EAGeR: The Effects of Aspirin in Gestation and Reproduction

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00467363
• Collaborator: (none)
• Enrollment: 1,228
• Locations: 4
• Arms: 2
• Duration (Months): 61
• Patients Per Site: 307
• Patients Per Site Per Month: 5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Birth; Spontaneous Abortion	Drug: acetylsalicylic-acid (aspirin); Dietary Supplement: Folic acid	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1228 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effects of Aspirin in Gestation and Reproduction: A Multi-center, Controlled, Double-blind Randomized Trial.
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Jul 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Aspirin 81mg of low-dose aspirin plus 400micrograms of folic acid.	Drug: acetylsalicylic-acid (aspirin); 81mg of low-dose aspirin plus 400micrograms of folic acid.; Other Names: aspirin
Placebo Comparator: Placebo 400micrograms of folic acid.	Dietary Supplement: Folic acid; 400micrograms of folic acid.

Outcome Measures

Primary Outcome Measures

1. Live Birth [after delivery]

   Live birth was obtained prospectively by maternal report and abstraction from medical records by trained staff .

Secondary Outcome Measures

1. hCG Recognized Pregnancy [within 8-weeks of gestation]

2. Clinically Recognized Pregnancy [8-weeks]

3. Early Pregnancy Loss (EPL) [8 weeks]

   Implantation failures

4. Pregnancy Losses Occurring Less Than 10 Weeks [less than 10-weeks]

   Includes preembryonic and embryonic losses (exclusive of implantation failures)

5. Fetal Pregnancy Loss [until 40 weeks]

6. Stillbirth [40 weeks]

7. Ectopic Pregnancy [within 6 weeks]

8. Molar Pregnancy [8 weeks]

9. Preeclampsia [until delivery]

10. Small for Gestational Age Infant [until delivery]

    birthweight

11. Preterm Birth [until delivery]

12. Abnormal Fetal Testing [8 weeks]

13. Fetal Intolerance of Labor [until delivery]

14. Abruption [until delivery]

    Partial or complete abruption (ie, premature separation of the placenta)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado, Denver School of Medicine, Department of Obstetrics and Gynecology	Denver	Colorado	United States	80045
2	Women's Health Research Center, Department of Social and Preventive Medicine, University at Buffalo	Buffalo	New York	United States	14260
3	Moses Taylor Hospital	Scranton	Pennsylvania	United States	18510
4	University of Utah Medical Center	Salt Lake City	Utah	United States	84112

Sponsors and Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Enrique F Schisterman, PhD, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Principal Investigator: Jean Wactawski-Wende, PhD, University at Buffalo
• Principal Investigator: Robert Silver, MD, University of Utah
• Principal Investigator: Noya Galai, PhD, University of Haifa
• Principal Investigator: Janet Townsend, M.D., The Commonwealth Medical College
• Principal Investigator: Anne Lynch, M.D., University of Colorado, Denver

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• EAGeR Trial Home Page

Publications

None provided.

• Responsible Party: Enrique Schisterman, Chief and Senior Investigator, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• ClinicalTrials.gov Identifier: NCT00467363
• Other Study ID Numbers: EAGeR
• First Posted: Apr 30, 2007
• Last Update Posted: Feb 3, 2017
• Last Verified: Dec 1, 2016

• Additional relevant MeSH terms: Abortion, Spontaneous; Aspirin; Folic Acid

Study Results

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 Detail	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.

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Period Title: Overall Study
STARTED	615	613
COMPLETED	535	543
NOT COMPLETED	80	70

Baseline Characteristics

Arm/Group Title	Aspirin	Placebo	Total
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.	Total of all reporting groups
Overall Participants	615	613	1228
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.8 (4.9)	28.7 (4.7)	28.7 (4.8)
Gender (Count of Participants)
Female	615 100%	613 100%	1228 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	576 93.7%	586 95.6%	1162 94.6%
Non-White	39 6.3%	27 4.4%	66 5.4%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Analyses were based on the intention-to-treat principle (excluding participants lost to follow-up).

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	535	543
Number [livebirths]	309	286

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments	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%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0984
	Comments	Only one outcome for primary outcome, so no adjustment of p-value for multiple comparisons was done. A priori threshold for statistical significance was p<0.05.
	Method	Fisher Exact
	Comments	No adjustments were done. Treatment groups were similar with respect to the assessed demographic and baseline characteristics
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	hCG Recognized Pregnancy
Time Frame	within 8-weeks of gestation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	535	543
Number [pregnancy]	394	363

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0165
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 1.02 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Clinically Recognized Pregnancy
Time Frame	8-weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	535	543
Number [pregnancy]	374	346

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0329
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 1.01 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Early Pregnancy Loss (EPL)
Description	Implantation failures
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	537	551
Number [pregnancy]	28	27

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.8902
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; .64 to 1.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Pregnancy Losses Occurring Less Than 10 Weeks
Description	Includes preembryonic and embryonic losses (exclusive of implantation failures)
Time Frame	less than 10-weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	537	551
Number [pregnancy]	56	53

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.6869
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; .76 to 1.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Fetal Pregnancy Loss
Time Frame	until 40 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	537	551
Number [pregnancy]	4	6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.7530
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	.68
	Confidence Interval	(2-Sided) 95%; .19 to 2.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Stillbirth
Time Frame	40 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	537	551
Number [participants]	2 0.3%	2 0.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; .15 to 7.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Ectopic Pregnancy
Time Frame	within 6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	537	551
Number [pregnancy]	3	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; .21 to 5.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Molar Pregnancy
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	535	543
Number [pregnancy]	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; .21 to 5.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Preeclampsia
Time Frame	until delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	535	543
Number [participants]	32 5.2%	30 4.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.7943
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; .67 to 1.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Small for Gestational Age Infant
Description	birthweight
Time Frame	until delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	535	543
Mean (Standard Deviation) [grams]	3327 (521)	3315 (550)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.7802
	Comments
	Method	t-test, 2 sided
	Comments

12. Secondary Outcome

Title	Preterm Birth
Time Frame	until delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	535	543
Number [infants]	22	31

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.2603
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	.72
	Confidence Interval	(2-Sided) 95%; .42 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Abnormal Fetal Testing
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

No data were collected for this Outcome Measure.

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	0	0

14. Secondary Outcome

Title	Fetal Intolerance of Labor
Time Frame	until delivery

Outcome Measure Data

Analysis Population Description

No data were collected for this Outcome Measure.

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	0	0

15. Secondary Outcome

Title	Abruption
Description	Partial or complete abruption (ie, premature separation of the placenta)
Time Frame	until delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.	400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
Measure Participants	615	613
Number [participants]	7 1.1%	5 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.77
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95%; -0.8 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	Aspirin		Placebo
Arm/Group Description	81mg of low-dose aspirin plus 400micrograms of folic acid. acetylsalicylic-acid (aspirin): 81mg of low-dose aspirin plus 400micrograms of folic acid.		400micrograms of folic acid. Folic acid: 400micrograms of folic acid.
All Cause Mortality
	Aspirin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Aspirin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/615 (1.1%)		5/613 (0.8%)
Pregnancy, puerperium and perinatal conditions
Transient Pulmonary Hypertension	1/615 (0.2%)	1	0/613 (0%)	0
Minor Birth Defects	4/615 (0.7%)	4	4/613 (0.7%)	4
Neonatal Death	2/615 (0.3%)	2	1/613 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Aspirin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/615 (3.9%)		8/613 (1.3%)
Pregnancy, puerperium and perinatal conditions
Vaginal Bleeding	24/615 (3.9%)		8/613 (1.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.