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To evaluate complications and safety of preconception low-dose aspirin in 1,228 U.S. women (2007–2011).
Evaluation of the safety of low-dose aspirin in the participants and their fetuses was a planned secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial, a multi-center, block-randomized, double-blind, placebo-controlled trial investigating the effect of low-dose aspirin on the incidence of live birth. Women aged 18–40 years with a history of 1–2 pregnancy losses trying to conceive were randomized to daily low-dose aspirin (81 mg, n=615) or placebo (n=613) and were followed for ≤6 menstrual cycles or through gestation if they became pregnant. Emergency care visits and possible aspirin-related symptoms were assessed at each study follow-up using standardized safety interviews. In addition, complications for both the participant and her fetus or neonate were captured prospectively using case report forms, interviews conducted during pregnancy and postpartum, and medical records.
The proportion of women with at least one possible aspirin-related symptom during the trial was similar between treatment arms (456 [74%] low-dose aspirin vs. 447 [73%] placebo, P=0.65), as was the proportion with at least one emergency care visit (104 [17%] low-dose aspirin vs. 99 [16%] placebo, P=0.76). Maternal complications were evenly distributed by treatment arm, with the exception of vaginal bleeding, which was more commonly reported in the low-dose aspirin arm (22% vs. 17%, P=0.02). The distribution of fetal and neonatal complications—which included 3 stillbirths, 3 neonatal deaths and 10 infants with birth defect(s) —was similar between treatment arms.
Although rare but serious complications due to low-dose aspirin cannot be ruled out, preconception low-dose aspirin appears to be well-tolerated by women trying to conceive, women who become pregnant, and by their fetuses and neonates.
Systematic reviews of numerous randomized trials have found that low-dose aspirin during pregnancy can reduce the risk of preeclampsia (1, 2). In fact, recent recommendations support the use of daily low-dose aspirin from the 12th week of gestation onward for the prevention of preeclampsia in women at high risk for this condition, citing the low incidence of harm associated with low-dose aspirin (3)(4)(5). Evidence of low harm is based on studies that have primarily evaluated low-dose aspirin initiated after the first trimester (2). Newer findings, however, suggest that low-dose aspirin may be more effective in improving pregnancy outcomes associated with preeclampsia if therapy is started earlier in pregnancy (6). Previous findings from the Effects of Aspirin in Gestation and Reproduction trial have shown that preconception low-dose aspirin may also be associated with other improved pregnancy outcomes—higher live birth rate and lower risk of preterm birth—in normotensive women with a history of 1 pregnancy loss (<20 weeks of gestation) within the past year (7, 8). Given the benefits of low-dose aspirin on preeclampsia and potentially other reproductive outcomes, there may be increasing interest in initiating this widely available and low-cost therapy prior to conception, even among women with a low risk of developing preeclampsia. Therefore, evaluation of maternal and fetal and neonatal complications and safety associated with preconception low-dose aspirin use in low-risk women is critical and timely.
The objective of our study was to evaluate the risk of side effects and maternal and fetal and neonatal complications associated with preconception low-dose aspirin use among women in the Effects of Aspirin in Gestation and Reproduction trial.
The study design of the Effects of Aspirin in Gestation and Reproduction trial has been described in detail (9, 10). Briefly, the trial was a multi-center, block-randomized, double-blinded, placebo-controlled trial of 1228 U.S. women conducted in 2007–2011. Study sites were located in: Salt Lake City, UT; Denver, CO; Scranton, PA; and Buffalo, NY. Women 18 to 40 years old with a history of 1 or 2 pregnancy losses who were trying to conceive by natural conception were eligible for the study (Clinical Trials Registration: number NCT00467363). Women with contraindications to aspirin, a clinical indication for aspirin therapy, or any major medical disorder (e.g. hypertension) were ineligible (7, 10). The primary objective of the trial was incidence of live birth (7). Herein we present a planned secondary analysis of the trial: to evaluate the safety of low-dose aspirin in participants and their fetuses.
