Clinical trial NCT00467363: The Effects of Aspirin in Gestation and Reproduction
Official title: The Effects of Aspirin in Gestation and Reproduction: A Multi-center, Controlled, Double-blind Randomized Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Birth
Spontaneous Abortion
Lead sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Sponsor class: NIH
First posted: 2007-04-30
Enrollment: 1228
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to help elucidate the effects of low-dose aspirin in combination with folic acid on the incidence of live births and spontaneous abortions among a group of women who become pregnant compared to a control group.

Detailed description: Despite the fundamental nature of reproduction, for many it is a process fraught with frustration, inefficiency and imperfections, the effects of which can be severe. Infertility affects 10-15% of couples attempting to conceive. Among all women who conceive, the incidence of spontaneous abortion (SA) has been estimated to be between 15 and 31%, and in many cases the cause is unknown. Additionally, of the four million births yearly in the United States, between 8 and 15% will be born prematurely and experience increased morbidity and mortality as a result. An intervention with even a small absolute effect on any of these outcomes has great implications at the population level due to the large potential attributable benefit.

One such potential intervention is low-dose acetylsalicylic-acid (aspirin). Aspirin has been a primary target of interest because of its anti-inflammatory, vasodilatory and platelet aggregation inhibition properties. To evaluate the effects of low-dose aspirin in combination with folic acid on the incidence of live births and spontaneous abortion, we are conducting a multi-site randomized controlled trial study with two sites and one data coordinating center. Women aged 18-40 currently trying to become pregnant and who have had a single spontaneous abortion in the past year will be eligible for the study. The recruitment goal is 1600 women. Participating women will be randomly assigned to one of two treatment groups. Those randomized to treatment will receive daily low-dose aspirin. Those randomized to placebo will receive daily placebo. Both groups will receive folic acid daily in accordance with recommendations from the U.S. Public Health Service for prevention of birth defects. The duration of treatment regimens (LDA and folic acid or placebo and folic acid) will be 6 menstrual cycles, with those who become pregnant continuing until the end of pregnancy. Monthly urine and blood samples will be collected and questionnaires administered.

Eligibility criteria: Inclusion Criteria:

* Women experiencing one or two pregnancy losses at any point in gestation in the past that were not elective termination(s). At least one of these losses must be well documented by one of the following:

  * Sonogram demonstrating anembryonic loss, embryonic loss or fetal death.
  * Histologic confirmation of products of conception that were spontaneously passed per vagina or surgically obtained.
  * Hospital records of fetus delivery.
  * Late menses and positive serum hCG or positive urine hCG documented by hospital or clinic records followed by either a negative hospital/clinic pregnancy test or a decline in urinary hCG level over 3 days.
  * Home pregnancy tests without hCG confirmation from a healthcare provider (either serum or urine) will not be accepted.
* No more than 5 pregnancies in total including the pregnancy loss(es).\*
* Up to two prior pregnancies that did not end in a loss.\*

  \*Women may have up to two pregnancies beyond 20 weeks that were not losses, two spontaneous pregnancy losses at any time in the past, and up to one therapeutic or elective termination (two therapeutic or elective terminations if no other pregnancies). Ectopic and molar pregnancies would, for the purpose of enrollment, be considered in the same category as therapeutic termination pregnancies. Women with more than two live births or those with more than two losses, regardless of the week of gestation of the loss, are excluded.
* Presence of intact tubes (both), ovaries (both), and uterus.
* Between 18 and 40 years of age at time of baseline visit.
* Regular menstrual periods between 21 - 42 days in length (within the last 12 months). Regular menstrual periods are defined as no more than an 8-day difference between the woman's shortest and longest cycle.
* No more than one missed menses in the past 12 months (other than those missed due to pregnancy or breastfeeding).
* Actively trying to conceive with a male partner and not using contraception by the baseline visit.
* Not currently pregnant at the baseline or randomization visits.
* Ability and willingness to give informed consent.
* Willingness to be randomized and to take daily study pills for 6 months to a possible 15 months

