Verena Sengpiel

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

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.

Associations between cervical intraepithelial neoplasia during pregnancy, previous excisional treatment, cone-length and preterm delivery: a register-based study from western Sweden

Abstract Background Excisional treatment of cervical intraepithelial neoplasia (CIN) has been associated with increased risk of preterm delivery (PTD), although the underlying mechanism is as yet unclear. Studies on formalin-fixed excised tissue indicate that the risk increases with cone-length, but the magnitude of increase is uncertain, especially in case of minor excisions (≤10 mm), as well compared to women with untreated CIN during pregnancy. This study assesses the impact of cone-length at previous treatment for CIN as well as diagnosis of CIN during pregnancy on the risk of PTD. Methods A register-based cohort study in western Sweden linking cervical cytology, histology, and treatment data from the Swedish National Cervical Screening Registry to data on obstetric outcomes in singleton pregnancies 2008–2016 from the Swedish Medical Birth Registry. These groups were compared for PTD and other obstetric outcomes: (1) women with one excisional treatment (n=3250, including a subgroup (n=2408) with cone-length measured before fixation; (2) women with untreated CIN diagnosed during pregnancy (n=1380); and (3) women with normal cytology (n=42,398). Logistic regression analyses were adjusted for socioeconomic and health-related confounders. Results Treated women had increased risk of PTD (adjusted odds ratio (aOR) 1.60, 95% confidence interval (CI) 1.21–2.12), spontaneous PTD (aOR 1.95, 95% CI 1.40–2.72) and preterm prelabor rupture of membranes (pPROM) (aOR 2.74, 95% CI 1.66–4.51) compared to the CIN during pregnancy group. ORs were similar when compared to the normal cytology group. Risks of these outcomes increased with cone-length. Mean cone-length was 9.1 mm. Cone-length ≤10 mm was associated with increased risk of PTD (aOR 1.41, 95% CI 1.02–1.94), spontaneous PTD (aOR 1.73, 95% CI 1.18–2.54), and pPROM (aOR 2.44, 95% CI 1.40–4.28), compared to the CIN during pregnancy group. The PTD risk was similar for cone-lengths 3–10 mm, thereafter increasing by 15% with each additional millimeter. Conclusions This study suggests that all excisional treatment, including small cones, are associated with increased risk of PTD and pPROM. Risks increase further with cone-length. In women of reproductive age, clinicians should aim to remove all CIN but minimal healthy cervical tissue. Cone-length should be recorded at treatment, for future prenatal risk estimation.

Pregnancy Outcomes in Women With a Prior Cervical Intraepithelial Neoplasia Grade 3 Diagnosis

Treatment of cervical intraepithelial neoplasia grade 3 (CIN 3) removes or destroys part of the cervix and might subsequently influence pregnancy outcomes. To investigate pregnancy outcomes in women diagnosed with CIN 3. Population- and sibling-matched cohort study. Sweden, 1973 to 2018. The general population comparison included 78 450 singletons born to women diagnosed with CIN 3 and 784 500 matched singletons born to women in the general population who had no CIN 3 diagnosis; the sibling comparison included 23 199 singletons born to women diagnosed with CIN 3 and 28 135 singletons born to their sisters without a CIN 3 diagnosis. Preterm birth, including spontaneous or iatrogenic preterm birth; infection-related outcomes, including chorioamnionitis and infant sepsis; and early neonatal death, defined as death during the first week after birth. Compared with the matched general population, women previously diagnosed with CIN 3 were more likely to have a preterm birth, especially extremely preterm (22 to 28 weeks; odds ratio [OR], 3.00 [95% CI, 2.69 to 3.34]) or spontaneous preterm (OR, 2.12 [CI, 2.05 to 2.20]); infection-related outcomes, including chorioamnionitis (OR, 3.23 [CI, 2.89 to 3.62]) and infant sepsis (OR, 1.72 [CI, 1.60 to 1.86]); or early neonatal death (OR, 1.83 [CI, 1.61 to 2.09]). Sibling comparison analyses rendered largely similar results. Over time, the risk difference attenuated for all outcomes and disappeared for early neonatal death. Lack of data on CIN 3 treatment and spontaneous abortion. History of CIN 3 is associated with adverse pregnancy outcomes even after accounting for familial factors. Decreasing risk estimates over time suggest that adverse pregnancy outcomes among women diagnosed with CIN 3 may be minimized by improving treatment methods. The Swedish Research Council, the Swedish Cancer Society, and the Swedish Research Council for Health, Working Life and Welfare.