Trial Outcomes & Findings for Aspirin Supplementation for Pregnancy Indicated Risk Reduction In Nulliparas (ASPIRIN) (NCT NCT02409680)

Last Updated: 2024-11-21

Results Overview

The primary outcome of this study is incidence of preterm birth, which will be defined as delivery at or after 20 0/7 weeks and prior to 37 0/7 weeks. This will be determined based on actual date of delivery in comparison to the projected estimated due date (EDD), independent of whether or not the preterm delivery is indicated or spontaneous.

Recruitment status

COMPLETED

Study phase

Target enrollment

11976 participants

Primary outcome timeframe

At delivery

Results posted on

2024-11-21

Participant Flow

Randomized, multi-country, double-masked, placebo-controlled trial of low-dose aspirin (81 mg daily) initiated between 6 weeks and 0 days of pregnancy, and 13 weeks and 6 days of pregnancy, in nulliparous women with an ultrasound confirming gestational age and a singleton viable pregnancy.

Participants were randomly assigned (1:1, stratified by site) to receive aspirin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating center.

Participant milestones

Participant milestones
Measure	Intervention Arm Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Overall Study STARTED	5990	5986
Overall Study Treated	5943	5936
Overall Study Included in mITT Analysis	5787	5771
Overall Study COMPLETED	5975	5956
Overall Study NOT COMPLETED	15	30

Reasons for withdrawal

Reasons for withdrawal
Measure	Intervention Arm Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Overall Study Lost to Follow-up	15	30