Exclusions Criteria:

* Known allergies to aspirin or non-steroidal anti-inflammatory agents.
* Clinical indication for anticoagulant therapy. These include prior or current thrombosis, antiphospholipid syndrome (APS) or known major thrombophilia.
* Clinical indication for chronic use of NSAIDs such as rheumatoid arthritis.
* Indication for additional folic acid supplementation, such as prior infant with neural tube defect (NTD), seizure disorder.
* Medical contraindication to aspirin therapy. These include uncontrolled asthma, nasal polyps, bleeding disorders, or history of gastrointestinal ulcer.
* Presence of major medical disorders (regardless of severity). These include diabetes, hypertension, systemic lupus erythematosus (SLE), untreated or active cancer (any cancer in remission or non-melanoma skin cancer is not included in the exclusion criteria), liver disease, renal disease, rheumatoid arthritis, cardiac disease, pulmonary disease other than mild asthma, neurologic disease requiring medical treatment, uncontrolled hypothyroidism, uncontrolled seizure disorder. Untreated vitamin B12 deficiency, severe anemia (Hct \< 30%), hemophilia, gout, nasal polyps, among others.
* Currently undergoing/planned use of assisted reproductive techniques during trial (IVF; IUI; Clomid).
* History of infertility or sub-fertility. This includes any of the following:

  * No conception after ≥ 1 year of unprotected intercourse and actively trying to conceive.
  * Any prior medical treatment for infertility.
  * Prior treatment for known pelvic inflammatory disease.
  * Known male infertility or sperm abnormality (current partner).
  * Known tubal occlusion, anovulation, uterine abnormality, or endometriosis stage III or IV.
  * History of polycystic ovarian syndrome.
* Presence of unstable mental disorder. These include bipolar illness, schizophrenia, uncontrolled depression, uncontrolled anxiety disorder.
* Known current or recent alcohol abuse or illicit drug use.
* Current diagnosis of sexually transmitted infection (STI) (temporary exclusion)

