Abstract
Aim
To conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) that evaluated the efficacy of low-dose aspirin (LDA, ≤ 160 mg/day) on preventing preterm birth (PB).
Methods
Five databases were screened from inception until June 25, 2023. The RCTs were assessed for quality according to Cochrane’s risk of bias tool. The endpoints were summarized as risk ratio (RR) with 95% confidence interval (CI).
Results
Overall, 40 RCTs were analyzed. LDA significantly decreased the risk of PB < 37 weeks (RR: 0.91, 95% CI 0.87, 0.96, p < 0.001, moderate certainty of evidence) with low between-study heterogeneity (I2 = 23.2%, p = 0.11), and PB < 34 weeks (RR: 0.78, 95% CI 0.61, 0.99, p = 0.04, low certainty of evidence) with high between-study heterogeneity (I2 = 58.3%, p = 0.01). There were no significant differences between both groups regarding the risk of spontaneous (RR: 0.94, 95% CI 0.83, 1.07, p = 0.37) and medically indicated (RR: 1.28, 95% CI 0.87, 1.88, p = 0.21) BP < 37 weeks. Sensitivity analysis revealed robustness for all outcomes, except for the risk of PB < 34 weeks. For PB < 37 weeks and PB < 34 weeks, publication bias was detected based on visual inspection of funnel plots for asymmetry and statistical significance for Egger’s test (p = 0.009 and p = 0.0012, respectively).
Conclusion
LDA can significantly reduce the risk of PB < 37 and < 34 weeks. Nevertheless, further high-quality RCTs conducted in diverse populations, while accounting for potential confounding factors, are imperative to elucidate the optimal aspirin dosage, timing of initiation, and treatment duration for preventing preterm birth and to arrive at definitive conclusions.
Similar content being viewed by others
Data availability
All data are available within the manuscript and its supplementary files.
Code availability
STATA Software version 17 for Windows.
References
Steer P (2005) The epidemiology of preterm labour. International J Obstetrics Gynaecology 112(s1):1–3. https://doi.org/10.1111/j.1471-0528.2005.00575.x
Shevchenko A, Syusyuka V, Kyryliuk A, Deynichenko O, Onopchenko S (2022) Modern aspects of predicting premature birth. Multidisciplinary academic res, innovation results 13:356
Cr C, ump (2020) Preterm birth and mortality in adulthood: a systematic review. J Perinatol 40(6):833–843
Cheong JL, Burnett AC, Treyvaud K, Spittle AJ (2020) Early environment and long-term outcomes of preterm infants. J Neural Transm 127:1–8
Guhn M, Emerson SD, Mahdaviani D, Gadermann AM (2020) Associations of birth factors and socio-economic status with indicators of early emotional development and mental health in childhood: a population-based linkage study. Child Psychiatry Hum Dev 51:80–93
Landman AJ, de Boer MA, Visser L, Nijman TA, Hemels MA, Naaktgeboren CN et al (2022) Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study): A multicentre, randomised, double-blinded, placebo-controlled trial. PLoS Med 19(2):e1003892
Bij de Weg JM, Landman AJ, de Vries JI, Thijs A, Harmsze AM, Oudijk MA et al (2022) The effect of low-dose aspirin on platelet function during pregnancy compared to placebo: An explorative study. Eur J of Obstetrics Gynecology Reproductive Biol 278:67–71
Loussert L, Vidal F, Parant O, Hamdi SM, Vayssiere C, Guerby P (2020) Aspirin for prevention of preeclampsia and fetal growth restriction. Prenat Diagn 40(5):519–527
Patterson JK, Neuwahl S, Goco N, Moore J, Goudar SS, Derman RJ et al (2023) Cost-effectiveness of low-dose aspirin for the prevention of preterm birth: a prospective study of the Global Network for Women’s and Children’s Health Research. Lancet Glob Health 11(3):e436–e444
Van Doorn R, Mukhtarova N, Flyke IP, Lasarev M, Kim K, Hennekens CH et al (2021) Dose of aspirin to prevent preterm preeclampsia in women with moderate or high-risk factors: A systematic review and meta-analysis. PLoS ONE 16(3):e0247782
