly in the first trimester) is often the result of random fetal chromosomal anomalies.1,2”

• cites [1] 1. Greenwold N, Jauniaux E. Collection of villous tissue under ultra- sound guidance to improve the cytogenetic study of early pregnancy failure. Hum Reprod. 2002;17(2):452-6. sourceNot checked — no full text of the source
• cites [2] 2. Saravelos SH, Li TC. Unexplained recurrent miscarriage: how can we explain it? Hum Reprod. 2012;27(7):1882-6. sourceNot checked — no full text of the source

A woman's risk of miscarriage is directly related to the outcomes of previous pregnancies.

“i) a woman's risk of miscarriage is directly related to the outcomes of previous pregnancies”

• cites [5] 5. Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368(9535): 601-11. sourceNot checked — no full text of the source

The average observed incidence of recurrent miscarriage is higher than what would be expected by chance alone.

“ii) the average observed incidence of recurrent miscarriage is higher than what would be expected by chance alone”

• cites [5] 5. Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368(9535): 601-11. sourceNot checked — no full text of the source

The greatest determinant of the incidence of recurrent miscarriage is age.

“Overall, the greatest determinant of the incidence of recurrent miscarriage is age, 7”

• cites [7] 7. Saravelos SH, Regan L. Unexplained recurrent pregnancy loss. Obstet Gynecol Clin North Am. 2014;41(1):157-66. sourceNot checked — no full text of the source

The number of previous miscarriages affects the chance of a live birth across all age groups.

“while the number of previous miscarriages affects the chance of a live birth across all age groups.8”

• cites [8] 8. Kolte AM, Westergaard D, Lidegaard O, Brunak S, Nielsen HS. Chance of live birth: a nationwide, registry-based cohort study. Hum Reprod. 2021;36(4):1065-73. sourceNot checked — no full text of the source

An observational database study found an increased risk of spontaneous miscarriage in the first trimester for women consuming five or more alcoholic drinks/week (approximately 10 units/week).

“An observational database study found an increased risk of spontaneous miscarriage in the first trimester for women consuming five or more alcoholic drinks/week (approximately 10 units/week).26”

• cites [26] 26. Kesmodel U, Wisborg K, Olsen SF, Henriksen TB, Secher NJ. Moderate alcohol intake in pregnancy and the risk of spontaneous abortion. Alcohol Alcohol. 2002;37(1):87-92. sourceNot checked — no full text of the source

The lack of laboratory standardisation of clinical assays of other aPL may lead to confusion and overdiagnosis of APS.

“In addition, the lack of laboratory standardisation of these clinical assays may lead to confusion and overdiagnosis of APS.”

The magnitude of the association between inherited thrombophilias and fetal loss varies according to the type of thrombophilia, timing of fetal loss, maternal ethnicity and maternal age.

“Meta-analyses of pooled data suggest that the magnitude of the association between inherited thrombophilias and fetal loss varies according to the type of thrombophilia, timing of fetal loss, maternal ethnicity and maternal age.”

• cites [41] 41. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361(9361):901-8. sourceNot checked — no full text of the source
• cites [42] 42. Gao H, Tao FB. Prothrombin G20210A mutation is associated with recurrent pregnancy loss: a systematic review and meta-analysis up- date. Thromb Res. 2015;135(2):339-46. sourceNot checked — no full text of the source

The association between environmental risk factors (such as air pollution and household chemicals) and pregnancy loss is based mainly on women with sporadic rather than recurrent miscarriage.

“The association between environmental risk factors (such as air pollution and household chemicals) and pregnancy loss is based mainly on women with sporadic rather than recurrent miscarriage.32”

• cites [32] 32. Gaskins AJ, Hart JE, Chavarro JE, Missmer SA, Rich-Edwards JW, Laden F, et al. Air pollution exposure and risk of sponta- neous abortion in the Nurses' Health Study II. Hum Reprod. 2019;34(9):1809-17. sourceNot checked — no full text of the source

Observational studies have reported that obesity increases the risk of sporadic miscarriage.

“Observational studies have reported that obesity increases the risk of sporadic miscarriage.[28][29][30]”

• cites [28] 28. Lashen H, Fear K, Sturdee DW. Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case- control study. Hum Reprod. 2004;19(7):1644-6. sourceNot checked — no full text of the source
• cites [29] 29. Metwally M, Ledger WL, Li TC. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence. Fertil Steril. 2008;90(3):714-26. sourceNot checked — no full text of the source
• cites [30] 30. Metwally M, Saravelos SH, Ledger WL, Li TC. Body mass index and risk of miscarriage in women with recurrent miscarriage. Fertil Steril. 2010;94(1):290-5. sourceNot checked — no full text of the source

Observational studies have not demonstrated an association between consanguinity and recurrent miscarriage.

“Observational studies have not demonstrated an association between consanguinity and recurrent miscarriage.23,24”

• cites [23] 23. Gowri V, Udayakumar AM, Bsiso W, Al Farsi Y, Rao K. Recurrent early pregnancy loss and consanguinity in Omani couples. Acta Obstet Gynecol Scand. 2011;90(10):1167-9. sourceNot checked — no full text of the source
• cites [24] 24. Saad FA, Jauniaux E. Recurrent early pregnancy loss and consan- guinity. Reprod Biomed Online. 2002;5(2):167-70. sourceNot checked — no full text of the source

Inherited thrombophilias have a weak association with recurrent miscarriage.

“Inherited thrombophilias have a weak association with recurrent miscarriage.”

• Also stated in: § Inherited thrombophilias · plain

  “There is a weak association with recurrent miscarriage.”

Smoking has been shown to increase the risk of sporadic miscarriage.

“Smoking has been shown to increase the risk of sporadic miscarriage.25”

• cites [25] 25. Nielsen A, Hannibal CG, Lindekilde BE, Tolstrup J, Frederiksen K, Munk C, et al. Maternal smoking predicts the risk of spontaneous abortion. Acta Obstet Gynecol Scand. 2006;85(9):1057-65. sourceNot checked — no full text of the source

IgG and IgM anticardiolipin antibodies were found to have the second strongest association with recurrent miscarriage, with odds ratios of 3.57 (95% CI 2.26-5.65) and 5.61 (95% CI 1.26-25.03) respectively.

“IgG and IgM aCL antibodies were found to have the second strongest association with recurrent miscarriage, with odds ratios of 3.57 (95% CI 2.26-5.65)and 5.61 (95% CI 1.26-25.03)respectively.”

• cites [39] 39. Opatrny L, David M, Kahn SR, Shrier I, Rey E. Association be- tween antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis. J Rheumatol. 2006;33(11):2214-21.Not checked — no full text of the source

There is a stronger and more consistent association between second trimester miscarriages and inherited thrombophilias.

“It is generally recognised that there is a stronger and more consistent association between second trimester miscarriages and inherited thrombophilias.41,42”

• cites [41] 41. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361(9361):901-8. sourceNot checked — no full text of the source
• cites [42] 42. Gao H, Tao FB. Prothrombin G20210A mutation is associated with recurrent pregnancy loss: a systematic review and meta-analysis up- date. Thromb Res. 2015;135(2):339-46. sourceNot checked — no full text of the source

Factor V Leiden appears to be associated with first and particularly second trimester recurrent miscarriages.

“Factor V Leiden appears to be associated with first and particularly second trimester recurrent miscarriages.41,43”

• cites [41] 41. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361(9361):901-8. sourceNot checked — no full text of the source
• cites [43] 43. Bradley LA, Palomaki GE, Bienstock J, Varga E, Scott JA. Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy out- comes?: Results from a targeted evidence-based review. Genet Med. 2012;14(1):39-50. sourceNot checked — no full text of the source

Lupus anticoagulant was found to have the strongest association with recurrent miscarriage (OR 7.79; 95% CI 2.30-26.45).