Participants were block-randomized by study center and eligibility stratum to either the intervention (81 mg low-dose aspirin daily) (n=615) or an identical looking placebo (n=613) with both study arms provided with 400 mcg folic acid daily as a separate supplement. Participants were followed for up to 6 menstrual cycles or through gestation if they became pregnant. Institutional Review Board approval was obtained at each of the clinical sites and the data coordinating center. All participants provided written informed consent. A data safety and monitoring board ensured continued patient safety and ongoing monitoring of viability of the trial. Compliance to treatment assignment was measured by regularly administered questionnaires and bottle weighing at study visits.
Information on demographics and baseline characteristics were obtained from questionnaires administered at the first study visit. Pregnancy history was derived from information reported on the health and reproduction baseline questionnaire and from medical record abstraction for women who became pregnant during the study. Modified National Institute for Health and Care Excellence guidelines were used to categorize participants at risk for preeclampsia (11). Baseline body mass index was calculated using height and weight measured at baseline by trained study staff.
Medical complications and possible aspirin-related symptoms, including but not limited to trial adverse events, were captured using multiple sources: case/incident report forms completed by study staff; systematic safety interviews administered by staff; other questionnaires completed by participants during pregnancy and postpartum; and medical record abstraction. Adverse events, defined in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines (3), were monitored prospectively and were reported within 24 hours of becoming aware of each event. A multidisciplinary adverse events committee periodically reviewed all reported events and determined by consensus for each event the final diagnosis, severity, expectedness, and relatedness to low-dose aspirin. Trial adverse events have been previously reported (7).
The current report describes maternal health outcomes and complications highlighted in a recent systematic review of randomized trials of low-dose aspirin in pregnant women (2): maternal death, bleeding (subcategorized into: vaginal bleeding; subchorionic hemorrhage; combined vaginal bleeding [restricted to during pregnancy only] or subchorionic hemorrhage; and epistaxis), premature separation of the placenta (including both partial and complete abruption), and postpartum hemorrhage. We also report preterm contractions, emesis, and kidney stones due to their frequent incidence in pregnancy. Other pregnancy outcomes—including but not limited to preeclampsia, preterm birth, pregnancy loss, and cesarean delivery—have been reported previously (7, 8). The following fetal and neonatal health outcomes were also selected for evaluation: fetal death (>20 weeks of gestation); neonatal death (within 4–6 weeks after birth); newborn received specialized care (neonatal intensive care unit [NICU], special care unit, Intermediate Care, or step down unit); intracranial or intraventricular hemorrhage; pulmonary hypertension and structural birth defects (2).
Safety interviews were administered during the trial at regularly scheduled follow-ups conducted either in person or by telephone. While participants were attempting to conceive, follow-ups occurred at the middle and end of each menstrual cycle (timed using fertility monitors and took place approximately every 2 weeks). If the participant became pregnant, the safety interview was administered every 4 weeks up until 36 weeks of gestation. The safety interview follow-ups began with: “Since your last visit to our clinic or your last phone interview have you experienced any of the following health problems?” and listed 10 symptoms that have been associated with aspirin use in adults (12): gastrointestinal discomfort, unusual or excessive bleeding, allergic reaction, unusual rashes, swelling, breathing difficulties, asthma attack, kidney problems, elevation in blood pressure, and development of nasal polyps. Participants could report experiencing a symptom even if it wasn’t diagnosed or recognized by a medical care provider; possible symptoms could also be reported by participants assigned to the placebo. Two additional questions were added to the interview approximately 15 months into recruitment (approximately 30% of study timeline) to better assess the symptoms of nausea and/or vomiting and vaginal bleeding, which were subcategories of gastrointestinal discomfort and unusual or excessive bleeding, respectively. Lastly, each safety interview included a question regarding emergency care visits: “Have you been to an ER or been admitted to a hospital since the last visit or the last phone interview?”
Complications during pregnancy were assessed using a pregnancy questionnaire completed by the participant, which was administered during the prenatal study clinic visits (every 4 weeks up until 36 weeks of gestation). The pregnancy questionnaire captured information on: vaginal bleeding; nausea and vomiting; abdominal cramping; and reasons for any visit to the doctor during the previous 4 weeks. Complications discovered after a live birth were identified using a postpartum questionnaire conducted by telephone approximately 4 to 6 weeks post-delivery. The postpartum questionnaire included open-ended questions about medical problems encountered after delivery for the participant and her baby, separately.