Ayala DE, Ucieda R, Hermida RC (2013) Chronotherapy with low-dose aspirin for prevention of complications in pregnancy. Chronobiol Int 30(1–2):260–279
Bakhti A, Vaiman D (2011) Prevention of gravidic endothelial hypertension by aspirin treatment administered from the 8th week of gestation. Hypertens Res 34(10):1116–1120
Bauserman M, Leuba SI, Hemingway-Foday J, Nolen TL, Moore J, McClure EM et al (2022) The efficacy of low-dose aspirin in pregnancy among women in malaria-endemic countries. BMC Pregnancy Childbirth 22(1):1–10
Xu Tt Zhou F, Cy D, Gq H, Jk Li, Wang Xd (2015) Low dose aspirin for preventing preeclampsia and its complications a metaanalysis. J Clinical Hypertension 17(7):567–573. https://doi.org/10.1111/jch.12541
Man R, Morton VH, Devani P, Morris RK (2021) Aspirin for preventing adverse outcomes in low risk nulliparous women with singleton pregnancies: A systematic review and meta-analysis. Eur J Obstetrics Gynecology Reproductive Biol 262:105–112
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, The PRISMA et al (2020) statement: an updated guideline for reporting systematic reviews. BMJ 2021:372
Moutquin JM (2003) Classification and heterogeneity of preterm birth. BJOG 110(Suppl 20):30–33
Savitz DA, Dole N, Herring AH, Kaczor D, Murphy J, Siega-Riz AM et al (2005) Should spontaneous and medically indicated preterm births be separated for studying aetiology? Paediatr Perinat Epidemiol 19(2):97–105
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928
Higgins JPT (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560
Kowal P, Chatterji S, Naidoo N, Biritwum R, Fan W, Lopez Ridaura R et al (2012) Data resource profile: the World Health Organization Study on global AGEing and adult health (SAGE). Int J Epidemiol 41(6):1639–1649
Abdi N, Rozrokh A, Alavi A, Zare S, Vafaei H, Asadi N et al (2020) The effect of aspirin on preeclampsia, intrauterine growth restriction and preterm delivery among healthy pregnancies with a history of preeclampsia. J Chin Med Assoc 83(9):852
Abramovici A, Jauk V, Wetta L, Cantu J, Edwards R, Biggio J et al (2014) Low-dose aspirin, smoking status, and the risk of spontaneous preterm birth. American J Perinatology 32(05):445–450
Allshouse A, Jessel R, Heyborne K (2016) The impact of low-dose aspirin on preterm birth: secondary analysis of a randomized controlled trial. J Perinatol 36(6):427–431
Andrikopoulou M, Purisch SE, Handal-Orefice R, Gyamfi-Bannerman C (2018) Low-dose aspirin is associated with reduced spontaneous preterm birth in nulliparous women. American J Obstetrics Gynecology 219(4):399 .e1-e6
Blomqvist L, Hellgren M, Strandell A (2018) Acetylsalicylic acid does not prevent first-trimester unexplained recurrent pregnancy loss: A randomized controlled trial. Acta Obstet Gynecol Scand 97(11):1365–1372
Byaruhanga R, Chipato T, Rusakaniko S (1998) A randomized controlled trial of low-dose aspirin in women at risk from pre-eclampsia. Int J Gynecol Obstet 60(2):129–135
Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E et al (1998) Low-dose aspirin to prevent preeclampsia in women at high risk. N Engl J Med 338(11):701–705
Caspi E, Raziel A, Sherman D, Arieli S, Bukovski I, Weinraub Z (1994) Prevention of pregnancy-induced hypertension in twins by early administration of low-dose aspirin: a preliminary report. Am J Reprod Immunol 31(1):19–24
Diguisto C, Le Gouge A, Marchand M-S, Megier P, Ville Y, Haddad G et al (2022) Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: A double blinded randomized placebo-controlled trial. PLoS ONE 17(10):e0275129
Ebrashy A, Ibrahim M, Marzook A, Yousef D. Usefulness of aspirin therapy in high-risk pregnant women with abnormal uterine artery Doppler ultrasound at 14–16 weeks pregnancy: randomized controlled clinical trial. Croatian med j 2005 46 (5).