“Lupus anticoagulant was found to have the strongest association with recurrent miscarriage (OR 7.79; 95% CI 2.30-26.45).”

• cites [39] 39. Opatrny L, David M, Kahn SR, Shrier I, Rey E. Association be- tween antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis. J Rheumatol. 2006;33(11):2214-21.Not checked — no full text of the source

Prothrombin gene mutation is associated with recurrent miscarriage.

“Prothrombin gene mutation is associated with recurrent miscarriage.[41][42][43]”

• cites [41] 41. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361(9361):901-8. sourceNot checked — no full text of the source
• cites [42] 42. Gao H, Tao FB. Prothrombin G20210A mutation is associated with recurrent pregnancy loss: a systematic review and meta-analysis up- date. Thromb Res. 2015;135(2):339-46. sourceNot checked — no full text of the source
• cites [43] 43. Bradley LA, Palomaki GE, Bienstock J, Varga E, Scott JA. Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy out- comes?: Results from a targeted evidence-based review. Genet Med. 2012;14(1):39-50. sourceNot checked — no full text of the source

Protein C deficiency has not shown a consistent association with recurrent miscarriage.

“Protein C deficiency has not shown a consistent association with recurrent miscarriage.41,44”

• cites [41] 41. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361(9361):901-8. sourceNot checked — no full text of the source
• cites [44] 44. Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J, et al. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996;348(9032):913-6. sourceNot checked — no full text of the source

In a recurrent miscarriage population, women with submucosal and intramural/subserosal myomas had a higher proportion of second trimester miscarriages compared with women with unexplained recurrent miscarriage (21.7% and 17.6% versus 8.0% respectively; P < 0.01).

“women with submucosal and intramural/subserosal myomas were found to have a higher proportion of second trimester miscarriages compared with women with unexplained recurrent miscarriage (21.7% and 17.6% versus 8.0% respectively; P < 0.01).”

• cites [70] 70. Saravelos SH, Yan J, Rehmani H, Li TC. The prevalence and impact of fibroids and their treatment on the outcome of pregnancy in women with recurrent miscarriage. Hum Reprod. 2011;26(12):3274-9. sourceNot checked — no full text of the source

A large prospective study by Prior et al. (2018), using 3D ultrasound solely to diagnose the arcuate uterus, reported similar clinical pregnancy and live birth rates between arcuate and normal uteri.

“a large prospective study by Prior et al. (2018), using gold standard 3D ultrasound solely to diagnose the arcuate uterus (in contrast to the varying diagnostic modalities included in the studies of the meta-analysis), reported similar clinical pregnancy and live birth rates between arcuate and normal uteri.63”

• cites [63] 63. Prior M, Richardson A, Asif S, Polanski L, Parris-Larkin M, Chandler J, et al. Outcome of assisted reproduction in women with congenital uterine anomalies: a prospective observational study. Ultrasound Obstet Gynecol. 2018;51(1):110-7. sourceNot checked — no full text of the source

Embryoscopic studies have shown a further 18% of fetuses with missed miscarriages and a normal karyotype to have morphological defects.

“When examining missed miscarriages with a normal karyotype, embryoscopic studies have also shown a further 18% of fetuses to have morphological defects, 56”

• cites [56] 56. Philipp T, Philipp K, Reiner A, Beer F, Kalousek DK. Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed preg- nancies. Hum Reprod. 2003;18(8):1724-32. sourceNot checked — no full text of the source

Newer studies using microarray techniques have been reporting even higher number of cytogenetic anomalies in women with sporadic miscarriages of up to 59.4% (1106/2389).

“This may be reflected by the fact that newer studies using microarray techniques have been reporting even higher number of cytogenetic anomalies in women with sporadic miscarriages of up to 59.4% (1106/2389).55”

• cites [55] 55. Levy B, Sigurjonsson S, Pettersen B, Maisenbacher MK, Hall MP, Demko Z, et al. Genomic imbalance in products of conception: single-nucleotide polymorphism chromosomal microarray analy- sis. Obstet Gynecol. 2014;124(2 Pt 1):202-9. sourceNot checked — no full text of the source

Investigations have been reported to reveal a diagnosis in only approximately 50% of cases in dedicated clinics.

“Although investigations have been reported to reveal a diagnosis in only approximately 50% of cases in dedicated clinics, 76”

• cites [76] 76. McNamee KM, Dawood F, Farquharson RG. Mid-trimester preg- nancy loss. Obstet Gynecol Clin North Am. 2014;41(1):87-102. sourceNot checked — no full text of the source

A finding of an aneuploid embryo confers an improved prognosis in the subsequent pregnancy.

“Equally, a finding of an aneuploid embryo has been found to confer an improved prognosis in the subsequent pregnancy.58,59”

• cites [58] 58. Carp H, Toder V, Aviram A, Daniely M, Mashiach S, Barkai G. Karyotype of the abortus in recurrent miscarriage. Fertil Steril. 2001;75(4):678-82. sourceNot checked — no full text of the source
• cites [59] 59. Suzumori N, Sugiura-Ogasawara M. Genetic Factors as a Cause of Miscarriage. Curr Med Chem. 2010;17(29):3431-7. sourceNot checked — no full text of the source

• AssumptionThe authors state this as an assumption: The women are age adjusted when comparing prognosis after aneuploid versus euploid miscarriage.

Polycystic ovarian morphology, elevated serum luteinising hormone levels or elevated serum testosterone levels do not appear to predict an increased risk of future pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously.

“Polycystic ovarian morphology, elevated serum luteinising hormone levels or elevated serum testosterone levels do not appear to predict an increased risk of future pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously.90”

• cites [90] 90. Rai R, Backos M, Rushworth F, Regan L. Polycystic ovaries and re- current miscarriage--a reappraisal. Hum Reprod. 2000;15(3):612-5, Polycystic ovaries and recurrent miscarriage-a reappraisal. 14710528, 0, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17515, Wiley Online Library on [04/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License sourceNot checked — no full text of the source

The incidence of diabetes mellitus and thyroid dysfunction in women who suffer recurrent miscarriage appears similar to that reported in the general population.

“The incidence of diabetes mellitus and thyroid dysfunction in women who suffer recurrent miscarriage appears similar to that reported in the general population.83,84”

• cites [83] 83. Bussen S, Sutterlin M, Steck T. Endocrine abnormalities during the follicular phase in women with recurrent spontaneous abortion. Hum Reprod. 1999;14(1):18-20. sourceNot checked — no full text of the source
• cites [84] 84. Li TC, Spuijbroek MD, Tuckerman E, Anstie B, Loxley M, Laird S. Endocrinological and endometrial factors in recurrent miscarriage. BJOG. 2000;107(12):1471-9. sourceNot checked — no full text of the source

A meta-analysis in 2008 concluded that the available data are not consistent with more than modest associations between cytokine polymorphisms and recurrent miscarriage.

“A meta-analysis in 2008 concluded that the available data are not consistent with more than modest associations between cytokine polymorphisms and recurrent miscarriage.”

• cites [99] 99. Su D, Zhang Y, Wang Q, Wang J, Jiao B, Wang G, et al. Association of interleukin-10 gene promoter polymorphisms with recurrent mis- carriage: a meta-analysis. Am J Reprod Immunol. 2016;76(2):172-80. sourceNot checked — no full text of the source

Another study reported marginally lower prolactin levels in women with recurrent miscarriage who experienced a live birth versus those who miscarried.