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Intervention Arm n=5787 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5771 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.	Total n=11558 Participants Total of all reporting groups
Age, Customized Maternal Age (years) · <20 years	2233 Participants n=5787 Participants	2273 Participants n=5771 Participants	4506 Participants n=11558 Participants
Age, Customized Maternal Age (years) · 20-29 years	3429 Participants n=5787 Participants	3372 Participants n=5771 Participants	6801 Participants n=11558 Participants
Age, Customized Maternal Age (years) · >29 years	125 Participants n=5787 Participants	126 Participants n=5771 Participants	251 Participants n=11558 Participants
Sex: Female, Male Female	5787 Participants n=5787 Participants	5771 Participants n=5771 Participants	11558 Participants n=11558 Participants
Sex: Female, Male Male	0 Participants n=5787 Participants	0 Participants n=5771 Participants	0 Participants n=11558 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Maternal Education No formal schooling	830 Participants n=5787 Participants	828 Participants n=5771 Participants	1658 Participants n=11558 Participants
Maternal Education 1-6 years of schooling	857 Participants n=5787 Participants	856 Participants n=5771 Participants	1713 Participants n=11558 Participants
Maternal Education 7-12 years of scholling	3470 Participants n=5787 Participants	3454 Participants n=5771 Participants	6924 Participants n=11558 Participants
Maternal Education >= 13 years of schooling	629 Participants n=5787 Participants	632 Participants n=5771 Participants	1261 Participants n=11558 Participants
Maternal Education Missing	1 Participants n=5787 Participants	1 Participants n=5771 Participants	2 Participants n=11558 Participants
Number of pregnancies 0	5274 Participants n=5787 Participants	5226 Participants n=5771 Participants	10500 Participants n=11558 Participants
Number of pregnancies 1	451 Participants n=5787 Participants	469 Participants n=5771 Participants	920 Participants n=11558 Participants
Number of pregnancies 2	62 Participants n=5787 Participants	76 Participants n=5771 Participants	138 Participants n=11558 Participants
Projected gestational age at enrollment	10.1 weeks n=5787 Participants	10.1 weeks n=5771 Participants	10.1 weeks n=11558 Participants
Maternal Height	153.1 cm STANDARD_DEVIATION 6.9 • n=5787 Participants	153.1 cm STANDARD_DEVIATION 7.0 • n=5771 Participants	153.1 cm STANDARD_DEVIATION 7.0 • n=11558 Participants
Maternal Weight	49.3 kg STANDARD_DEVIATION 8.9 • n=5787 Participants	49.2 kg STANDARD_DEVIATION 8.7 • n=5771 Participants	49.2 kg STANDARD_DEVIATION 8.8 • n=11558 Participants
Maternal body-mass-index	21.0 kg/m^2 STANDARD_DEVIATION 3.8 • n=5787 Participants	21.0 kg/m^2 STANDARD_DEVIATION 3.6 • n=5771 Participants	21.0 kg/m^2 STANDARD_DEVIATION 3.7 • n=11558 Participants
Antenatal care visits	5 visits n=5787 Participants	5 visits n=5771 Participants	5 visits n=11558 Participants
Delivery attendant Physician	2938 Participants n=5787 Participants	2908 Participants n=5771 Participants	5846 Participants n=11558 Participants
Delivery attendant Nurse or midwife	2240 Participants n=5787 Participants	2239 Participants n=5771 Participants	4479 Participants n=11558 Participants
Delivery attendant Traditional birth attendant	464 Participants n=5787 Participants	473 Participants n=5771 Participants	937 Participants n=11558 Participants
Delivery attendant Family, self, or other acquaintance	142 Participants n=5787 Participants	147 Participants n=5771 Participants	289 Participants n=11558 Participants
Delivery attendant Missing	3 Participants n=5787 Participants	4 Participants n=5771 Participants	7 Participants n=11558 Participants
Delivery mode Vaginal	4257 Participants n=5787 Participants	4324 Participants n=5771 Participants	8581 Participants n=11558 Participants
Delivery mode Caesarean section	1523 Participants n=5787 Participants	1440 Participants n=5771 Participants	2963 Participants n=11558 Participants
Delivery mode Miscarriage	0 Participants n=5787 Participants	0 Participants n=5771 Participants	0 Participants n=11558 Participants
Delivery mode Medical termination of pregnancy	5 Participants n=5787 Participants	4 Participants n=5771 Participants	9 Participants n=11558 Participants
Delivery mode Missing	2 Participants n=5787 Participants	3 Participants n=5771 Participants	5 Participants n=11558 Participants
Delivery location Hospital	3479 Participants n=5787 Participants	3494 Participants n=5771 Participants	6973 Participants n=11558 Participants
Delivery location Clinic or health care	1818 Participants n=5787 Participants	1765 Participants n=5771 Participants	3583 Participants n=11558 Participants
Delivery location Home or other	488 Participants n=5787 Participants	509 Participants n=5771 Participants	997 Participants n=11558 Participants
Delivery location Missing	2 Participants n=5787 Participants	3 Participants n=5771 Participants	5 Participants n=11558 Participants
Site Democratic Republic of the Congo	655 Participants n=5787 Participants	665 Participants n=5771 Participants	1320 Participants n=11558 Participants
Site Guatemala	836 Participants n=5787 Participants	835 Participants n=5771 Participants	1671 Participants n=11558 Participants
Site India (Belagavi)	1327 Participants n=5787 Participants	1323 Participants n=5771 Participants	2650 Participants n=11558 Participants
Site India (Nagpur)	1026 Participants n=5787 Participants	1020 Participants n=5771 Participants	2046 Participants n=11558 Participants
Site Kenya	673 Participants n=5787 Participants	655 Participants n=5771 Participants	1328 Participants n=11558 Participants
Site Pakistan	771 Participants n=5787 Participants	762 Participants n=5771 Participants	1533 Participants n=11558 Participants
Site Zambia	499 Participants n=5787 Participants	511 Participants n=5771 Participants	1010 Participants n=11558 Participants

PRIMARY outcome

Timeframe: At delivery

Population: Modified ITT; numbers reported reflect available data and therefore do not always reflect the total population defined in the mITT

Outcome measures

Outcome measures
Measure	Intervention Arm n=5780 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5764 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Incidence of Preterm Birth	668 Participants	754 Participants

SECONDARY outcome

Timeframe: Evidence of hypertensive disorder during the pregnancy (prior to delivery/birth)

Population: Modified ITT; numbers reported reflect available data and therefore do not always reflect the total population defined in the mITT

\- Hypertensive disorders of pregnancy is defined by the characterization of evidence of a hypertensive disorder, including either preeclampsia or eclampsia occurring during the pregnancy.

