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.
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.
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.
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.
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.
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.
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.
Local treatment for cervical intraepithelial neoplasia (CIN) by Loop Electrosurgical Excision Procedure (LEEP) has been correlated with reproductive morbidity, while the cervicovaginal microbiota is ...also known to affect the risk of preterm delivery. CIN and treatment by LEEP might change the cervical microbiota. The main aim of this study was to describe the cervical microbiota before and after LEEP and assess its associaton with cone depth and HPV persistence. Further, we aimed to compare the microbiota to references with normal cervical cytology.
Between 2005 and 2007, we prospectively identified 89 women planned for LEEP in a Norwegian hospital and recruited 100 references with a normal cervical cytology. Endocervical swabs were collected prior to treatment and at six (n = 77) and 12 months (n = 72) post LEEP for bacterial culture and PCR, and post LEEP for DNA testing for human papillomavirus (HPV). We compared the cervical microbiota composition before and after treatment and between women planned for LEEP vs references.
There was a reduction in the number of non-Lactobacillus bacterial species six and 12 months after LEEP compared to before treatment and a tendency towards a concomitant increase in Lactobacillus. No association between the detection of cervical bacteria, HPV persistence or cone depth was found. Women planned for LEEP carried significantly more Bacteroides spp., Gardnerella vaginalis, Mycoplasma hominis and Ureaplasma parvum as well as a greater number of bacterial species than the references.
Local excisional treatment appears to alter the cervical microbiota towards a less diverse microbiota. Women with CIN have a more diverse cervical microbiota compared to women with normal cervical cytology.
Birth by caesarean section (CS) is associated with development of allergic diseases, but its role in the development of atopic dermatitis (AD) is less convincing.
Our primary aim was to determine if ...birth mode was associated with AD in 3-year-olds and secondarily to determine if birth mode was associated with early onset and/or persistent AD in the first 3 years of life.
We included 2129 mother–child pairs from the Scandinavian population-based prospective PreventADALL cohort with information on birth mode including vaginal birth, either traditional (81.3%) or in water (4.0%), and CS before (6.3%) and after (8.5%) onset of labor. We defined early onset AD as eczema at 3 months and AD diagnosis by 3 years of age. Persistent AD was defined as eczema both in the first year and at 3 years of age, together with an AD diagnosis by 3 years of age.
AD was diagnosed at 3, 6, 12, 24, and/or 36 months in 531 children (25%). Compared to vaginal delivery, CS was overall associated with increased odds of AD by 3 years of age, with adjusted odds ratio (95% confidence interval) of 1.33 (1.02-1.74), and higher odds of early onset AD (1.63, 1.06-2.48). The highest odds for early onset AD were observed in infants born by CS after onset of labor (1.83, 1.09-3.07). Birth mode was not associated with persistent AD.
CS was associated with increased odds of AD by 3 years of age, particularly in infants presenting with eczema at 3 months of age.
Excisional treatment of cervical intraepithelial neoplasia or very early stages of cervical cancer increases the risk of preterm prelabor rupture of membranes in subsequent pregnancies. The risk ...increases with the length of the excised cone. The subset of cases with preterm prelabor rupture of membranes and a history of cervical excisional treatment could also be at higher risk of intraamniotic infection/inflammation. However, there is a paucity of relevant information on this subject.
This study aimed to assess the differences in the rates of intraamniotic infection/inflammation and early-onset neonatal sepsis between singleton preterm prelabor rupture of membranes pregnancies without and with a history of cervical excisional treatment, and to investigate the association between these complications of preterm prelabor rupture of membranes and the excised cone length.
This retrospective cohort study included 770 preterm prelabor rupture of membranes pregnancies in which transabdominal amniocentesis was performed as part of standard clinical management to assess the intraamniotic environment. The maternal and perinatal medical records of all included women were reviewed to obtain information on the absence or presence of history of cervical excisional treatment and neonatal outcomes. Women whose records contained any information on history of cervical excisional treatment were contacted by phone and in writing to inform them of the study and request permission to collect relevant information from their medical records. Women were divided into 4 subgroups according to the presence of microorganisms and/or their nucleic acids (through culturing and molecular biology methods) in amniotic fluid and/or intraamniotic inflammation (through amniotic fluid interleukin-6 concentration evaluation): intraamniotic infection (presence of both), sterile intraamniotic inflammation (intraamniotic inflammation alone), microbial invasion of the amniotic cavity without inflammation (presence of microorganisms and/or their nucleic acids in amniotic fluid alone), and negative amniotic fluid for infection/inflammation (absence of both).