“while another study reported marginally lower prolactin levels in women with recurrent miscarriage who experienced a live birth versus those who miscarried.93”

• cites [93] 93. Li W, Ma N, Laird SM, Ledger WL, Li TC. The relationship be- tween serum prolactin concentration and pregnancy outcome in women with unexplained recurrent miscarriage. Journal of obstet- rics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 2013;33(3):285-8. sourceNot checked — no full text of the source

An elevated free androgen index appears to be a prognostic factor for a subsequent miscarriage in women with recurrent miscarriage.

“An elevated free androgen index appears to be a prognostic factor for a subsequent miscarriage in women with recurrent miscarriage.89”

• cites [89] 89. Cocksedge KA, Li TC, Saravelos SH, Metwally M. A reappraisal of the role of polycystic ovary syndrome in recurrent miscarriage. Reprod Biomed Online. 2008;17(1):151-60. sourceNot checked — no full text of the source

An imbalance in Th1/Th2 cytokines has been implicated in adverse pregnancy outcomes including recurrent miscarriage.

“An imbalance in Th1/Th2 cytokines has been implicated in adverse pregnancy outcomes including recurrent miscarriage.97”

• cites [97] 97. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cy- tokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993;14(7):353-6. sourceNot checked — no full text of the source

Another study found no correlation between the presence of a luteal phase defect (midluteal progesterone less than 10 ng/ml) and the chance of subsequent miscarriage in 197 women with recurrent miscarriage.

“whereas another study found no correlation between the presence of a luteal phase defect (midluteal progesterone less than 10 ng/ml) and the chance of subsequent miscarriage in 197 women with recurrent miscarriage.95”

• cites [95] 95. Ogasawara M, Kajiura S, Katano K, Aoyama T, Aoki K. Are serum progesterone levels predictive of recurrent miscarriage in future pregnancies? Fertil Steril. 1997;68(5):806-9. sourceNot checked — no full text of the source

Research into the role of cytokines in recurrent miscarriage is hampered by fluctuating levels, discordance between blood and endometrial levels and laboratory variability in measurement.

“However, research into the role of cytokines in recurrent miscarriage is hampered by a number of factors including fluctuating levels, discordance between blood and endometrial levels and laboratory variability in measurement.98”

• cites [98] 98. Wang NF, Kolte AM, Larsen EC, Nielsen HS, Christiansen OB. Immunologic Abnormalities, Treatments, and Recurrent Pregnancy Loss: What Is Real and What Is Not? Clin Obstet Gynecol. 2016;59(3):509-23. sourceNot checked — no full text of the source

One study reported an increased level of prolactin in women with recurrent miscarriage versus controls.

“One study reported an increased level of prolactin in women with recurrent miscarriage versus controls, 83”

• cites [83] 83. Bussen S, Sutterlin M, Steck T. Endocrine abnormalities during the follicular phase in women with recurrent spontaneous abortion. Hum Reprod. 1999;14(1):18-20. sourceNot checked — no full text of the source

One study found a higher incidence of a luteal phase defect (midluteal progesterone less than 30 nmol/l) in women with recurrent miscarriage versus fertile controls (27% versus 11%).

“One study found a higher incidence of a luteal phase defect (midluteal progesterone less than 30 nmol/l) in women with recurrent miscarriage versus fertile controls (27% versus 11%), 84”

• cites [84] 84. Li TC, Spuijbroek MD, Tuckerman E, Anstie B, Loxley M, Laird S. Endocrinological and endometrial factors in recurrent miscarriage. BJOG. 2000;107(12):1471-9. sourceNot checked — no full text of the source

The data are more consistent for an association between abnormal sperm DNA parameters (sperm DNA fragmentation, nuclear chromatin decondensation, and sperm aneuploidy) and miscarriage.

“The data are more consistent with regard to the association between abnormal sperm DNA parameters such as sperm DNA fragmentation, nuclear chromatin decondensation, and sperm aneuploidy and miscarriage.”

When used in combination with routine investigations into recurrent miscarriage, cytogenetic analysis of the pregnancy tissue has been shown to provide a diagnosis in over 90% of couples.

“Other than the prognostic advantages, when used in combination with routine investigations into recurrent miscarriage, cytogenetic analysis of the pregnancy tissue have shown to provide a diagnosis in over 90% of couples.137”

• cites [137] 137. Popescu F, Jaslow CR, Kutteh WH. Recurrent pregnancy loss eval- uation combined with 24-chromosome microarray of miscarriage tissue provides a probable or definite cause of pregnancy loss in over 90% of patients. Hum Reprod. 2018;33(4):579-87. sourceNot checked — no full text of the source

Systematic review and meta-analyses have not found a persistent association between recurrent and/or second trimester miscarriage and protein C deficiency, antithrombin deficiency and methylenetetrahydrofolate reductase (MTHFR) mutation.

“Systematic review and meta-analyses have not found a persistent association between recurrent and/or second trimester miscarriage and protein C deficiency, antithrombin deficiency and methylenetetrahydrofolate reductase (MTHFR) mutation and therefore do not recommend testing.41,47,136”

• cites [41] 41. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361(9361):901-8. sourceNot checked — no full text of the source
• cites [47] 47. Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15(2):153-6. sourceNot checked — no full text of the source
• cites [136] 136. Pritchard AM, Hendrix PW, Paidas MJ. Hereditary Thrombophilia and Recurrent Pregnancy Loss. Clin Obstet Gynecol. 2016;59(3): 487-97. sourceNot checked — no full text of the source

The evidence for an association between bacterial vaginosis and first trimester miscarriage is inconsistent.

“However, the evidence for an association with first trimester miscarriage is inconsistent.114,115”

• cites [114] 114. Ralph SG, Rutherford AJ, Wilson JD. Influence of bacterial vagi- nosis on conception and miscarriage in the first trimester: cohort study. BMJ. 1999;319(7204):220-3. sourceNot checked — no full text of the source
• cites [115] 115. van Oostrum N, De Sutter P, Meys J, Verstraelen H. Risks associated with bacterial vaginosis in infertility patients: a systematic review and meta-analysis. Hum Reprod. 2013;28(7):1809-15. sourceNot checked — no full text of the source

In detection of lupus anticoagulant, the dilute Russell's viper venom time (dRVVT) test together with a platelet neutralisation procedure is more sensitive and specific than either the activated partial thromboplastin time (aPTT) or the kaolin clotting time (KCT) tests.

“In detection of lupus anticoagulant, the dilute Russell's viper venom time (dRVVT) test together with a platelet neutralisation procedure is more sensitive and specific than either the activated partial thromboplastin time (aPTT) or the kaolin clotting time (KCT) tests.133”

• cites [133] 133. Rai RS, Regan L, Clifford K, Pickering W, Dave M, Mackie I, et al. Antiphospholipid antibodies and beta 2-glycoprotein-I in 500 women with recurrent miscarriage: results of a comprehensive screening approach. Hum Reprod. 1995;10(8):2001-5. sourceNot checked — no full text of the source

When comparing different criteria for the diagnosis of the septate uterus, the incidence changes according to criteria used, with the highest incidences in descending order being from the ESHRE-ESGE to the CUME and ASRM classifications.

“When comparing different criteria for the diagnosis of the septate uterus it is clear that the incidence changes according to criteria used, 147 with the highest incidences in descending order being from the ESHRE-ESGE to the CUME and ASRM classifications.65”

• cites [147] 147. Ouyang Y, Yi Y, Gong F, Lin G, Li X. ESHRE-ESGE versus ASRM classification in the diagnosis of septate uterus: a retrospective study. Arch Gynecol Obstet. 2018;298(4):845-50. sourceNot checked — no full text of the source
• cites [65] 65. Ludwin A, Martins WP, Nastri CO, Ludwin I, Coelho Neto MA, Leitao VM, et al. Congenital Uterine Malformation by Experts (CUME): better criteria for distinguishing between nor- mal/arcuate and septate uterus? Ultrasound Obstet Gynecol. 2018;51(1):101-9. sourceNot checked — no full text of the source

Several studies reported that uterine NK cell density in the endometrium around the time of implantation was increased.

