HPV vaccination before pregnancy was linked to slightly lower odds of preterm birth in 624,713 Swedish births

The vaccine against human papillomavirus, or HPV, was introduced to prevent cervical cancer. A study of first births across Sweden over 18 years suggests it may be doing something else as well. Women who had been vaccinated before they became pregnant were a little less likely to give birth too early.

The differences are small, and the study, published this week in The BMJ, cannot show that the vaccine produced them. But the pattern fits what is already known about the virus and the cervix, and it was strongest in the women vaccinated youngest, which is what would be expected if the effect were real. One of the obstetricians who commented on the work was not persuaded.

Why HPV might affect pregnancy outcomes

HPV is a very common infection passed on through sex. Most infections clear, but some persist, and a few types cause cancer. The vaccine used in this study is called quadrivalent. The quadrivalent HPV vaccine targets four types of HPV, including two (HPV types 16 and 18) that are responsible for about 70% of all cervical cancers.

There are two ways the virus could harm a pregnancy.

The first is through treatment. Persistent infection can produce precancerous changes in the cervix, which are removed or destroyed to prevent cancer. That protects the woman and weakens the cervix. A review in The BMJ pooling 71 studies found that 10.7% of women who had been treated went on to deliver before 37 weeks, against 5.4% of women who had not. Techniques removing or ablating more tissue were associated with worse outcomes, ablating meaning destroying. “Surgery on the cervix is a well-known risk factor for preterm birth,” said Kevin Ault, an obstetrician-gynecologist at Penn State Health who was not involved in the Swedish study.

The second is the infection itself. A Canadian study followed 899 pregnant women and tested them for the virus. Its authors concluded that persistent HPV-16/18 infection is associated with an increased risk of preterm birth, independent of cervical treatment. They ended with a request: future studies should investigate the association of HPV vaccination and vaccination programs with the risk of preterm birth.

How the Swedish pregnancy study was done

The new paper is one answer to that request. It is a nationwide, population based matched case-control study drawing on Sweden’s health registers.

The population it drew on was 624,713 singleton births among nulliparous women aged 16-35 years in Sweden between 2006 and 2023. Singleton means one baby, and nulliparous means a woman who has not given birth before. Of those mothers, 92,620, or 14.8%, were women who had received quadrivalent human papillomavirus vaccination before pregnancy.

In a case-control study, researchers start from the outcome. Here the cases were women whose pregnancy had gone wrong in one of several defined ways, such as a preterm birth, a stillbirth or a baby much smaller than expected. Each case was matched with up to 10 control women of the same age and year of conception whose pregnancy had not gone wrong in that way. The question is then whether vaccination was less common among the cases.

The analysis adjusted for other things that affect pregnancy. They included self-reported cigarette smoking and body mass index at first antenatal visit, along with the mother’s existing diagnoses, use of fertility treatment, country of birth, family income and education. Body mass index is a measure of weight for height, and antenatal means during pregnancy.

Most of the vaccinated women had received the vaccine as teenagers. In the study, mothers vaccinated against HPV were immunized at a median age of 16.

Lower odds of preterm birth, by a small margin

After those adjustments, quadrivalent human papillomavirus vaccination was associated with lower odds of all included adverse pregnancy outcomes. For several of them the difference was too small to separate from chance. These were the ones the authors counted as clear, though for waters breaking early the range just touches no difference.

Outcome	Odds in vaccinated women compared with unvaccinated	Plausible range
Preterm birth, before 37 weeks	5% lower	1% to 9% lower
Very preterm birth, 28 to 31 weeks	15% lower	3% to 25% lower
Preterm birth that began without being induced	5% lower	1% to 9% lower
Waters breaking early, before 37 weeks	7% lower	0% to 13% lower
Severely small baby for the stage of pregnancy	8% lower	3% to 13% lower

A 5% reduction in odds is modest for any one woman. A sense of scale comes from the review of cervical treatment, in which 5.4% of untreated women delivered preterm. Odds 5% lower than that would mean roughly three fewer preterm births in every 1,000. That figure is an illustration from another dataset; the Swedish paper reports relative differences.

The researchers argue that small differences add up. Jiayao Lei of Karolinska Institutet, one of the authors, made the point in the university’s announcement that HPV vaccination is administered to millions of young people worldwide, so that even a slight shift matters across a population.

The authors’ own summary goes further. They describe the result as extending benefits of human papillomavirus vaccination beyond cancer prevention.

Earlier HPV vaccination, stronger link

One feature of the data is what a real effect would produce. Risk reduction was generally more pronounced among women vaccinated at younger ages.

