Women at risk of preterm birth who took daily low-dose aspirin did not have significantly lower rates of preterm birth than those who did not take aspirin, according to preliminary findings from a small randomized controlled trial. There was a trend toward lower rates, especially among those with the highest compliance, but the study was underpowered to detect a difference with statistical significance, said Anadeijda Landman, MD, of the Amsterdam University Medical Center. Dr. Landman presented the findings Jan. 28 at a meeting sponsored by the Society for Maternal-Fetal Medicine.
Dr. Anadeijda Landman
Preterm birth accounts for a third of all neonatal mortality, she told attendees. Among 15 million preterm births worldwide each year, 65% are spontaneous, indicating the need for effective preventive interventions. Dr. Landman reviewed several mechanisms by which aspirin may help reduce preterm birth via different pathways.
The researchers’ multicenter, placebo-controlled trial involved 8 tertiary care and 26 secondary care hospitals in the Netherlands between May 2016 and June 2019. Starting between 8 and 15 weeks’ gestation, women took either 80 mg of aspirin or a placebo daily until 36 weeks’ gestation or delivery. Women also received progesterone, cerclage, or pessary as indicated according to local protocols.
The study enrolled 406 women with singleton pregnancy and a history of preterm birth delivered between 22 and 37 weeks’ gestation. The final analysis, after exclusions for pregnancy termination, congenital anomalies, multiples pregnancy, or similar reasons, included 193 women in the intervention group and 194 in the placebo group. The women had similar baseline characteristics across both groups except a higher number of past mid-trimester fetal deaths in the aspirin group.
“It’s important to realize these women had multiple preterm births, as one of our inclusion criteria was previous spontaneous preterm birth later than 22 weeks’ gestation, so this particular group is very high risk for cervical insufficiency as a probable cause,” Dr. Landman told attendees.
Among women in the aspirin group, 21.2% delivered before 37 weeks, compared with 25.4% in the placebo group (P = .323). The rate of spontaneous birth was 20.1% in the aspirin group and 23.8% in the placebo group (P = .376). Though still not statistically significant, the difference between the groups was larger when the researchers limited their analysis to the 245 women with at least 80% compliance: 18.5% of women in the aspirin group had a preterm birth, compared with 24.8% of women in the placebo group (P = .238).
There were no significant differences between the groups in composite poor neonatal outcomes or in a range of prespecified newborn complications. The aspirin group did have two stillbirths, two mid-trimester fetal losses, and two extremely preterm newborns (at 24+2 weeks and 25+2 weeks). The placebo group had two mid-trimester fetal losses.
“These deaths are inherent to the study population, and it seems unlikely they are related to the use of aspirin,” Dr. Landman said. “Moreover other aspirin studies have not found an increased perinatal mortality rate, and some large studies indicated the neonatal mortality rate is even reduced.”
Although preterm birth only trended lower in the aspirin group, Dr. Landman said the researchers believe they cannot rule out an effect from aspirin.
“It’s also important to note that our study was underpowered as the recurrence risk of preterm birth in our study was lower than expected, so it’s possible a small treatment effect of aspirin could not be demonstrated in our study,” she said. “And, despite the proper randomization procedure, many more women in the aspirin group had a previous mid-trimester fetal loss. This indicates that the aspirin group might be more at risk for preterm birth than the placebo group, and this imbalance could also have diminished a small protective effect of aspirin.”
In response to an audience question, Dr. Landman acknowledged that more recent studies on aspirin have used 100- to 150-mg dosages, but that evidence was not as clear when their study began in 2015. She added that her research team does not advise changing clinical care currently and believes it is too soon to recommend aspirin to this population.
Dr. Tracy Manuck
Tracy Manuck, MD, MS, an associate professor of ob.gyn. at the University of North Carolina in Chapel Hill, agreed that it is premature to begin prescribing aspirin for preterm birth prevention, but she noted that most of the patients she cares for clinically already meet criteria for aspirin based on their risk factors for preeclampsia.
“Additional research is needed in the form of a well-designed and large [randomized, controlled trial],” Dr Manuck, who moderated the session, said in an interview. “However, such a trial is becoming increasingly difficult to conduct because so many pregnant women qualify to receive aspirin for the prevention of preeclampsia due to their weight, medical comorbidities, or prior pregnancy history.”
She said she anticipates seeing patient-level data meta-analyses in the coming months as more data on aspirin for preterm birth prevention are published.
“Given that these data are supportive of the overall trends seen in prior publications, I do think that low-dose aspirin will eventually bear out as a helpful preventative measure to prevent recurrent preterm birth. Aspirin is low risk, readily available, and is inexpensive,” Dr. Manuck said. “I hope that meta-analysis data will provide additional information regarding the benefit of low-dose aspirin for prematurity prevention.”
The research was funded by the Dutch Organization for Health Care Research and the Dutch Consortium for Research in Women’s Health. Dr. Landman and Dr. Manuck had no disclosures.