“Several studies reported that uterine NK cell density in the endometrium around the time of implantation was increased.[105][106][107]”

• cites [105] 105. Clifford K, Flanagan AM, Regan L. Endometrial CD56+ natural killer cells in women with recurrent miscarriage: a histomorpho- metric study. Hum Reprod. 1999;14(11):2727-30. sourceNot checked — no full text of the source
• cites [106] 106. Tuckerman E, Laird SM, Prakash A, Li TC. Prognostic value of the measurement of uterine natural killer cells in the endo- metrium of women with recurrent miscarriage. Hum Reprod. 2007;22(8):2208-13. 107. 100. Quenby S, Bates M, Doig T, Brewster J, Lewis-Jones DI, Johnson PM, et al. Pre-implantation endometrial leukocytes in women with re- current miscarriage. Hum Reprod. 1999;14(9):2386-91. sourceNot checked — no full text of the source
• cites [107] sourceNot checked — no full text of the source

A range of organisms, including ureaplasma/mycoplasma, bacterial vaginosis-associated organisms, and Chlamydia trachomatis, have been implicated in first and second trimester miscarriage.

“A whole range of organisms have been implicated in first and second trimester miscarriage, including ureaplasma/ mycoplasma, organisms causing bacterial vaginosis and chlamydia trachomatis.110”

• cites [110] 110. Check JH. A practical approach to the prevention of miscarriage. Part 4--role of infection. Clin Exp Obstet Gynecol. 2010;37(4):252-5.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Using morphometric analysis to measure plasma cell count, a study found that the incidence of chronic endometritis in women with recurrent miscarriage was 10.8%, twice higher than that of fertile women (5.0%).

“Using morphometric analysis to measure plasma cell count, a study found that the incidence of chronic endometritis in women with recurrent miscarriage was 10.8%, twice higher than that of fertile women (5.0%).117”

• cites [117] 117. Liu Y, Chen X, Huang J, Wang CC, Yu MY, Laird S, et al. Comparison of the prevalence of chronic endometritis as determined by means of different diagnostic methods in women with and without repro- ductive failure. Fertil Steril. 2018;109(5):832-9. sourceNot checked — no full text of the source

Limited studies are available evaluating interventions that may affect sperm DNA fragmentation such as lifestyle modification, treatment of infections, control of diabetes, treatment of varicocele, antioxidant therapy, and sperm selection.

“To date, however, limited studies are available evaluating interventions that may affect sperm DNA fragmentation such as lifestyle modification (smoking cessation, weight loss/exercise, reduction in pollutant exposure), treatment of infections, control of diabetes, treatment of varicocele, antioxidant therapy, sperm selection and others.”

The rates of anti-sperm antibodies have not been consistently shown to be increased in women and men with recurrent miscarriage.

“The rates of anti-sperm antibodies have not been consistently shown to be increased in women and men with recurrent miscarriage, with some studies showing a higher incidence, 124 while others have not.125”

• cites [124] 124. Motak-Pochrzest H, Malinowski A. The occurrence of immuno- logical disturbances in patients with recurrent miscarriage (RM) of unknown etiology. Neuro Endocrinol Lett. 2013;34(7):701-7.Not checked — no full text of the source
• cites [125] 125. Al-Hussein K, Al-Mukhalafi Z, Bertilsson PA, Jaroudi K, Shoukri M, Hollander J. Value of flow cytometric assay for the detection of antisperm antibodies in women with a history of recurrent abor- tion. Am J Reprod Immunol. 2002;47(1):31-7. sourceNot checked — no full text of the source

The prognostic value of uterine NK cell measurement remains unconfirmed.

“Nevertheless, the prognostic value of uterine NK cell measurement remains unconfirmed.106”

• cites [106] 106. Tuckerman E, Laird SM, Prakash A, Li TC. Prognostic value of the measurement of uterine natural killer cells in the endo- metrium of women with recurrent miscarriage. Hum Reprod. 2007;22(8):2208-13. 107. 100. Quenby S, Bates M, Doig T, Brewster J, Lewis-Jones DI, Johnson PM, et al. Pre-implantation endometrial leukocytes in women with re- current miscarriage. Hum Reprod. 1999;14(9):2386-91. sourceNot checked — no full text of the source

A meta-analysis in 2014 showed no significant difference in uterine NK cell density between women with recurrent miscarriage and controls (SMD 0.40; 95% CI 1.24-2.04; P = 0.63).

“A meta-analysis in 2014 showed no significant difference between women with recurrent miscarriage and controls (SMD 0.40; 95% CI 1.24-2.04;P = 0.63) 100”

• cites [100] 100. Seshadri S, Sunkara SK. Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis. Hum Reprod Update. 2014;20(3):429-38. sourceNot checked — no full text of the source

A systematic review and international consensus has reported that the most accurate methodologies for diagnosing congenital uterine anomalies in descending order of overall accuracy are: 3D ultrasound (97.6%, 95% CI 94.3-100), saline-infusion ultrasound (96.5%, 95% CI 93.4-99.5), hysterosalpingography (86.9%, 95% CI 79.8-94.0) and 2D ultrasound (86.6%, 95% CI 81.3-91.8).

“A systematic review and international consensus has reported that the most accurate methodologies for diagnosing congenital uterine anomalies in descending order of overall accuracy are: 3D ultrasound (97.6%, 95% CI 94.3-100), saline-infusion ultrasound (96.5%, 95% CI 93.4-99.5),hysterosalpingography (86.9%, 95% CI 79.8-94.0)and 2D ultrasound (86.6%, 95% CI 81.3-91.8).140”

• cites [140] 140. Grimbizis GF, Di Spiezio SA, Saravelos SH, Gordts S, Exacoustos C, Van Schoubroeck D, et al. The Thessaloniki ESHRE/ESGE con- sensus on diagnosis of female genital anomalies. Hum Reprod. 2016;31(1):2-7. sourceNot checked — no full text of the source

A meta-analysis showed a statistically significant increase in second trimester miscarriages with bacterial vaginosis (OR 6.32, 95% CI 3.65-10.94).

“A meta-analysis showed a statistically significant increase in second trimester miscarriages (OR 6.32, 95% CI 3.65-10.94).113”

• cites [113] 113. Leitich H, Kiss H. Asymptomatic bacterial vaginosis and interme- diate flora as risk factors for adverse pregnancy outcome. Best Pract Res Clin Obstet Gynaecol. 2007;21(3):375-90. sourceNot checked — no full text of the source

Comparative studies have shown MRI to be at least similar in accuracy compared with 3D ultrasound when expert examiners are used.

“There were no studies reporting on the use of magnetic resonance imaging (MRI) as a screening tool, however comparative studies have shown MRI to be at least similar in accuracy compared with 3D ultrasound when expert examiners are used (i.e. a radiologist with an interest/expertise in gynaecological imaging).141”

• cites [141] 141. Graupera B, Pascual MA, Hereter L, Browne JL, Ubeda B, Rodriguez I, et al. Accuracy of three-dimensional ultrasound compared with magnetic resonance imaging in diagnosis of Mullerian duct anom- alies using ESHRE-ESGE consensus on the classification of con- genital anomalies of the female genital tract. Ultrasound Obstet Gynecol. 2015;46(5):616-22. sourceNot checked — no full text of the source

The finding of lower sperm parameters in men with recurrent miscarriage has not been reproduced in other studies.