Primary outcomes:
measure: Live Birth
timeFrame: after delivery
Secondary outcomes:
measure: hCG Recognized Pregnancy
timeFrame: within 8-weeks of gestation
measure: Clinically Recognized Pregnancy
timeFrame: 8-weeks
measure: Early Pregnancy Loss (EPL)
timeFrame: 8 weeks
measure: Pregnancy Losses Occurring Less Than 10 Weeks
timeFrame: less than 10-weeks
measure: Fetal Pregnancy Loss
timeFrame: until 40 weeks
measure: Stillbirth
timeFrame: 40 weeks
measure: Ectopic Pregnancy
timeFrame: within 6 weeks
measure: Molar Pregnancy
timeFrame: 8 weeks
measure: Preeclampsia
timeFrame: until delivery
measure: Small for Gestational Age Infant
timeFrame: until delivery
measure: Preterm Birth
timeFrame: until delivery
measure: Abnormal Fetal Testing
timeFrame: 8 weeks
measure: Fetal Intolerance of Labor
timeFrame: until delivery
measure: Abruption
timeFrame: until delivery
Other outcomes:
Locations:
city: Denver
country: United States
facility: University of Colorado, Denver School of Medicine, Department of Obstetrics and Gynecology
state: Colorado
city: Buffalo
country: United States
facility: Women's Health Research Center, Department of Social and Preventive Medicine, University at Buffalo
state: New York
city: Scranton
country: United States
facility: Moses Taylor Hospital
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah Medical Center
state: Utah
Study officials:
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Enrique F Schisterman, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University at Buffalo
name: Jean Wactawski-Wende, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah
name: Robert Silver, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Haifa
name: Noya Galai, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Commonwealth Medical College
name: Janet Townsend, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Colorado, Denver
name: Anne Lynch, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schliep KC, Hinkle SN, Kim K, Sjaarda LA, Silver RM, Stanford JB, Purdue-Smithe A, Plowden TC, Schisterman EF, Mumford SL. Prospectively assessed perceived stress associated with early pregnancy losses among women with history of pregnancy loss. Hum Reprod. 2022 Sep 30;37(10):2264-2274. doi: 10.1093/humrep/deac172.
citation: Zolton JR, Sjaarda LA, Mumford SL, Holland TL, Kim K, Flannagan KS, Yisahak SF, Hinkle SN, Connell MT, White MV, Perkins NJ, Silver RM, Hill MJ, DeCherney AH, Schisterman EF. Preconception hemoglobin A1c concentration in healthy women is not associated with fecundability or pregnancy loss. F S Rep. 2022 Jan 20;3(1):39-46. doi: 10.1016/j.xfre.2022.01.002. eCollection 2022 Mar.
citation: Zhong Y, Brooks MM, Kennedy EH, Bodnar LM, Naimi AI. Use of Machine Learning to Estimate the Per-Protocol Effect of Low-Dose Aspirin on Pregnancy Outcomes: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2022 Mar 1;5(3):e2143414. doi: 10.1001/jamanetworkopen.2021.43414.
citation: Purdue-Smithe AC, Kim K, Schliep KC, DeVilbiss EA, Hinkle SN, Ye A, Perkins NJ, Sjaarda LA, Silver RM, Schisterman EF, Mumford SL. Preconception caffeine metabolites, caffeinated beverage intake, and fecundability. Am J Clin Nutr. 2022 Apr 1;115(4):1227-1236. doi: 10.1093/ajcn/nqab435.
citation: Purdue-Smithe AC, Kim K, Andriessen VC, Pollack AZ, Sjaarda LA, Silver RM, Schisterman EF, Mumford SL. Preconception leukocyte telomere length and pregnancy outcomes among women with demonstrated fecundity. Hum Reprod. 2021 Nov 18;36(12):3122-3130. doi: 10.1093/humrep/deab201.
citation: Alkhalaf Z, Kim K, Kuhr DL, Radoc JG, Purdue-Smithe A, Pollack AZ, Yisahak SF, Silver RM, Thoma M, Kissell K, Perkins NJ, Sjaarda LA, Mumford SL. Markers of vitamin D metabolism and premenstrual symptoms in healthy women with regular cycles. Hum Reprod. 2021 Jun 18;36(7):1808-1820. doi: 10.1093/humrep/deab089.
