SAN FRANCISCO -- An interval of 9 days between antibiotic doses for treating syphilis during pregnancy was less effective in preventing congenital syphilis than ensuring all intervals were 6-8 days, according to a small observational study.
Mother-infant dyads who received at least one dose of benzathine penicillin G (BPG) with a 9-day interval during pregnancy had more than triple the odds of congenital syphilis than those whose dose intervals never exceeded 8 days (OR 3.7, 95% CI 1.2-11.6), reported Kelly Johnson, MD, MPH, of the California Department of Public Health in Richmond and the University of California San Francisco.
"Given the lack of data otherwise and while awaiting larger studies with higher statistical power, clinicians should consider erring on the side of caution and avoiding intervals outside 6 to 8 days" since a randomized controlled trial will never be conducted for ethical reasons, Johnson said in a presentation at the Conference on Retroviruses and Opportunistic Infections annual meeting.
Congenital syphilis rates are currently at their highest rates since the 1990s -- 105.8 cases per 100,000 live births in 2023, a more than ten-fold increase since 2012. The key to prevention is diagnosing and treating syphilis before or during pregnancy, she said.
Currently, the only recommended treatment for late latent syphilis or syphilis of unknown duration during pregnancy is BPG, given as three weekly intramuscular injections. While the gold standard for intervals between doses is 7 days, CDC treatment guidelines for sexually transmitted infections suggest that intervals up to 9 days are acceptable without having to restart the full 3-dose series. Those recommendations regarding the 9-day interval, however, are based on expert opinion, not data.
Johnson's group demonstrated in a 2023 study that congenital syphilis is not more likely with a prenatal dose schedule using 6- to 8-day intervals, compared to 7-day intervals (OR 1.0, 95% CI 0.4-3), but that study did not assess 9-day intervals.
Using CDPH STI surveillance data, the researchers identified mother-infant dyads between 2016-2023 where the mother had late latent syphilis during pregnancy with reactive Rapid Plasma Reagin (RPR). They divided the dyads into three groups.
One group of 677 dyads received adequate treatment, with three BPG doses given at 6-to 8-day intervals and started at least 30 days before delivery. The second group of 22 dyads included those who received 3 doses of BPG with at least one 9-day interval but no intervals outside 6-9 days, also started at least 30 days before delivery. The third group of 410 dyads received no treatment or inadequate treatment.
Baseline characteristics between the dyads receiving adequate treatment and those receiving treatment with at least one 9-day interval did not significantly differ in maternal HIV status, a maternal RPR ratio of at least 1:32, presence of prenatal care, or gestational age at syphilis treatment.
The adequate treatment group had 38 cases (5.6%, P=0.01 compared to 9-day interval group) of congenital syphilis versus four cases (18.2%) in the group with an interval up to 9 days, and 151 cases (36.8%, P=0.8 compared to 9-day interval group) in the inadequate treatment group. Odds of congenital syphilis were nearly ten-fold higher in the inadequate treatment group (OR 9.8, 95% CI 6.7-14.4).
Among the four cases of congenital syphilis in the 9-day interval group, one was a syphilitic stillbirth, one had abnormal x-rays, and two had elevated cerebrospinal fluid protein/white blood cell count.
The odds of congenital syphilis approached four-fold higher among dyads who received BPG with 9-day intervals compared to 6-to 8-day intervals, which suggested, contrary to current national guidelines, that congenital syphilis may be more likely with BPG intervals extended to 9 days.
A study limitation was the small numbers of cases, which precluded the ability to control for confounders or performing adjusted analyses. Other limitations included lack of data for all variables of interest, such as maternal weight, and potentially overly sensitive congenital syphilis surveillance data criteria, though the criteria was applied uniformly across the treatment groups. In addition, all but five of the 6-to 9-day interval dyads were from a later period (July 2019-December 2023) than the 6-to 8-day interval dyads.
The findings were "very interesting" but leave a lot of questions, said Chibuzor Babalola, MD, MPH, of the University of Southern California-Klausner Research Group in Los Angeles. While the findings were very straightforward, it doesn't necessarily seem justified that 9 days would differ from 8 days in effectiveness, given what is known about the drug and how long it remains in the system, she told MedPage Today.
That said, "there are things to learn" from these findings, added Babalola, who was not involved in the study. "First of all, we don't have the data from pharmacokinetics in pregnancy, so that pauses me from jumping into the conclusion" that there is not a real difference between 8 and 9 days. The lack of data on other confounders, such as when during pregnancy the treatment was administered (besides 30 days before delivery), also makes it difficult to draw many actionable conclusions from the findings, she noted.
Ideally, the doses should be given as close to a week apart as possible, Babalola said, "but the truth is, [this] is not practical" since people will return late. Many women, particularly across the rest of the world, do not even get all three doses, she added.
author['full_name']
Tara Haelle is an independent health/science journalist based near Dallas, Texas. She has more than 15 years of experience covering a range of medical topics and conferences. Follow
Disclosures
Johnson and Babalola disclosed no relationships with industry.
Primary Source
Conference on Retroviruses and Opportunistic Infections
Source Reference: Johnson K, et al "Higher odds of congenital syphilis with 9- vs 7-day prenatal treatment intervals for late syphilis" CROI 2025; Abstract 161.