“However, this has not been reproduced in other studies.122,123”

• cites [122] 122. Bhattacharya SM. Association of various sperm parameters with unexplained repeated early pregnancy loss--which is most import- ant? Int Urol Nephrol. 2008;40(2):391-5. sourceNot checked — no full text of the source
• cites [123] 123. Hill JA, Abbott AF, Politch JA. Sperm morphology and recurrent abortion. Fertil Steril. 1994;61(4):776-8. sourceNot checked — no full text of the source

Screening women (and their male partners if applicable) for parental chromosome rearrangements does not appear to be cost-effective.

“Although screening women (and their male partners if applicable) for parental chromosome rearrangements does not appear to be cost-effective, 50 peripheral blood karyotyping of both parents should be offered in cases where the pregnancy tissue report an unbalanced structural chromosomal abnormality.”

• cites [50] 50. Barber JC, Cockwell AE, Grant E, Williams S, Dunn R, Ogilvie CM. Is karyotyping couples experiencing recurrent miscarriage worth the cost? BJOG. 2010;117(7):885-8. sourceNot checked — no full text of the source

Toxoplasmosis, rubella, cytomegalovirus, herpes simplex (TORCH) and listeria infections do not fulfil the criteria for an infective agent implicated in recurrent miscarriage.

“Toxoplasmosis, rubella, cytomegalovirus, herpes simplex (TORCH) and listeria infections do not fulfil these criteria and therefore routine TORCH screening should not be undertaken.111”

• cites [111] 111. Regan L, Jivraj S, editors. Infection and pregnancy loss. London: RCOG Press; 2001. sourceNot checked — no full text of the source

• AssumptionRests on an assumption: For an infective agent to be implicated in the aetiology of recurrent miscarriage, it must be capable of persisting in the genital tract and avoiding detection or must cause insufficient symptoms to disturb the woman.

The detection of antiphospholipid antibodies is subject to considerable inter-laboratory variation.

“The detection of aPL is subject to considerable inter-laboratory variation.134”

• cites [134] 134. Robert JM, Macara LM, Chalmers EA, Smith GC. Inter-assay varia- tion in antiphospholipid antibody testing. BJOG. 2002;109(3):348-9. sourceNot checked — no full text of the source

There were no studies reporting on the use of magnetic resonance imaging (MRI) as a screening tool for congenital uterine anomalies.

“There were no studies reporting on the use of magnetic resonance imaging (MRI) as a screening tool, however comparative studies have shown MRI to be at least similar in accuracy compared with 3D ultrasound when expert examiners are used (i.e. a radiologist with an interest/expertise in gynaecological imaging).141”

• cites [141] 141. Graupera B, Pascual MA, Hereter L, Browne JL, Ubeda B, Rodriguez I, et al. Accuracy of three-dimensional ultrasound compared with magnetic resonance imaging in diagnosis of Mullerian duct anom- alies using ESHRE-ESGE consensus on the classification of con- genital anomalies of the female genital tract. Ultrasound Obstet Gynecol. 2015;46(5):616-22. sourceNot checked — no full text of the source

Meta-analyses of women with recurrent miscarriage combining women with and without thrombophilia have not shown any improvement in reproductive outcomes when using aspirin and/or heparin versus placebo.

“Meta-analyses of women with recurrent miscarriage combining women with and without thrombophilia have not shown any improvement in reproductive outcomes when using aspirin and/or heparin versus placebo.176”

• cites [176] 176. de Jong PG, Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev. 2014;7:CD004734. sourceNot checked — no full text of the source

There is a lack of evidence to support routine treatment for women with Factor V Leiden, protein S deficiency and prothrombin gene mutation to reduce the incidence of recurrent miscarriage or second trimester loss.

“There is a lack of evidence to support routine treatment for women with Factor V Leiden, protein S deficiency and prothrombin gene mutation to reduce the incidence of recurrent miscarriage or second trimester loss.2-C Subgroup metaanalysis of RCTs do not show a consistent benefit of treatment in women with inherited thrombophilia, however the subgroups were underpowered for firm conclusions.”

There appears to be an association between sperm DNA fragmentation and miscarriage.

“Although there appears to be an association between sperm DNA fragmentation and miscarriage, there are yet to be any prospective trials demonstrating improved outcomes with intervention.”

The meta-analysis did not show a significant reduction in miscarriage rates in the aspirin plus low molecular weight heparin (LMWH) group.

“The meta-analysis did not show a significant reduction in miscarriage rates in aspirin plus low molecular weight heparin (LMWH) group, but commented that further investigation is required.”

There is a lack of studies demonstrating a clear link between acquired uterine anomalies and recurrent miscarriage.

“Although there is a lack of studies demonstrating a clear link between acquired uterine anomalies and recurrent miscarriage, these can be opportunistically diagnosed during the assessment for congenital uterine anomalies and treated accordingly on an individual basis (e.g. if there is associated symptomatology).”

Two prospective studies have shown that the loss in bone mineral density at the lumbar spine associated with low-dose long-term heparin therapy is similar to that which occurs normally during pregnancy.

“Two prospective studies have shown, however, that the loss in bone mineral density at the lumbar spine associated with low-dose long-term heparin therapy is similar to that which occurs normally during pregnancy.171,172”

• cites [171] 171. Backos M, Rai R, Thomas E, Murphy M, Dore C, Regan L. Bone density changes in pregnant women treated with heparin: a pro- spective, longitudinal study. Hum Reprod. 1999;14(11):2876-80. sourceNot checked — no full text of the source
• cites [172] 172. Carlin AJ, Farquharson RG, Quenby SM, Topping J, Fraser WD. Prospective observational study of bone mineral density during pregnancy: low molecular weight heparin versus control. Hum Reprod. 2004;19(5):1211-4. sourceNot checked — no full text of the source

There is a lack of consistent association between infection testing, associated treatment, and recurrent miscarriage.

“There is a lack of consistent association between infection testing, associated treatment, and recurrent miscarriage.”

Meta-analyses have demonstrated that treatment of antiphospholipid syndrome (APS) with aspirin and heparin confers a significant benefit.

“Metaanalyses have demonstrated that treatment of APS with aspirin and heparin confers a significant benefit.”

Well-designed prospective RCTs are lacking for the treatment of chronic endometritis in women with recurrent miscarriage.

“Prospective observational studies have suggested a higher subsequent miscarriage rate in women with recurrent miscarriage and untreated chronic endometritis versus no endometritis or treated endometritis, 153,154 however welldesigned prospective RCTs are lacking.”

There is a lack of consistent association between various immunological tests and recurrent miscarriage.

“There is a lack of consistent association between various immunological tests and recurrent miscarriage.”

There are yet to be any prospective trials demonstrating improved outcomes with intervention for sperm DNA fragmentation in couples with recurrent miscarriage.

“Although there appears to be an association between sperm DNA fragmentation and miscarriage, there are yet to be any prospective trials demonstrating improved outcomes with intervention.”

Pregnancies associated with APS treated with aspirin and heparin remain at high risk of complications during all three trimesters.

“Pregnancies associated with APS treated with aspirin and heparin remain at high risk of complications during all three trimesters.174,175”

• cites [174] 174. Backos M, Rai R, Baxter N, Chilcott IT, Cohen H, Regan L. Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin. Br J Obstet Gynaecol. 1999;106(2):102-7. sourceNot checked — no full text of the source
• cites [175] 175. Branch DW, Silver RM, Blackwell JL, Reading JC, Scott JR. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet Gynecol. 1992;80(4):614-20.Not checked — no full text of the source

A 2020 meta-analysis reported improvements in live birth with both UFH and LMWH in combination with aspirin.