Outcome measures

Outcome measures
Measure	Intervention Arm n=5780 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5764 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Incidence of Hypertensive Disorders of Pregnancy	352 Participants	325 Participants

SECONDARY outcome

Timeframe: At delivery or at Day 42 after delivery

Population: Modified ITT; numbers reported reflect available data and therefore do not always reflect the total population defined in the mITT

\- Small for gestational age (SGA) as defined by the INTERGROWTH-21st standard

Outcome measures

Outcome measures
Measure	Intervention Arm n=5492 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5467 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Incidence of Small for Gestational Age (SGA)	1506 Participants	1564 Participants

SECONDARY outcome

Timeframe: At delivery or at Day 42 after delivery

Population: Modified ITT; numbers reported reflect available data and therefore do not always reflect the total population defined in the mITT

\- Incidence of Perinatal Mortality

Outcome measures

Outcome measures
Measure	Intervention Arm n=5779 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5763 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Incidence of Perinatal Mortality	264 Participants	309 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery or at Day 42 after delivery

Population: ITT population; numbers reported reflect available data and therefore do not always reflect the total population defined in the ITT

\- Vaginal bleeding

Outcome measures

Outcome measures
Measure	Intervention Arm n=5933 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5940 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Maternal Outcome 1 - Incidence of Vaginal Bleeding	214 Participants	246 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery or at Day 42 after delivery

Population: Modified ITT; numbers reported reflect available data and therefore do not always reflect the total population defined in the mITT

\- Antepartum hemorrhage

Outcome measures

Outcome measures
Measure	Intervention Arm n=5761 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5746 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Maternal Outcome 2 - Incidence of Antepartum Hemorrhage	26 Participants	25 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery or at Day 42 after delivery

Population: Safety population (women receiving at least one dose of drug or placebo); numbers reported reflect available data

\- Postpartum hemorrhage

Outcome measures

Outcome measures
Measure	Intervention Arm n=5928 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5907 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Maternal Outcome 3 - Incidence of Postpartum Hemorrhage	54 Participants	43 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery or at Day 42 after delivery

Population: ITT population; numbers reported reflect available data and therefore do not always reflect the total population defined in the ITT

\- Incidence of Maternal Mortality

Outcome measures

Outcome measures
Measure	Intervention Arm n=5958 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5948 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Maternal Outcome 4 - Incidence of Maternal Mortality	9 Participants	12 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery or at Day 42 after delivery

Population: ITT population; numbers reported reflect available data and therefore do not always reflect the total population defined in the ITT

\- Incidence of Late Abortion

Outcome measures

Outcome measures
Measure	Intervention Arm n=5819 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5808 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Maternal Outcome 5 - Incidence of Late Abortion	23 Participants	30 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At enrollment, 4 weeks post enrollment, and 26-30 weeks GA.

Hemoglobin \< 7.0 gm/dl at 26-30 weeks gestation or a drop of 3.5+ gm/dl from screening to 26-30 weeks gestation

Outcome measures

Outcome measures
Measure	Intervention Arm n=5393 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5398 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Maternal Outcome 6 - Change in Maternal Hemoglobin	290 Participants	333 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery or at Day 42 after delivery

Population: Modified ITT; numbers reported reflect available data and therefore do not always reflect the total population defined in the mITT

Early preterm delivery (\<34 weeks) and hypertensive disorders (i.e.: preeclampsia)

Outcome measures

Outcome measures
Measure	Intervention Arm n=5780 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5764 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Maternal Outcome 7 - Incidence of Preterm, Preeclampsia	8 Participants	21 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery

Population: Modified ITT; numbers reported reflect available data and therefore do not always reflect the total population defined in the mITT

\- Early preterm delivery (\<34 weeks)

Outcome measures

Outcome measures
Measure	Intervention Arm n=5780 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5764 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Fetal Outcome 1 - Incidence of Early Preterm Delivery (<34 Weeks)	189 Participants	230 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery

Population: Modified ITT; numbers reported reflect available data and therefore do not always reflect the total population defined in the mITT

\- Birth weight \<2500g

Outcome measures

Outcome measures
Measure	Intervention Arm n=5628 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5624 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Fetal Outcome 2 - Incidence of Actual Birth Weight <2500g	1078 Participants	1153 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery

Population: Modified ITT; numbers reported reflect available data and therefore do not always reflect the total population defined in the mITT