Eubanks AA, Nobles CJ, Mumford SL, Kim K, Hill MJ, Decherney AH et al (2020) The safety of low-dose aspirin on the mode of delivery: secondary analysis of the effect of aspirin in gestation and reproduction randomized controlled trial. American j perinatology. 39(06):658–665
Golding J (1998) Group JLDAS A randomised trial of low dose aspirin for primiparae in pregnancy. BJOG: International J Obstetrics Gynaecology 105(3):293–9
Gu W, Lin J, Hou Y-Y, Lin N, Song M-F, Zeng W-J et al (2020) Effects of low-dose aspirin on the prevention of preeclampsia and pregnancy outcomes: A randomized controlled trial from Shanghai, China. Eur J Obstetrics Gynecology Reproductive Biol 248:156–163
Haapsamo M, Martikainen H, Räsänen J (2008) Low-dose aspirin reduces uteroplacental vascular impedance in early and mid gestation in IVF and ICSI patients: a randomized, placebo-controlled double-blind study. Ultrasound Obstetrics Gynecology: Official J International Soc Ultrasound Obstetrics Gynecology 32(5):687–693
Hauth JC, Goldenberg RL, Parker CR Jr, Philips JB III, Copper RL, DuBard MB et al (1993) Low-dose aspirin therapy to prevent preeclampsia. Am J Obstet Gynecol 168(4):1083–1093
RnC H, Ayala DE, Iglesias M, Mojón A, Is S, Ucieda R et al (1997) Time-dependent effects of low-dose aspirin administration on blood pressure in pregnant women. Hypertension 30(3):589–95
Hoffman MK, Goudar SS, Kodkany BS, Metgud M, Somannavar M, Okitawutshu J et al (2020) Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial. Lancet 395(10220):285–293
Ibrahim Z, Mohamed M, Gadallah A, Mahmoud E, Shora H (2019) Low Dose Aspirin in prevention of Spontaneous Preterm Birth in Suez Canal University Hospital. Madridge J Intern Emerg Med 3(2):146–151
Jamal A, Milani F, Al-Yasin A (2012) Evaluation of the effect of metformin and aspirin on utero placental circulation of pregnant women with PCOS. Iranian J Reproductive Med 10(3):265
Khazardoost S, Mousavi S, Borna S, Hantoushzadeh S, Alavi A, Khezerlou N (2014) Effect of aspirin in prevention of adverse pregnancy outcome in women with elevated alpha-fetoprotein. J Matern Fetal Neonatal Med 27(6):561–565
Lambers MJ, Groeneveld E, Hoozemans DA, Schats R, Homburg R, Lambalk CB et al (2009) Lower incidence of hypertensive complications during pregnancy in patients treated with low-dose aspirin during in vitro fertilization and early pregnancy. Hum Reprod 24(10):2447–2450
Leslie G, Gallery E, Arnold J, Ross M, Gyory A (1995) Neonatal outcome in a randomized, controlled trial of low-dose aspirin in high-risk pregnancies. J Paediatr Child Health 31(6):549–552
Lin L, Huai J, Li B, Zhu Y, Juan J, Zhang M et al (2022) A randomized controlled trial of low-dose aspirin for the prevention of preeclampsia in women at high risk in China. American J Obstetrics Gynecology 226(2):251.e1-e12
Mirzaei F, Asaran M, Danaei M (2016) Effects of aspirin on adverse pregnancy outcome in patients with abnormal aneuploidy screening biochemistry tests: A randomized clinical trial. Social Determinants of Health, 2(3):84–91
Morris JM, Fay RA, Ellwood DA, Devonald KJ (1996) A randomized controlled trial of aspirin in patients with abnormal uterine artery blood flow. Obstet Gynecol 87(1):74–78
Movahed F, Lalooha F, Moinodin R, Dabbaghi Ghale T, Rezaee Majd Z, Yazdi Z (2017) The effect of aspirin in the prevention of preeclampsia in women with abnormal uterine artery doppler ultrasonography findings. Journal of Advances in Medical and Biomedical Research 25(108):11–19
Pattison NS, Chamley LW, Birdsall M, Zanderigo AM, Liddell HS, McDougall J (2000) Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial. Am J Obstet Gynecol 183(4):1008–1012
Schiff E, Peleg E, Goldenberg M, Rosenthal T, Ruppin E, Tamarkin M et al (1989) The use of aspirin to prevent Ppregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostcyclin in relatively high risk pregnancies. N Engl J Med 321(6):351–356