“In addition, a 2020 metaanalysis reported improvements in live birth with both UFH and LMWH in combination with aspirin.168”

• cites [168] 168. Liu X, Qiu Y, Yu ED, Xiang S, Meng R, Niu KF, et al. Comparison of therapeutic interventions for recurrent pregnancy loss in association with antiphospholipid syndrome: A systematic review and network meta-analysis. Am J Reprod Immunol. 2020;83(4):e13219. 169. 102. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007;2:CD004659. 170. 103. Ginsberg JS, Hirsh J, Turner DC, Levine MN, Burrows R. Risks to the fetus of anticoagulant therapy during pregnancy. Thromb Haemost. 1989;61(2):197-203. sourceNot checked — no full text of the source

Two prospective studies and one RCT reported no difference in efficacy and safety between UFH or LMWH when combined with aspirin in the treatment of women with recurrent miscarriage associated with aPL.

“Two prospective studies and one RCT, however, reported no difference in efficacy and safety between UFH or LMWH when combined with aspirin in the treatment of women with recurrent miscarriage associated with aPL.166,167”

• cites [166] 166. Noble LS, Kutteh WH, Lashey N, Franklin RD, Herrada J. Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfraction- ated heparin. Fertil Steril. 2005;83(3):684-90. 167. 101. Stephenson MD, Ballem PJ, Tsang P, Purkiss S, Ensworth S, Houlihan E, et al. Treatment of antiphospholipid antibody syn- drome (APS) in pregnancy: a randomized pilot trial comparing low molecular weight heparin to unfractionated heparin. J Obstet Gynaecol Can. 2004;26(8):729-34. sourceNot checked — no full text of the source
• cites [167] sourceNot checked — no full text of the source

There are no studies assessing the dietary intake of certain foods, antioxidants, vitamins, supplements and others in the recurrent miscarriage population.

“There are no studies assessing the dietary intake of certain foods, antioxidants, vitamins, supplements and others in the recurrent miscarriage population.”

The findings on associations between smoking, alcohol and caffeine and sporadic miscarriage can be extrapolated to populations of women and people with recurrent miscarriage.

“These findings can be extrapolated on to populations of women and people with recurrent miscarriage.”

There is a lack of prospective data to determine which classification for septate uterus would lead to the most favourable reproductive outcomes (i.e. increase in live birth rate).

“Although there are concerns of potential over-diagnosis and treatment of septate uteri by using the ESHRE-ESGE classification, there are still a lack of prospective data to determine the use of which classification would lead to the most favourable reproductive outcomes (i.e. increase in live birth rate).”

Knowing thyroid peroxidase antibody status allows for the stratification of women and people who will require thyroid function monitoring during pregnancy.

“Although the presence of TPO antibodies in euthyroid women may not warrant treatment, knowing the antibody status allows for the stratification of women and people who will require thyroid function monitoring during pregnancy.149”

• cites [149] 149. Dhillon-Smith RK, Boelaert K, Jeve YB, Maheshwari A. Coomarasamy A; Royal College of Obstetricians and Gynaecologists. Subclinical Hypothyroidism and Antithyroid Autoantibodies in Women with Subfertility or Recurrent Pregnancy Loss: Scientific Impact Paper No. 70 June 2022. BJOG. 2022 Nov;129(12):e75-88. sourceNot checked — no full text of the source

Two further meta-analyses showed similar reduction in recurrent miscarriage for the aspirin and UFH group (OR 0.26, 95% CI 0.14-0.48).

“Two further meta-analyses showed similar reduction in recurrent miscarriage for the aspirin and UFH group (OR 0.26, 95% CI 0.14-0.48).164”

• cites [164] 164. Ziakas PD, Pavlou M, Voulgarelis M. Heparin treatment in anti- phospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol. 2010;115(6):1256-62. sourceNot checked — no full text of the source

The inclusion of saline infusion with the 3D ultrasound assessment may be particularly useful for the diagnosis of intrauterine adhesions if these are suspected based on the clinical history.

“The inclusion of saline infusion with the 3D ultrasound assessment may be particularly useful for the diagnosis of intrauterine adhesions if these are suspected based on the clinical history (e.g.prior surgical management of miscarriage with subsequent oligomenorrhoea).148”

• cites [148] 148. Amin TN, Saridogan E, Jurkovic D. Ultrasound and intrauterine adhesions: a novel structured approach to diagnosis and manage- ment. Ultrasound Obstet Gynecol. 2015;46(2):131-9. sourceNot checked — no full text of the source

The TABLET study, in which euthyroid women with TPO and a history of miscarriage were randomised to thyroxine or placebo, found no difference in live birth outcome.

“The 'TABLET' study, in which euthyroid women with TPO and a history of miscarriage were randomised to thyroxine or placebo, found no difference in live birth outcome.”

There were insufficient data to perform a subgroup analysis for women with recurrent miscarriage in the TABLET study.

“There were insufficient data to perform a subgroup analysis for women with recurrent miscarriage but the ongoing 'T4-Life' study (RCT) will examine this group.”

Live birth rates are similar following natural conception and preimplantation genetic diagnosis (PGD) in couples with chromosomal rearrangements.

“Live birth rates are similar following natural conception and PGD, and therefore PGD should not be routinely offered in this situation.”

Meta-analyses have reported a possible benefit from progestogen supplementation.

“Meta-analyses have reported a possible benefit from progestogen supplementation.”

In a later RCT, subgroup analysis of women with recurrent miscarriage with and without thrombophilia did not demonstrate a significant difference in live birth rate when comparing enoxaparin alone, enoxaparin/aspirin combined, and aspirin alone.

“In a later RCT, subgroup analysis of women with recurrent miscarriage with and without thrombophilia did not demonstrate a significant difference in live birth rate when comparing enoxaparin alone, enoxaparin/aspirin combined, and aspirin alone.179”

• cites [179] 179. Visser J, Ulander VM, Helmerhorst FM, Lampinen K, Morin- Papunen L, Bloemenkamp KW, et al. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial. Thromb Haemost. 2011;105(2):295-301. sourceNot checked — no full text of the source

The TABLET study, a double-blind, placebo-controlled trial comparing live birth rates among euthyroid women with TPO antibodies and a history of miscarriage treated with levothyroxine versus placebo, found no difference between the two groups, including subgroup analysis of women with recurrent miscarriage.

“The TABLET study, which was a double-blind, placebo-controlled trial comparing live birth rates among euthyroid women with TPO antibodies and a history of miscarriage, treated with levothyroxine versus placebo, found no difference between the two groups, including subgroup analysis of women with recurrent miscarriage.”

The group of women with thrombophilias would have been underpowered in these analyses because the investigators concluded that because of the lack of data, such an analysis was not possible.

“Unfortunately, although the investigators planned to compare the thrombophilia versus no thrombophilia groups, they concluded that because of the lack of data, such an analysis was not possible.This means that the group of women with thrombophilias would have been underpowered in these analyses.”

One prospective randomised trial demonstrated the efficacy of LMWH for the treatment of women with a history of a single late miscarriage after 10 weeks of gestation who have the Factor V Leiden or prothrombin gene mutation or have protein S deficiency.

“One prospective randomised trial demonstrated the efficacy of LMWH for the treatment of women with a history of a single late miscarriage after 10 weeks of gestation who have the Factor V Leiden or prothrombin gene mutation or have protein S deficiency.The live birth rate in women treated with enoxaparin was 86% compared with 29% in women taking low dose aspirin alone (OR 15.5, 95% CI 7-34).178”

• cites [178] 178. Gris JC, Mercier E, Quere I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombo- philic disorder. Blood. 2004;103(10):3695-9. sourceNot checked — no full text of the source

There are no published RCTs assessing the effectiveness and possible complications of hysteroscopic septum resection dedicated to women and people with recurrent miscarriage.