\- Birth weight \<1500g

Outcome measures

Outcome measures
Measure	Intervention Arm n=5628 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5624 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Fetal Outcome 3 - Incidence of Actual Birth Weight <1500g	78 Participants	101 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery

Population: ITT population; numbers reported reflect available data and therefore do not always reflect the total population defined in the ITT

\- Incidence of Fetal Loss

Outcome measures

Outcome measures
Measure	Intervention Arm n=5818 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5807 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Fetal Outcome 4 - Incidence of Fetal Loss	303 Participants	353 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery

Population: ITT population; numbers reported reflect available data and therefore do not always reflect the total population defined in the ITT

\- Incidence of Spontaneous Abortion

Outcome measures

Outcome measures
Measure	Intervention Arm n=5956 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5946 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Fetal Outcome 5 - Incidence of Spontaneous Abortion	134 Participants	152 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery

Population: Modified ITT; numbers reported reflect available data and therefore do not always reflect the total population defined in the mITT

\- Incidence of All stillbirth

Outcome measures

Outcome measures
Measure	Intervention Arm n=5780 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5764 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Fetal Outcome 6 - Incidence of All Stillbirth	141 Participants	166 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At delivery

Population: ITT population; numbers reported reflect available data and therefore do not always reflect the total population defined in the ITT

\- Incidence of Medical Termination of Pregnancy

Outcome measures

Outcome measures
Measure	Intervention Arm n=5956 Participants Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5946 Participants Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Fetal Outcome 7 - Incidence of Medical Termination of Pregnancy	42 Participants	30 Participants

Adverse Events

Intervention Arm

Serious events: 832 serious events

Other events: 0 other events

Deaths: 9 deaths

Placebo Arm

Serious events: 857 serious events

Other events: 0 other events

Deaths: 12 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

Additional Information

Elizabeth McClure

RTI International

Phone: 919-316-3773

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Intervention Arm n=5943 participants at risk Daily administration of low dose (81 mg) aspirin \[also known as acetylsalicylic acid (ASA\], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA.	Placebo Arm n=5936 participants at risk Identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.
Pregnancy, puerperium and perinatal conditions Maternal death	0.15% 9/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	0.20% 12/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Pregnancy, puerperium and perinatal conditions Fetal loss	2.4% 142/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	2.7% 162/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Pregnancy, puerperium and perinatal conditions Neonatal death up to 28 days	2.7% 163/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	3.2% 190/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Pregnancy, puerperium and perinatal conditions Miscarriage, abortion, or medical termination of pregnancy	0.86% 51/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	0.91% 54/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Pregnancy, puerperium and perinatal conditions Preterm labour or preterm birth evaluation before delivery	0.76% 45/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	0.94% 56/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Pregnancy, puerperium and perinatal conditions Antepartum haemorrhage	0.59% 35/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	0.56% 33/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Pregnancy, puerperium and perinatal conditions Post-partum harmorrhage	0.84% 50/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	0.72% 43/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Reproductive system and breast disorders Vaginal spotting, bleeding, or leaking	0.17% 10/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	0.17% 10/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Congenital, familial and genetic disorders Congenital anomaly	0.54% 32/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	0.61% 36/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Blood and lymphatic system disorders Anaemia	0.40% 24/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	0.39% 23/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Infections and infestations Fever or infection	0.91% 54/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	0.77% 46/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Pregnancy, puerperium and perinatal conditions Other	0.96% 57/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	0.96% 57/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Gastrointestinal disorders Upper gastrointestinal bleeding	0.07% 4/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	0.02% 1/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Pregnancy, puerperium and perinatal conditions Pre-eclampsia or eclampsia	2.5% 150/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	2.4% 141/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.
Cardiac disorders Hypertension admission or medical visit before delivery	2.0% 120/5943 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.	1.8% 106/5936 • Adverse events were monitored continuously throughout the study (from enrollment through 6-weeks post delivery) and recorded every 2-weeks. SAEs were monitored for any event that: resulted in maternal or fetal death; was life-threatening; required hospitalization; resulted in persistent or significant disability; or any other serious or unexpected AE that the investigators felt should be reported. Specific AEs to be monitored included maternal death, upper GI bleeding, fetal anomaly, gastroschisis, post-partum hemorrhage, or antepartum hemorrhage. Other \[Not Including Serious\] AEs were not monitored/assessed.