The cut-off examined was 17. Among women vaccinated before age 17, the risk of premature delivery was 10% lower than among unvaccinated mothers, twice the overall figure. “We also observed that the associations were stronger among women who had been vaccinated before the age of 17,” said Zhongsong Zhang, the doctoral student at Karolinska Institutet who is first author.

The logic is that the vaccine prevents infection and does nothing for an infection already present. A girl vaccinated at 12 is almost certainly vaccinated before any exposure. A woman vaccinated at 22 may not be. If the vaccine were protecting pregnancies by preventing infection, early vaccination is where the protection would show.

That matters for what comes next. The women in this study were vaccinated late by current standards. In Sweden today, girls are offered HPV vaccines in school-based programs at ages 10 through 12, and coverage is far higher than the 14.8% in the study.

What other studies of HPV vaccination and preterm birth found

The Swedish paper is the largest of the three studies described here, and the others do not all agree with it.

The closest comparison is Danish. A registry study there followed 243,136 first-time mothers and looked at spontaneous preterm birth, meaning birth that starts early without being induced. Overall it found no protective link; the estimate ran slightly the other way, at odds 4% higher in vaccinated women, within the range of chance. The age pattern, though, was the same as in Sweden. Compared with unvaccinated women, the odds of preterm birth were lower among women vaccinated before the age of 17 years, by 13%, an estimate whose plausible range reached no difference. This association was not present for women vaccinated at 17 or older.

A Finnish study drew its vaccinated women from communities that had been randomly assigned to HPV vaccination in an earlier trial, and compared them with unvaccinated women born slightly earlier. It was much smaller, with about 6,200 vaccinated women. In all, 4.1% of vaccinated first-time mothers and 5.2% of unvaccinated primiparas had a preterm birth, primiparas being first-time mothers. The difference pointed toward protection but was too uncertain to be sure of. Its authors still concluded that prophylactic HPV-vaccination is likely to reduce the incidence of preterm births, prophylactic meaning preventive.

So the Swedish and Danish studies point the same way for girls vaccinated young, the Danish one without reaching certainty. For vaccination overall, one finds a small benefit, one finds none, and the Finnish study cannot tell.

Why the vaccine may not be the explanation

Who gets vaccinated. Mark Einstein, chair of obstetrics and gynecology and women’s health at Montefiore Medical Center in New York, is not among the study’s authors and raised the central doubt. “It could be that those that seek HPV vaccination are more likely to be from the social and racial demographics that put them at lower risk of preterm birth,” Einstein told CIDRAP News. The study adjusted for income, education and smoking. An adjusted difference of 5% is small enough that an unmeasured difference of the same kind could account for it.

Later vaccination was more of a choice. Half of the vaccinated women received the vaccine at 16 or older, later than school programs now deliver it. Families who sought out vaccination then may differ in health habits from those who did not.

The pathway was not traced. The authors acknowledge incomplete information on spontaneous abortions, and limited investigation of the underlying clinical pathways. Spontaneous abortion is the medical term for miscarriage. The study did not measure infections, so it could not show that vaccinated women had fewer of them and that this was what lowered their risk.

First births only. The analysis was limited to first births of a single baby in women aged 16 to 35.

An older vaccine. The women received the four-type vaccine. HPV vaccines have since been updated to protect against nine strains, and the results may not transfer exactly.

Others read the result more favorably. The lower risk appeared even among mothers who had never been treated for cervical lesions, which counts against surgery as the whole explanation. Rebecca Perkins, an obstetrician and gynecologist at Tufts Medical Center who was not involved in the study, took that as a sign that infection alone carries risk. “Infection-related risks may arise from inflammation or placental dysfunction,” Perkins said. Placental dysfunction means the placenta not working as it should.

The authors draw one conclusion that does not depend on the size of the benefit. “Together with previous research showing the safety of human papillomavirus vaccination during pregnancy, our results suggest that human papillomavirus vaccination is not only safe with respect to pregnancy outcomes but may also confer additional benefits by reducing the risk of adverse events,” they wrote. A vaccine associated with slightly better pregnancy outcomes is, at the least, not associated with worse ones.

Funding for the research came from the Swedish Research Council, the Swedish Cancer Society and other public and charitable bodies.

Decisions about vaccination depend on a person’s age and circumstances, which is assessed by their doctor.

Women vaccinated against HPV before pregnancy had about 5% lower odds of preterm birth and 15% lower odds of very preterm birth in Swedish register data on 624,713 first births, with a stronger link in those vaccinated before 17, in an observational study that could not rule out differences between women who were and were not vaccinated.