The Effects of Aspirin in Gestation and Reproduction

Study Overview
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Brief Summary
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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
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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.

Official Title
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The Effects of Aspirin in Gestation and Reproduction: A Multi-center, Controlled, Double-blind Randomized Trial.

Conditions
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Birth, Spontaneous Abortion

Intervention / Treatment
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* Drug: acetylsalicylic-acid (aspirin)
* Dietary Supplement: Folic acid


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Aspirin<br>81mg of low-dose aspirin plus 400micrograms of folic acid. | Drug: acetylsalicylic-acid (aspirin)<br>* 81mg of low-dose aspirin plus 400micrograms of folic acid.<br>* Other names: aspirin;|
| Placebo Comparator: Placebo<br>400micrograms of folic acid. | Dietary Supplement: Folic acid<br>* 400micrograms of folic acid.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Live Birth | Live birth was obtained prospectively by maternal report and abstraction from medical records by trained staff . | after delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| hCG Recognized Pregnancy |  | within 8-weeks of gestation | 
| Clinically Recognized Pregnancy |  | 8-weeks | 
| Early Pregnancy Loss (EPL) | Implantation failures | 8 weeks | 
| Pregnancy Losses Occurring Less Than 10 Weeks | Includes preembryonic and embryonic losses (exclusive of implantation failures) | less than 10-weeks | 
| Fetal Pregnancy Loss |  | until 40 weeks | 
| Stillbirth |  | 40 weeks | 
| Ectopic Pregnancy |  | within 6 weeks | 
| Molar Pregnancy |  | 8 weeks | 
| Preeclampsia |  | until delivery | 
| Small for Gestational Age Infant | birthweight | until delivery | 
| Preterm Birth |  | until delivery | 
| Abnormal Fetal Testing |  | 8 weeks | 
| Fetal Intolerance of Labor |  | until delivery | 
| Abruption | Partial or complete abruption (ie, premature separation of the placenta) | until delivery |