Standardized medical record chart abstraction forms captured complications and conditions documented during the following clinical encounters for each participant (if applicable): prenatal visits, ultrasounds, pregnancy loss visits, hospitalizations and emergency care visits prior to delivery, and delivery visits. In addition, certain complications and conditions were also assessed during an early pregnancy viability ultrasound conducted for study purposes. Chart abstraction captured information using check-boxes and open-ended fields. At least one chart abstraction form included a check-box assessing: subchorionic hemorrhage, vaginal bleeding, preterm contractions, preterm labor, labor, placental abruption, emesis, and postpartum hemorrhage. In addition, blood transfusion during or after delivery was specifically assessed in the delivery record chart abstraction form and this (as well as what the mother reported during the postpartum interview) was considered an indicator of postpartum hemorrhage for our analysis. Lastly, each of the fetal and neonatal outcomes was included as a check-box on at least one chart abstraction form.
After completion of the study, case report forms and free text data from open-ended questions on questionnaires and medical records were reviewed independently by two board-certified reproductive endocrinologists (S.Z. and K.K.) and a perinatal epidemiologist (K.A.) blinded to treatment assignment. Adverse events and health conditions were classified using standardized medical terminology software (MedDRA) at the preferred term level; up to 6 preferred terms were allowed per report (e.g. preterm contractions, vaginal bleeding, and vomiting could be identified as separate medical complications involved in a single adverse event described in a case report form).
Demographic and baseline characteristics were summarized by treatment arm. Possible aspirin-related symptoms reported during the follow-up safety interviews were collapsed by individual participant (any report vs. no report) and compared by assigned treatment arm among all women randomized (i.e. intention-to-treat analysis) and also after stratifying by pregnancy status at the time of interview (i.e. modified intention-to-treat analysis). Maternal and fetal and neonatal complications were similarly collapsed by individual participant using all other information available across the trial (case report forms, questionnaires, chart abstractions—as described above) and compared by treatment arm. Structural congenital anomalies were considered separately and listed by treatment arm.
Because pregnancy outcomes are conditional on becoming pregnant and factors that affect conception may also affect adverse pregnancy outcomes, we constructed inverse probability weights to control for bias potentially introduced by stratifying by pregnancy status, a potential consequence of treatment assignment (8). These weights effectively reweighted the participants so that baseline characteristics were more evenly distributed between those who became pregnant during the trial and those who did not, allowing for unbiased stratification by pregnancy status (i.e. removing bias potentially caused by ‘breaking’ the randomization and evaluating some outcomes only among women who became pregnant). Using inverse probability weights, we estimated the proportion of women reporting any possible aspirin-related symptom among those that completed safety interviews while pregnant and the proportion of fetuses and neonates with any complications, both of which were conditional on becoming pregnant during the trial. In addition, we applying the inverse probability weights to the maternal health complication of combined vaginal bleeding during pregnancy and/or subchorionic hemorrhage.
A series of Fisher’s exact tests were used to determine differences by treatment arm with alpha equal to 0.05; correction for multiple comparisons was not applied in order to maximize the detection of differences between study arms. For analyses using inverse probability weighted data, weighted chi-square tests were used in place of Fisher’s exact test. Unadjusted log-binomial models (unweighted or using inverse probability weights) were used to estimate risk differences and 95% confidence intervals. Reports of unusual or excessive bleeding symptoms were categorized by follow-up visit during which the report was obtained; comparisons between treatment arms for each visit used the Fisher’s exact test.
Table 1 shows demographics and baseline characteristics of participants randomized by treatment arm. Most participants were white, married and had experienced a pregnancy loss within the past 4 months. Characteristics were similar by treatment arm, with the exception of marital status (P=0.03), which indicated a higher proportion of women were married in the low-dose aspirin arm. Compliance with treatment assignment was similar between treatment arms (15%  of women in low-dose aspirin and 13%  in placebo self-reported permanently stopping the study drug) (7).