“There are no published RCTs assessing the effectiveness and possible complications of hysteroscopic septum resection dedicated to women and people with recurrent miscarriage.”

The only other RCT attempting to address hysteroscopic septum resection was stopped prematurely because of poor recruitment after recruiting only six patients.

“This may reflect the difficulty in recruiting patients to such a trial, as the only other RCT attempting to address this topic was stopped prematurely because of poor recruitment after recruiting only six patients (ISRCTN2896).188”

• cites [188] 188. Rikken JFW, van der Veen F, van Wely M, Goddijn M. Reply: Septum resection versus expectant management: paucity of good quality data. Hum Reprod. 2021;36(9):2627-8.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

There are currently insufficient data to support the routine use of PGT-A for couples with unexplained recurrent miscarriage.

“There are currently insufficient data to support the routine use of PGT-A for couples with unexplained recurrent miscarriage, while the treatment may carry a significant cost and potential risk.2-C Observational studies have not demonstrated improved outcomes to date, both in terms of live birth rate and time to pregnancy interval.”

Data from one retrospective analysis in a recurrent miscarriage population with no control group suggests a potential benefit from the resection of submucosal myomas.

“Data from one retrospective analysis in a recurrent miscarriage population with no control group suggests a potential benefit from the resection of submucosal myomas.70”

• cites [70] 70. Saravelos SH, Yan J, Rehmani H, Li TC. The prevalence and impact of fibroids and their treatment on the outcome of pregnancy in women with recurrent miscarriage. Hum Reprod. 2011;26(12):3274-9. sourceNot checked — no full text of the source

The 2017 RCT by Ismail et al. was retracted because of concerns regarding the accuracy and reliability of the study data.

“the 2017 RCT by Ismail et al. became the subject of an investigation by the Journal of Maternal-Fetal & Neonatal Medicine and was eventually retracted because of concerns raised regarding the accuracy and reliability of the study data.197”

• cites [197] 197. Statement 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;33(6):1073:1073. sourceNot checked — no full text of the source

Maternal age 25-29 years is associated with an odds ratio of 1.08 (95% CI 1.06-1.09) for miscarriage.

“25-29 years 3,a OR 1.08 (1.06-1.09)2++”

• cites 3,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

A significant proportion of women with unexplained recurrent miscarriage may be healthy women with repeated sporadic miscarriages and no persisting pathology.

“although it has been recognised that a significant proportion of women with unexplained recurrent miscarriage may be healthy women with repeated sporadic miscarriages and no persisting pathology.2,7”

• cites [2] 2. Saravelos SH, Li TC. Unexplained recurrent miscarriage: how can we explain it? Hum Reprod. 2012;27(7):1882-6. sourceNot checked — no full text of the source
• cites [7] 7. Saravelos SH, Regan L. Unexplained recurrent pregnancy loss. Obstet Gynecol Clin North Am. 2014;41(1):157-66. sourceNot checked — no full text of the source

Maternal age ≥45 years is associated with an odds ratio of 30.38 (95% CI 25.66-35.97) for miscarriage.

“≥ 45 years 3,a OR 30.38 (25.66-35.97)2++”

• cites 3,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Paternal age 40-44 years is associated with an odds ratio of 1.23 (95% CI 1.06-1.43) for miscarriage.

“40-44 years 18,a OR 1.23 (1.06-1.43)2++”

• cites 18,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Paternal age 35-39 years is associated with an odds ratio of 1.15 (95% CI 0.92-1.43) for miscarriage.

“35-39 years 18,a OR 1.15 (0.92-1.43) 2++”

• cites 18,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In a questionnaire study, women with recurrent miscarriage preferred a plan with one doctor who shows understanding, takes them seriously, has knowledge of their obstetric history, listens to them, gives information about recurrent miscarriage, shows empathy, informs on progress and enquires about emotional needs.

“A questionnaire study in women with recurrent miscarriage reported that women preferred the following supportive care options for their next pregnancy: • A plan with one doctor who shows understanding, takes them seriously, has knowledge of their obstetric history, listens to them, gives information about recurrent miscarriage, shows empathy, informs on progress and enquires about emotional needs.”

• cites [211] 211. Musters AM, Koot YE, van den Boogaard NM, Kaaijk E, Macklon NS, van der Veen F, et al. Supportive care for women with recur- rent miscarriage: a survey to quantify women's preferences. Hum Reprod. 2013;28(2):398-405. sourceNot checked — no full text of the source

Paternal age 30-34 years is associated with an odds ratio of 1.04 (95% CI 0.90-1.21) for miscarriage.

“30-34 years 18,a OR 1.04 (0.90-1.21) 2++”

• cites 18,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In the PRISM trial, there were no significant differences in live births at more than 34 weeks between 400 mg micronised vaginal progesterone twice daily and placebo (relative rate 1.03, 95% CI 1.00-1.07; P=0.08).

“The authors reported no significant differences in live births at more than 34 weeks (relative rate, 1.03, 95% CI 1.00-1.07;P = 0.08).”

• cites [202] 202. Coomarasamy A, Devall AJ, Cheed V, Harb H, Middleton LJ, Gallos ID, et al. A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy. N Engl J Med. 2019;380(19):1815-24. sourceNot checked — no full text of the source

Maternal age 30-34 years is associated with an odds ratio of 1.40 (95% CI 1.38-1.43) for miscarriage.

“30-34 years 3,a OR 1.40 (1.38-1.43)2++”

• cites 3,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In a questionnaire study, if a miscarriage occurred, most women with recurrent miscarriage would prefer to talk to a medical or psychological professional afterwards.

“• If a miscarriage occurred, most women would prefer to talk to a medical or psychological professional afterwards.”

• cites [211] 211. Musters AM, Koot YE, van den Boogaard NM, Kaaijk E, Macklon NS, van der Veen F, et al. Supportive care for women with recur- rent miscarriage: a survey to quantify women's preferences. Hum Reprod. 2013;28(2):398-405. sourceNot checked — no full text of the source

Maternal age ≥40-44 years is associated with an odds ratio of 7.08 (95% CI 6.80-7.37) for miscarriage.

“≥ 40-44 years 3,a OR 7.08 (6.80-7.37)2++”

• cites 3,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Anti-TNF agents could potentially cause serious morbidity including lymphoma, granulomatous disease such as tuberculosis, demyelinating disease, congestive heart failure and syndromes similar to systemic lupus erythematosus.

“Further, anti-TNF agents could potentially cause serious morbidity including lymphoma, granulomatous disease such as tuberculosis, demyelinating disease, congestive heart failure and syndromes similar to systemic lupus erythematosus.204”

• cites [204] 204. MedicinesComplete. British National Formulary (BNF) [https:// www.medic inesc omple te.com/ mc/bnf/current/]. Accessed 06 Apr 2023.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In the PRISM trial, subgroup analysis of women with recurrent miscarriage showed a significant improvement in live birth rate with progesterone (71.5% vs 57.4%; relative rate 1.28, 95% CI 1.08-1.51; P=0.007).

“However, on subgroup analysis of women with recurrent miscarriage, a significant improvement in live birth rate was observed (71.5% versus 57.4%; relative rate, 1.28, 95% CI 1.08-1.51;P = 0.007).202”

• cites [202] 202. Coomarasamy A, Devall AJ, Cheed V, Harb H, Middleton LJ, Gallos ID, et al. A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy. N Engl J Med. 2019;380(19):1815-24. sourceNot checked — no full text of the source

Maternal age 12-19 years is associated with an odds ratio of 1.22 (95% CI 1.19-1.25) for miscarriage.

“Maternal age a 12-19 years 3,a OR 1.22 (1.19-1.25)2++”

• cites 3,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

A Cochrane review found no evidence of a difference in miscarriage rate per clinical pregnancy with endometrial scratch/injury prior to intrauterine insemination or sexual intercourse (RR 0.73, 95% CI 0.38-1.39; six RCTs, 174 participants; I2=0%).

