Birth, Spontaneous Abortion
Conditions
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.
Interventions
DRUGacetylsalicylic-acid (aspirin)
81mg of low-dose aspirin plus 400micrograms of folic acid.
DIETARY_SUPPLEMENTFolic acid
400micrograms of folic acid.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Live Birth | after delivery | Live birth was obtained prospectively by maternal report and abstraction from medical records by trained staff . |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinically Recognized Pregnancy | 8-weeks | — |
| Early Pregnancy Loss (EPL) | 8 weeks | Implantation failures |
| Pregnancy Losses Occurring Less Than 10 Weeks | less than 10-weeks | Includes preembryonic and embryonic losses (exclusive of implantation failures) |
| Fetal Pregnancy Loss | until 40 weeks | — |
| Stillbirth | 40 weeks | — |
| Ectopic Pregnancy | within 6 weeks | — |
| hCG Recognized Pregnancy | within 8-weeks of gestation | — |
| Preeclampsia | until delivery | — |
| Small for Gestational Age Infant | until delivery | birthweight |
| Preterm Birth | until delivery | — |
| Abnormal Fetal Testing | 8 weeks | — |
| Fetal Intolerance of Labor | until delivery | — |
| Abruption | until delivery | Partial or complete abruption (ie, premature separation of the placenta) |
| Molar Pregnancy | 8 weeks | — |
Countries
United States
Participant flow
Recruitment details
Study participants were recruited using community-based advertisements and physician referral to four university medical centres in the US (2006-12).
Pre-assignment details
Out of the 1397 women with confirmed eligibility, consented, and expressed initial interest in the study, 60 (4.3%) chose to discontinue the enrolment process. An additional 109 (7.8%) tested positive for pregnancy at the baseline visit or became pregnant before their randomisation visit.
Participants by arm
| Arm | Count |
|---|---|
| Aspirin 81mg of low-dose aspirin plus 400micrograms of folic acid.
acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid. | 615 |
| Placebo 400micrograms of folic acid.
Folic acid: 400micrograms of folic acid. | 613 |
| Total | 1,228 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 80 | 70 |
Baseline characteristics
| Characteristic | Placebo | Aspirin | Total |
|---|---|---|---|
| Age, Continuous | 28.7 years STANDARD_DEVIATION 4.7 | 28.8 years STANDARD_DEVIATION 4.9 | 28.7 years STANDARD_DEVIATION 4.8 |
| Gender Female | 613 Participants | 615 Participants | 1228 Participants |
| Gender Male | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Non-White | 27 participants | 39 participants | 66 participants |
| Race/Ethnicity, Customized White | 586 participants | 576 participants | 1162 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 615 | 8 / 613 |
| serious Total, serious adverse events | 7 / 615 | 5 / 613 |
Outcome results
Primary
Live Birth
Live birth was obtained prospectively by maternal report and abstraction from medical records by trained staff .
Time frame: after delivery
Population: Analyses were based on the intention-to-treat principle (excluding participants lost to follow-up).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Live Birth | 309 livebirths |
| Placebo | Live Birth | 286 livebirths |
Comparison: The study was designed to detect a 10% absolute difference in livebirth rate with 80% power and a type I error rate of 5%, on the assumption that participants taking placebo who achieved pregnancy would have a livebirth rate of 75%.p-value: 0.098495% CI: [0.98, 1.22]Fisher Exact
Secondary
Abnormal Fetal Testing
Time frame: 8 weeks
Population: No data were collected for this Outcome Measure.
Secondary
Abruption
Partial or complete abruption (ie, premature separation of the placenta)
Time frame: until delivery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Abruption | 7 participants |
| Placebo | Abruption | 5 participants |
p-value: 0.7795% CI: [-0.8, 1.4]Fisher Exact
Secondary
Clinically Recognized Pregnancy
Time frame: 8-weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Clinically Recognized Pregnancy | 374 pregnancy |
| Placebo | Clinically Recognized Pregnancy | 346 pregnancy |
p-value: 0.032995% CI: [1.01, 1.19]Fisher Exact
Secondary
Early Pregnancy Loss (EPL)
Implantation failures
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Early Pregnancy Loss (EPL) | 28 pregnancy |
| Placebo | Early Pregnancy Loss (EPL) | 27 pregnancy |
p-value: 0.890295% CI: [0.64, 1.78]Fisher Exact
Secondary
Ectopic Pregnancy
Time frame: within 6 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Ectopic Pregnancy | 3 pregnancy |
| Placebo | Ectopic Pregnancy | 3 pregnancy |
p-value: 195% CI: [0.21, 5.06]Fisher Exact
Secondary
Fetal Intolerance of Labor
Time frame: until delivery
Population: No data were collected for this Outcome Measure.
Secondary
Fetal Pregnancy Loss
Time frame: until 40 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Fetal Pregnancy Loss | 4 pregnancy |
| Placebo | Fetal Pregnancy Loss | 6 pregnancy |
p-value: 0.75395% CI: [0.19, 2.41]Fisher Exact
Secondary
hCG Recognized Pregnancy
Time frame: within 8-weeks of gestation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | hCG Recognized Pregnancy | 394 pregnancy |
| Placebo | hCG Recognized Pregnancy | 363 pregnancy |
p-value: 0.016595% CI: [1.02, 1.19]Fisher Exact
Secondary
Molar Pregnancy
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Molar Pregnancy | 0 pregnancy |
| Placebo | Molar Pregnancy | 0 pregnancy |
p-value: 195% CI: [0.21, 5.06]Fisher Exact
Secondary
Preeclampsia
Time frame: until delivery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Preeclampsia | 32 participants |
| Placebo | Preeclampsia | 30 participants |
p-value: 0.794395% CI: [0.67, 1.76]Fisher Exact
Secondary
Pregnancy Losses Occurring Less Than 10 Weeks
Includes preembryonic and embryonic losses (exclusive of implantation failures)
Time frame: less than 10-weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Pregnancy Losses Occurring Less Than 10 Weeks | 56 pregnancy |
| Placebo | Pregnancy Losses Occurring Less Than 10 Weeks | 53 pregnancy |
p-value: 0.686995% CI: [0.76, 1.55]Fisher Exact
Secondary
Preterm Birth
Time frame: until delivery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Preterm Birth | 22 infants |
| Placebo | Preterm Birth | 31 infants |
p-value: 0.260395% CI: [0.42, 1.23]Fisher Exact
Secondary
Small for Gestational Age Infant
birthweight
Time frame: until delivery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Small for Gestational Age Infant | 3327 grams | Standard Deviation 521 |
| Placebo | Small for Gestational Age Infant | 3315 grams | Standard Deviation 550 |
p-value: 0.7802t-test, 2 sided
Secondary
Stillbirth
Time frame: 40 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Stillbirth | 2 participants |
| Placebo | Stillbirth | 2 participants |
p-value: 195% CI: [0.15, 7.26]Fisher Exact