citation: Naimi AI, Perkins NJ, Sjaarda LA, Mumford SL, Platt RW, Silver RM, Schisterman EF. The Effect of Preconception-Initiated Low-Dose Aspirin on Human Chorionic Gonadotropin-Detected Pregnancy, Pregnancy Loss, and Live Birth : Per Protocol Analysis of a Randomized Trial. Ann Intern Med. 2021 May;174(5):595-601. doi: 10.7326/M20-0469. Epub 2021 Jan 26.
citation: Mumford SL, Flannagan KS, Radoc JG, Sjaarda LA, Zolton JR, Metz TD, Plowden TC, Perkins NJ, DeVilbiss EA, Andriessen VC, A C PS, Kim K, Yisahak SF, Freeman JR, Alkhalaf Z, Silver RM, Schisterman EF. Cannabis use while trying to conceive: a prospective cohort study evaluating associations with fecundability, live birth and pregnancy loss. Hum Reprod. 2021 Apr 20;36(5):1405-1415. doi: 10.1093/humrep/deaa355.
citation: Flannagan KS, Mumford SL, Sjaarda LA, Radoc JG, Perkins NJ, Andriessen VC, Zolton JR, Silver RM, Schisterman EF. Is opioid use safe in women trying to conceive? Epidemiology. 2020 Nov;31(6):844-851. doi: 10.1097/EDE.0000000000001247.
citation: Sjaarda LA, Radoc JG, Flannagan KS, Mumford SL, Kim K, Perkins NJ, Silver RM, Schisterman EF. Urinary selective serotonin reuptake inhibitors across critical windows of pregnancy establishment: a prospective cohort study of fecundability and pregnancy loss. Fertil Steril. 2020 Dec;114(6):1278-1287. doi: 10.1016/j.fertnstert.2020.06.037. Epub 2020 Oct 14.
citation: Evans MB, Nobles CJ, Kim K, Hill MJ, DeCherney AH, Silver RM, Mumford SL, Sjaarda LA, Perkins NJ, Schisterman EF. Low-dose aspirin in reproductive health: effects on menstrual cycle characteristics. Fertil Steril. 2020 Dec;114(6):1263-1270. doi: 10.1016/j.fertnstert.2020.06.022. Epub 2020 Sep 4.
citation: Nobles CJ, Mendola P, Mumford SL, Silver RM, Kim K, Andriessen VC, Connell M, Sjaarda L, Perkins NJ, Schisterman EF. Preconception Blood Pressure and Its Change Into Early Pregnancy: Early Risk Factors for Preeclampsia and Gestational Hypertension. Hypertension. 2020 Sep;76(3):922-929. doi: 10.1161/HYPERTENSIONAHA.120.14875. Epub 2020 Aug 3.
citation: Hamulyak EN, Scheres LJ, Marijnen MC, Goddijn M, Middeldorp S. Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss. Cochrane Database Syst Rev. 2020 May 2;5(5):CD012852. doi: 10.1002/14651858.CD012852.pub2.
citation: Yeung EH, Guan W, Zeng X, Salas LA, Mumford SL, de Prado Bert P, van Meel ER, Malmberg A, Sunyer J, Duijts L, Felix JF, Czamara D, Hamalainen E, Binder EB, Raikkonen K, Lahti J, London SJ, Silver RM, Schisterman EF. Cord blood DNA methylation reflects cord blood C-reactive protein levels but not maternal levels: a longitudinal study and meta-analysis. Clin Epigenetics. 2020 Apr 30;12(1):60. doi: 10.1186/s13148-020-00852-2.
citation: Russo LM, Whitcomb BW, Freeman JR, Mumford SL, Sjaarda LA, Perkins NJ, Schliep KC, Grewal J, Silver RM, Schisterman EF. Physical activity and incidence of subclinical and clinical pregnancy loss: a secondary analysis in the effects of aspirin in gestation and reproduction randomized trial. Fertil Steril. 2020 Mar;113(3):601-608.e1. doi: 10.1016/j.fertnstert.2019.10.027.
citation: Robinson SL, Mumford SL, Guan W, Zeng X, Kim K, Radoc JG, Trinh MH, Flannagan K, Schisterman EF, Yeung E. Maternal fatty acid concentrations and newborn DNA methylation. Am J Clin Nutr. 2020 Mar 1;111(3):613-621. doi: 10.1093/ajcn/nqz311.
citation: Agrawala S, Sjaarda LA, Omosigho UR, Perkins NJ, Silver RM, Mumford SL, Connell MT, Naimi AI, Halvorson LM, Schisterman EF. Effect of preconception low dose aspirin on pregnancy and live birth according to socioeconomic status: A secondary analysis of a randomized clinical trial. PLoS One. 2019 Apr 18;14(4):e0200533. doi: 10.1371/journal.pone.0200533. eCollection 2019.
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citation: Mumford SL, Garbose RA, Kim K, Kissell K, Kuhr DL, Omosigho UR, Perkins NJ, Galai N, Silver RM, Sjaarda LA, Plowden TC, Schisterman EF. Association of preconception serum 25-hydroxyvitamin D concentrations with livebirth and pregnancy loss: a prospective cohort study. Lancet Diabetes Endocrinol. 2018 Sep;6(9):725-732. doi: 10.1016/S2213-8587(18)30153-0. Epub 2018 May 31.
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