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. 2021 May 10;18(5):e1003641.
doi: 10.1371/journal.pmed.1003641. eCollection 2021 May.

Associations of treated and untreated human papillomavirus infection with preterm delivery and neonatal mortality: A Swedish population-based study

Johanna Wiik  1   2   3 , Staffan Nilsson  4   5 , Cecilia Kärrberg  1   3   6 , Björn Strander  1   6 , Bo Jacobsson  1   3   7 , Verena Sengpiel  1   3
Affiliations

Associations of treated and untreated human papillomavirus infection with preterm delivery and neonatal mortality: A Swedish population-based study

Johanna Wiik et al. PLoS Med. .

Abstract

Background: Treatment of cervical intraepithelial neoplasia (CIN) is associated with an increased risk of preterm delivery (PTD) although the exact pathomechanism is not yet understood. Women with untreated CIN also seem to have an increased risk of PTD. It is unclear whether this is attributable to human papillomavirus (HPV) infection or other factors. We aimed to investigate whether HPV infection shortly before or during pregnancy, as well as previous treatment for CIN, is associated with an increased risk of PTD and other adverse obstetric and neonatal outcomes.

Methods and findings: This was a retrospective population-based register study of women with singleton deliveries registered in the Swedish Medical Birth Register 1999-2016 (n = 1,044,023). The study population had a mean age of 30.2 years (SD 5.2) and a mean body mass index of 25.4 kg/m2 (SD 3.0), and 44% of the women were nulliparous before delivery. Study groups were defined based on cervical HPV tests, cytology, and histology, as registered in the Swedish National Cervical Screening Registry. Women with a history of exclusively normal cytology (n = 338,109) were compared to women with positive HPV tests (n = 2,550) or abnormal cytology (n = 11,727) within 6 months prior to conception or during the pregnancy, women treated for CIN3 before delivery (n = 23,185), and women with CIN2+ diagnosed after delivery (n = 33,760). Study groups were compared concerning obstetric and neonatal outcomes by logistic regression, and comparisons were adjusted for socioeconomic and health-related confounders. HPV infection was associated with PTD (adjusted odds ratio [aOR] 1.19, 95% CI 1.01-1.42, p = 0.042), preterm prelabor rupture of membranes (pPROM) (aOR 1.52, 95% CI 1.18-1.96, p < 0.001), prelabor rupture of membranes (PROM) (aOR 1.24, 95% CI 1.08-1.42, p = 0.002), and neonatal mortality (aOR 2.69, 95% CI 1.25-5.78, p = 0.011). Treatment for CIN was associated with PTD (aOR 1.85, 95% CI 1.76-1.95, p < 0.001), spontaneous PTD (aOR 2.06, 95% CI 1.95-2.17, p < 0.001), pPROM (aOR 2.36, 95% CI 2.19-2.54, p < 0.001), PROM (aOR 1.11, 95% CI 1.05-1.17, p < 0.001), intrauterine fetal death (aOR 1.35, 95% CI 1.05-1.72, p = 0.019), chorioamnionitis (aOR 2.75, 95% CI 2.33-3.23, p < 0.001), intrapartum fever (aOR 1.24, 95% CI 1.07-1.44, p = 0.003), neonatal sepsis (aOR 1.55, 95% CI 1.37-1.75, p < 0.001), and neonatal mortality (aOR 1.79, 95% CI 1.30-2.45, p < 0.001). Women with CIN2+ diagnosed within 3 years after delivery had increased PTD risk (aOR 1.18, 95% CI 1.10-1.27, p < 0.001). Limitations of the study include the retrospective design and the fact that because HPV test results only became available in 2007, abnormal cytology was used as a proxy for HPV infection.

Conclusions: In this study, we found that HPV infection shortly before or during pregnancy was associated with PTD, pPROM, PROM, and neonatal mortality. Previous treatment for CIN was associated with even greater risks for PTD and pPROM and was also associated with PROM, neonatal mortality, and maternal and neonatal infectious complications.