Follow-up safety interviews were filled out by 1211/1228 study participants and included 13,064 separate interviews. On average, 6.7 follow-up interviews were filled out per participant (range: 1, 20). Most women reported at least one symptom during the course of the trial and this did not differ by treatment arm (74% [456/615] low-dose aspirin vs. 73% [447/613] placebo, P=0.65) (Table 2). Gastrointestinal discomfort and unusual or excessive bleeding were the most commonly reported symptoms (and did not vary by treatment arm). The percentages of safety interviews with reported unusual or excessive bleeding by follow-up visit is presented in Figure 1. No differences between treatment arms by visit were statistically significant.
As expected, symptoms were more commonly reported among women interviewed while pregnant (83% low-dose aspirin vs. 82% placebo, P=0.73) compared to women interviewed while they were not pregnant (53% [319/605] low-dose aspirin vs. 51% [307/606] placebo, P=0.49) (Table 3). For interviews conducted while the participant was not pregnant, only “swelling” significantly varied by treatment arm (3% [20/605] low-dose aspirin vs. 2% [9/606] placebo, P=0.04); among women who were pregnant at the time of the interview, there were no differences in symptoms reported by treatment arm.
In terms of maternal complications, the proportions of participants with preterm contractions, subchorionic hemorrhage, epistaxis, emesis, kidney stones, premature separation of placenta, and postpartum hemorrhage were similar between treatment arms. Vaginal bleeding occurred in a higher proportion of participants in the low-dose aspirin arm (22% [138/615] low-dose aspirin vs. 17% [104/613] placebo, P=0.02) as did the combined outcome of vaginal bleeding during pregnancy and/or subchorionic hemorrhage (26% in low-dose aspirin vs. 20% in placebo, P=0.01) (Table 4). Emesis was the most common maternal complication and occurred in similar proportion of participants between treatment arms (49% [299/615] low-dose aspirin vs. 46% [279/613] placebo, P=0.28). No maternal deaths were reported. As previously reported (7), pregnancy loss was similar between treatment arms (13% low-dose aspirin vs. 13% placebo, P=0.78).
Few fetal and neonatal complications occurred. There were 3 fetal deaths at >20 weeks of gestation (1 in low-dose aspirin vs. 2 in placebo, P=0.57) and 3 neonatal deaths (2 in low-dose aspirin vs. 1 in placebo, P=0.71) (Table 5). The fetal death in the low-dose aspirin group was due to a cord accident. In the placebo group one fetal death was diagnosed with trisomy 18 and the other cause of fetal death was unknown. Two neonatal deaths were in severely premature infants (< 22 weeks of gestation) and one was due to injury after uterine rupture resulting from a motor vehicle accident; none were due to congenital anomalies. There was one instance in the placebo group of left cerebral artery infarction (without information on hemorrhage) and one instance in the low-dose aspirin group of transient pulmonary hypertension, which resolved at 2 weeks of life. Structural congenital anomalies were observed among ten neonates (none were considered major, 8 were considered minor and reported previously, 2 were considered anomalies but not birth defects (7)): in the low-dose aspirin arm there were three cases of ventricular septal defect, one case of cleft palate with cleft lip, and one case of fetal hydronephrosis in the right kidney; in the placebo arm there was a case of ventricular septal defect in conjunction with two other heart defects (atrial septal defect and another heart defect, unspecified), a case of clubfoot, a case of patent foramen ovale, a case of one functioning kidney, and a case of suspected hypospadias.
In a large, randomized, placebo-controlled trial of women with a history of pregnancy loss, low-dose aspirin initiated prior to conception was associated with a low incidence of harm. Although rare but serious adverse health outcomes due to low-dose aspirin cannot be completely ruled out, preconception low-dose aspirin appears to be well tolerated by women trying to conceive, women who become pregnant and by their fetuses and neonates. Adverse effects in both women and their fetuses/neonates were similar between the low-dose aspirin and placebo treatment arms, with the exception of medical record-based reporting of unusual or excessive vaginal bleeding (22% low-dose aspirin, 17% placebo). However, as previously reported, pregnancy loss was similar between treatment arms (7). In light of our recent findings of higher live birth and lower preterm birth with low-dose aspirin treatment in women with a single recent pregnancy loss, the present findings regarding the safety of low-dose aspirin are reassuring.