Schröcksnadel H, Sitte B, Alge A, Steckel-Berger G, Schwegel P, Pastner E et al (1992) Low-dose aspirin in primigravidae with positive roll-over test. Gynecol Obstet Invest 34(3):146–150
Sibai BM, Caritis SN, Thom E, Klebanoff M, McNellis D, Rocco L et al (1993) Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. N Engl J Med 329(17):1213–1218
Silver RM, Ahrens K, Wong LF, Perkins NJ, Galai N, Lesher LL et al (2015) Low-dose aspirin and preterm birth: a randomized controlled trial. Obstet Gynecol 125(4):876
Sutton EF, Hauspurg A, Caritis SN, Powers RW, Catov JM (2018) Maternal outcomes associated with lower-range stage 1 hypertension. Obstet Gynecol 132(4):843
Tani C, Zucchi D, Haase I, Gerosa M, Larosa M, Cavagna L et al (2022) Impact of low-dose acetylsalicylic acid on pregnancy outcome in systemic lupus erythematosus: results from a multicentre study. Lupus Sci Med 9(1):e000714
Wallenburg H, Makovitz J, Dekker G, Rotmans P (1986) Low-dose aspirin prevents pregnancy-induced hypertension and pre-eclampsia in angiotensin-sensitive primigravidae. Lancet 327(8471):1–3
Yu C, Papageorghiou A, Parra M, Palma Dias R, Nicolaides K, Group FMFSTS (2003) Randomized controlled trial using low-dose aspirin in the prevention of pre-eclampsia in women with abnormal uterine artery Doppler at 23 weeks’ gestation. Ultrasound Obstetrics Gynecology 22(3):233–9
Zhang N, Zhang H-X, Li Y-W, Li Y (2023) Benefits of Hydroxychloroquine Combined with Low-Dose Aspirin on Pregnancy Outcomes and Serum Cytokines in Pregnant Women with Systemic Lupus Erythematosus. Drugs R&D 23(1):35–42
Groeneveld E, Lambers M, Lambalk C, Broeze K, Haapsamo M, De Sutter P et al (2013) Preconceptional low-dose aspirin for the prevention of hypertensive pregnancy complications and preterm delivery after IVF: a meta-analysis with individual patient data. Hum Reprod 28(6):1480–1488
Turner JM, Robertson NT, Hartel G, Kumar S (2020) Impact of low-dose aspirin on adverse perinatal outcome: meta-analysis and meta-regression. Ultrasound Obstet Gynecol 55(2):157–169
Roberge S, Nicolaides K, Demers S, Villa P, Bujold E (2013) Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis. Ultrasound Obstet Gynecol 41(5):491–499
Wang F, Yi W, Li L, Zhou M, Cao X, Yao J et al (2020) Low-dose aspirin for preventing preterm birthi: a meta-analysis. Open Access J Biomed Sci. https://doi.org/10.38125/OAJBS.000212
Mirabito Colafella KM, Neuman RI, Visser W, Danser AJ, Versmissen J (2020) Aspirin for the prevention and treatment of pre-eclampsia: A matter of COX-1 and/or COX-2 inhibition? Basic Clin Pharmacol Toxicol 127(2):132–141
Patrono C (2023) Cyclooxygenase inhibitors and cancer: The missing pieces. J Pharmacol Exp Ther 386(2):181–189
Hodgetts Morton V, Stock SJ (2022) Low-dose aspirin for the prevention of preterm birth: More questions than answers. PLoS Med 19(2):e1003908
Kupka E, Hesselman S, Hastie R, Lomartire R, Wikström AK, Bergman L (2023) Low-dose aspirin use in pregnancy and the risk of preterm birth: a Swedish register-based cohort study. Am J Obstet Gynecol 228:336.e1-e9
Funding
None.
Author information
Authors and Affiliations
Contributions
SB and AA-Z contributed to study conception, data analysis, study supervision, and manuscript writing. AT, GFH, AA, BH, YF, KK, SHA, and HA contributed to literature review, data collection, data interpretation, and revision of manuscript for editorial and intellectual contents. All authors read and approved the final draft of manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Ethical approval
Not required as this research does not involve direct patient or animal contact.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Baradwan, S., Tawfiq, A., Hakeem, G.F. et al. The effects of low-dose aspirin on preterm birth: a systematic review and meta-analysis of randomized controlled trials. Arch Gynecol Obstet 309, 1775–1786 (2024). https://doi.org/10.1007/s00404-024-07373-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00404-024-07373-w