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Conflict of interest statement

I have read the journal´s policy and the authors of this manuscript have the following competing interests: CK has research grants for clinical trial Assar Gabrielsson’s Foundation for Cancer-Related Clinical Research, Hjalmar Svensson’s Research Foundation. She is presently head of one Swedish site of a multicenter international academic clinical HPV-vaccine trial where the sponsor, Imperial College, London, receive some support from MSD. She is a member of the Screening and colposcopy national guidelines committee, and she is the secretary of The Swedish Society for Colposcopy and Cervical Cancer Prevention/C-ARG. She has received reimbursement from Gedeon Richter for lectures on meeting arranged by the company. BS has research grants for clinical trial by the Governmental agreement with Swedish counties, ALF, and by the Region of Västra Götaland. He is presently Swedish head of an multicenter international academic clinical HPV-vaccine trial where the sponsor, Imperial College, London, receive some support from MSD. The past five years he has served as chairman of the Swedish Cervical screening coordinating committee, as chairman of the Screening and colposcopy national guidelines committee, and as head of the Cervical screening process register. He has been a member of the National Board of health and welfare evaluation committee for the Cervical screening program. He has received no financial support or reimbursement from commercial companies for any activity. BJ has research grants from the Swedish Research Council, the Research Council of Norway, the March of Dimes, and the Burroughs Wellcome Fund. During the last five years, he has performed clinical diagnostic trials for Ariosa, Natera, Vanadis, and Hologic with reimbursement costs per recruited patient. He has conducted clinical trials on probiotics in pregnancy in collaboration with BioGaia and FukoPharma. He has also been involved in the IMPACT study where Roche and Thermo Fisher paid for PLGF-analyzes. He has also arranged scientific meetings with commercial partners (ESPBC 2016) and a Nordic educational meeting on NIPT and preeclampsia screening (2017). No lectures, travel, or personal reimbursements from the companies.

Figures

Fig 1
Fig 1. Flowchart of the study population.
CIN, cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus.
Fig 2
Fig 2. Risk of preterm delivery and spontaneous preterm delivery—adjusted logistic regression.
Preterm delivery (2a); spontaneous preterm delivery (2b). Women with HPV infection had an increased risk of preterm delivery and spontaneous preterm delivery; treatment increased the risk further. aORs are given, with 95% confidence intervals in parentheses. Analyses adjusted for year of delivery, maternal age, parity, BMI, marital status, country of birth, infant’s sex, smoking, income, education level, and assisted reproduction. aOR, adjusted odds ratio; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus.
Fig 3
Fig 3. Risk of pPROM—adjusted logistic regression.
Women with HPV infection had an increased risk of pPROM; treatment increased the risk further. aORs are given, with 95% confidence intervals in parentheses. Analyses adjusted for year of delivery, maternal age, parity, BMI, marital status, country of birth, infant’s sex, smoking, income, education level, and assisted reproduction. aOR, adjusted odds ratio; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; pPROM, preterm prelabor rupture of membranes.
Fig 4
Fig 4. Venn diagram illustrating the relationship between preterm delivery (PTD), preterm prelabor rupture of membranes (pPROM), and infectious complications in the treated group and the reference group.
The treated group had PTD, pPROM, and infectious complications more frequently. PTD and deliveries after pPROM were more often complicated by infections in the treated group than in the reference group. The deliveries with infectious complications were more frequently preterm and complicated by pPROM in the treated group than in the reference group.
Fig 5
Fig 5. Venn diagram illustrating the relationship between preterm delivery (PTD), infectious complications (chorioamnionitis/neonatal sepsis), and neonatal mortality in the treated group and the reference group.
The treated group more frequently had PTD, neonatal mortality, and infectious complications. The deliveries resulting in neonatal mortality more frequently had infectious complications in the treated group than in the reference group.
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