“A Cochrane review assessing women undergoing endometrial scratch/injury prior to intrauterine insemination or sexual intercourse found no evidence of a difference in miscarriage rate per clinical pregnancy (RR 0.73, 95% CI 0.38-1.39;six RCTs, 174 participants; I 2 statistic = 0%;).207”

• cites [207] 207. Lensen SF, Manders M, Nastri CO, Gibreel A, Martins WP, Templer GE, Farquhar C. Endometrial injury for pregnancy following sexual intercourse or intrauterine insemination. Cochrane Database Syst Rev. 2016;6:CD011424. sourceNot checked — no full text of the source

Maternal age 35-40 years is associated with an odds ratio of 2.52 (95% CI 2.46-2.57) for miscarriage.

“35-40 years 3,a OR 2.52 (2.46-2.57)2++”

• cites 3,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Paternal age ≥45 years is associated with an odds ratio of 1.43 (95% CI 1.13-1.81) for miscarriage.

“≥ 45 years 18,a OR 1.43 (1.13-1.81)2++”

• cites 18,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In a questionnaire study, women with recurrent miscarriage preferred an ultrasound examination during symptoms, directly after a positive pregnancy test and every 2 weeks.

“• An ultrasound examination during symptoms, directly after a positive pregnancy test and every 2 weeks.”

• cites [211] 211. Musters AM, Koot YE, van den Boogaard NM, Kaaijk E, Macklon NS, van der Veen F, et al. Supportive care for women with recur- rent miscarriage: a survey to quantify women's preferences. Hum Reprod. 2013;28(2):398-405. sourceNot checked — no full text of the source

High caffeine intake (350-699 mg/day) is associated with a relative risk of 1.40 (95% CI 1.16-1.68) for miscarriage.

“Caffeine high intake (350-699 mg/day) 27,a RR 1.40 (1.16-1.68)2++”

• cites 27,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Protein S deficiency is associated with an odds ratio of 14.72 (95% CI 0.99-218.1) for miscarriage (not reaching statistical significance).

“Protein S deficiency b OR *14.72 (0.99-218.1) 2++”

• cites bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Previous euploid miscarriage is associated with an odds ratio of 2.62 (95% CI 1.29-5.32) for miscarriage.

“Previous euploid miscarriage 57,b OR 2.62 (1.29-5.32)2+”

• cites 57,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Having 1 previous miscarriage is associated with an odds ratio of 1.61 (95% CI 1.57-1.64) for miscarriage compared with none.

“1 19,a OR 1.61 (1.57-1.64)2++”

• cites 19,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Low caffeine intake (50-149 mg/day) is associated with a relative risk of 1.02 (95% CI 0.85-1.24) for miscarriage.

“Caffeine low intake (50-149 mg/day) 27,a RR 1.02 (0.85-1.24) 2++”

• cites 27,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Black African race is associated with an adjusted odds ratio of 1.20 (95% CI 1.12-1.29) for miscarriage compared with White European.

“Black African 22,a aOR 1.20 (1.12-1.29)2+”

• cites 22,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

BMI >25 kg/m2 is associated with an odds ratio of 1.21 (95% CI 1.06-1.38) for miscarriage.

“BMI > 25 kg/m 231,b OR 1.21 (1.06-1.38)2++”

• cites 31,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Prothrombin gene mutation is associated with an odds ratio of 1.81 (95% CI 1.26-2.60) for miscarriage.

“Prothrombin gene mutation b OR 1.81 (1.26-2.60)2++”

• cites bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Having 5 previous miscarriages is associated with an odds ratio of 7.02 (95% CI 6.11-8.08) for miscarriage compared with none.

“5 19,b OR 7.02 (6.11-8.08)2++”

• cites 19,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

IgG cardiolipin is associated with an odds ratio of 3.57 (95% CI 2.26-5.65) for miscarriage.

“IgG cardiolipin b OR 3.57 (2.26-5.65)2++”

• cites bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Having 4 previous miscarriages is associated with an odds ratio of 5.15 (95% CI 4.72-5.62) for miscarriage compared with none.

“4 19,b OR 5.15 (4.72-5.62)2++”

• cites 19,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Black Caribbean race is associated with an adjusted odds ratio of 1.31 (95% CI 1.21-1.41) for miscarriage compared with White European.

“Black Caribbean 22,a aOR 1.31 (1.21-1.41)2+”

• cites 22,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Having 6 previous miscarriages is associated with an odds ratio of 13.84 (95% CI 11.00-17.41) for miscarriage compared with none.

“6 19,b OR 13.84 (11.00-17.41)2++”

• cites 19,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Moderate caffeine intake (150-349 mg/day) is associated with a relative risk of 1.16 (95% CI 0.94-1.41) for miscarriage.

“Caffeine moderate intake (150-349 mg/day) 27,a RR 1.16 (0.94-1.41) 2++”

• cites 27,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Congenital all anomalies are associated with a relative risk of 1.13 (95% CI 1.06-1.22) for miscarriage.

“All anomalies 62,b RR 1.13 (1.06-1.22)2++”

• cites 62,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Thyroid autoantibodies are associated with an odds ratio of 1.86 (95% CI 1.18-2.94) for miscarriage.

“Thyroid autoantibodies 88,b OR 1.86 (1.18-2.94)2++”

• cites 88,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Fibroids are associated with a relative risk of 1.16 (95% CI 0.80-1.52) for miscarriage (not reaching statistical significance).

“Fibroids 67,a RR *1.16 (0.80-1.52) 3”

• cites 67,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Parental chromosome rearrangements are associated with an odds ratio of 2.22 (95% CI 1.60-3.08) for miscarriage.

“Parental chromosome rearrangements 49,b OR 2.22 (1.60-3.08)2+”

• cites 49,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Sperm DNA fragmentation is associated with a relative risk of 2.28 (95% CI 1.55-3.35) for miscarriage.

“Sperm DNA fragmentation 127,a RR 2.28 (1.55-3.35)2++”

• cites 127,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Lupus anticoagulant is associated with an odds ratio of 7.79 (95% CI 2.30-26.4) for miscarriage.

“Lupus anticoagulant b OR 7.79 (2.30-26.4)2++”

• cites bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Smoking is associated with an odds ratio of 1.20 (95% CI 1.04-1.39) for miscarriage.

“Smoking 25,a OR 1.20 (1.04-1.39)2+”

• cites 25,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

BMI <19 kg/m2 is associated with an odds ratio of 1.2 (95% CI 1.12-1.28) for miscarriage.

“BMI < 19 kg/m 231,b OR 1.2 (1.12-1.28)2++”

• cites 31,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

IgM cardiolipin is associated with an odds ratio of 5.61 (95% CI 1.26-25.03) for miscarriage.

“IgM cardiolipin b OR 5.61 (1.26-25.03)2++”

• cites bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Anti-beta-2-glycoprotein-I is associated with an odds ratio of 2.12 (95% CI 0.69-6.53) for miscarriage (not reaching statistical significance).

“Anti-beta-2-glycoprotein-I b OR *2.12 (0.69-6.53) 2++”

• cites bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Alcohol consumption is associated with an adjusted hazard ratio of 3.7 (95% CI 2.0-6.8) for miscarriage.

“Alcohol 26,a aHR 3.7 (2.0-6.8)2+”

• cites 26,aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Having 2 or 3 previous miscarriages is associated with an odds ratio of 3.05 (95% CI 2.95-3.16) for miscarriage compared with none.

“2 or 3 19,b OR 3.05 (2.95-3.16)2++”

• cites 19,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.