Our findings are consistent with pooled analyses of low-dose aspirin use initiated after the first trimester indicating no differences in maternal death, postpartum hemorrhage, maternal blood loss, placental abruption, admission to special care baby units, intracranial or intraventricular hemorrhage, or other neonatal bleeding (1, 2). However, previous low-dose aspirin trials in pregnant women have not evaluated vaginal bleeding or subchorionic hemorrhage. We observed conflicting results regarding vaginal bleeding, with data from systemic safety interviews showing no difference by treatment arm, but medical record-based reports showing higher vaginal bleeding (with or without subchorionic hemorrhage) in the low-dose aspirin arm. One explanation may be more frequent recording in medical records of severe bleeding, but less frequent recording of bleeding considered mild by the care provider. If anything, trials of low-dose aspirin in pregnant women report lower risks of health complications, including preeclampsia, preterm birth, intrauterine growth restriction, and perinatal mortality (1, 2). No prior low-dose aspirin trials enrolled women preconceptionally, so our findings regarding non-pregnant low-dose aspirin users are novel.
The potential for low-dose aspirin to harm fetal development was of particular concern in our trial as women received treatment during the first trimester, a time when most malformations occur. Longer term fetal harm due to in utero exposure to low-dose aspirin is largely unexplored, but a large randomized trial of 60 mg low-dose aspirin initiated after the first trimester demonstrated that 18-month old infants showed no increased risk of congenital malformations, major motor deficit, or severe neuromotor or developmental delay compared to unexposed infants (13). Likewise, we found a similar number of infants with structural congenital malformations in each treatment arm. These findings differ from previous observational studies of aspirin use during the first trimester which noted increased gastroschisis (14–16); cryptorchidism (17); and oral clefts, neural tube defects, micropthalmia, and limb body wall defects (18), but are similar to other large studies reporting no association with birth defects overall (19, 20). Furthermore, no association between low-dose aspirin and malformations has been reported, possibly because low-dose aspirin is metabolized in maternal hepatic circulation resulting in low fetal exposure (21). Alternatively, our study and others may be underpowered to detect effects on specific birth defects.
Of note, high doses of cyclo-oxygenase inhibitors, including aspirin, have been associated with premature closure of the ductus arteriosus, which may lead to persistent pulmonary hypertension (22–24). Accordingly, our case of pulmonary hypertension in an infant exposed to low-dose aspirin raises concern. However, this link, especially regarding low-dose aspirin, remains uncertain as systematic reviews have not noted this association (1, 2).
The major limitation of our study was insufficient sample size to assess rare but potentially serious complications such as specific birth defects, which are individually prevalent in fewer than 10 per 10,000 live births (25). In addition, our population included healthy, mostly well-educated, non-Hispanic white women of high socio-economic status, with 1–2 prior pregnancy losses, limiting generalizability to other populations. In addition, our study excluded women with major medical disorders, which might explain the lower risk of certain pregnancy conditions compared to other populations. However, the parent study was a large randomized, double-blind, placebo-controlled trial providing balanced measured and unmeasured baseline characteristics between treatment arms. High quality data regarding health complications were obtained via both medical records and patient questionnaires, including over 13,000 safety interviews.
In summary, preconception low-dose aspirin was well-tolerated and most self-reported symptoms were similar between treatment arms. Also, no increase in the risk of congenital malformations or other health complications was associated with low-dose aspirin. With such low and varied incidences of maternal and fetal complications to consider, large registries and meta-analyses will be needed to assess the risk of yet unknown rare but serious complications in ongoing clinical-use cohorts and additional studies, respectively. Future analyses should also consider pre vs. post-conception initiation of therapy separately.
The authors thank the Effects of Aspirin in Gestation and Reproduction participants for their extraordinary commitment to the study, all of the trial investigators and staff who devoted their time and energy to the success of this trial, and the members of the data safety monitoring board for continuous oversight, constant support, and advice throughout the trial. The authors also thank Dr. Kerri Kissell, Acting Section Chief, Department of Endocrinology, Guthrie Clinic, Sayre, Pennsylvania, for her assistance coding chart abstractions data.
Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Health and Human Development (National Institutes of Health, Bethesda, MD, USA; contract numbers HHSN267200603423, HHSN267200603424, and HHSN267200603426).
Presented at the 27th annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research in Seattle, Washington USA on June 24-27, 2014.
The authors did not report any potential conflicts of interest.