A history of cervical excisional treatment was found in 10% (76/765) of the women. Of these, 82% (62/76) had a history of only 1 treatment, and information on cone length was available for 97% (60/62) of them. Women with a history of cervical excisional treatment had higher rates of intraamniotic infection (with, 25% 19/76 vs without, 12% 85/689; adjusted odds ratio, 2.5; adjusted P=.004), microbial invasion of the amniotic cavity without inflammation (with, 25% 19/76 vs without, 11% 74/689; adjusted odds ratio, 3.1; adjusted P<.0001), and early-onset neonatal sepsis (with, 8% 11/76 vs without, 3% 23/689; adjusted odds ratio, 2.9; adjusted P=.02) compared with those without such history. Quartiles of cone length (range: 3–32 mm) were used to categorize the women into 4 quartile subgroups (first: 3–8 mm; second: 9–12 mm; third: 13–17 mm; and fourth: 18–32 mm). Cone length of ≥18 mm was associated with higher rates of intraamniotic infection (with, 29% 5/15 vs without, 12% 85/689; adjusted odds ratio, 3.0; adjusted P=.05), microbial invasion of the amniotic cavity without inflammation (with, 40% 6/15 vs without, 11% 74/689; adjusted odds ratio, 6.1; adjusted P=.003), and early-onset neonatal sepsis (with, 20% 3/15 vs without, 3% 23/689; adjusted odds ratio, 5.7; adjusted P=.02).
History of cervical excisional treatment increases risks of intraamniotic infection, microbial invasion of the amniotic cavity without inflammation, and development of early-onset neonatal sepsis in a subsequent pregnancy complicated by preterm prelabor rupture of membranes.
Excisional treatment of cervical intraepithelial neoplasia or very early stages of cervical cancer increases the risk of preterm prelabor rupture of membranes (PPROM) in subsequent pregnancies. The ...risk increases with the length of the excised cone. The subset of PPROM with a history of cervical excisional treatment could also be jeopardized by a higher risk intra-amniotic infection/inflammation . However, there is a paucity of relevant information on this field.To assess the differences in the rates of intra-amniotic infection/inflammation and early-onset neonatal sepsis between singleton PPROM pregnancies without and with a history of cervical excisional treatment and to identify an association between these complications of PPROM and the excised cone length.This retrospective cohort study included 770 PPROM pregnancies in whom transabdominal amniocentesis was performed as part of standard clinical management to determine intra-amniotic environment. The maternal and perinatal medical records of all included women were reviewed to obtain information on the absence or presence of a history of cervical excisional treatment and neonatal outcomes. Women whose records contained any information on a history of cervical excisional treatment were contacted by phone and in writing to inform them of the study and request permission to collect relevant information from their medical records. Women were divided into four subgroups according to the presence of microorganisms and/or their nucleic acids (through culturing and molecular biology method) in amniotic fluid and/or intra-amniotic inflammation (through amniotic fluid interleukin-6 concentration evaluation): intra-amniotic infection (presence of both), sterile intra-amniotic inflammation (intra-amniotic inflammation alone), microbial invasion of the amniotic cavity without inflammation (the presence of microorganisms and/or their nucleic acids in amniotic fluid alone), and negative amniotic fluid for infection/inflammation (absence of both).A history of cervical excisional treatment was found in 10% (76/765) of the women. Of these, 82% (62/76) had a history of only one treatment, and information on the cone length was available for 97% (60/62) of them. Women with a history of cervical excisional treatment had higher rates of intra-amniotic infection with: 25% (19/76) vs. without: 12% (85/689), adj. OR: 2.5, adj. p = 0.004, microbial invasion of the amniotic cavity without inflammation with: 25% (19/76) vs. without: 11% (74/689), adj. OR: 3.1, adj. p < 0.0001, and early-onset neonatal sepsis with: 8% (11/76) vs. without: 3% (23/689), adj. OR: 2.9, adj. p = 0.02 than those without cervical excisional treatment. Quartiles of the cone length (range: 3-32 mm) were used to categorize the women into four quartile subgroups (1st quartile: 3-8 mm; 2nd quartile: 9-12 mm; 3rd quartile: 13-17 mm, and 4th quartile: 18-32 mm). Cone length of ≥ 18 mm was associated with higher rates of intra-amniotic infection with: 29% (5/15) vs. without: 12% (85/689), adj. OR: 3.0, adjusted p = 0.05, microbial invasion of the amniotic cavity without inflammation with: 40% (6/15) vs. without: 11% (74/689), adj. OR: 6.1, adj. p = 0.003), and early-onset neonatal sepsis with: 20% (3/15) vs. without: 3% (23/689), adj. OR: 5.7, adj. p = 0.02.History of cervical excisional treatment increases risks of intra-amniotic infection, microbial invasion of the amniotic cavity without inflammation, and development of early-onset neonatal sepsis in a subsequent pregnancy complicated by preterm prelabor rupture of membranes.
Skin emollients applied during early infancy could prevent atopic dermatitis, and early complementary food introduction might reduce food allergy in high-risk infants. The study aimed to determine if ...either regular skin emollients applied from 2 weeks of age, or early complementary feeding introduced between 12 and 16 weeks of age, reduced development of atopic dermatitis by age 12 months in the general infant population.
This population-based 2×2 factorial, randomised clinical trial was done at Oslo University Hospital and Østfold Hospital Trust, Oslo, Norway; and Karolinska University Hospital, Stockholm, Sweden. Infants of women recruited antenatally at the routine ultrasound pregnancy screening at 18 weeks were cluster-randomised at birth from 2015 to 2017 to the following groups: (1) controls with no specific advice on skin care while advised to follow national guidelines on infant nutrition (no intervention group); (2) skin emollients (bath additives and facial cream; skin intervention group); (3) early complementary feeding of peanut, cow's milk, wheat, and egg (food intervention group); or (4) combined skin and food interventions (combined intervention group). Participants were randomly assigned (1:1:1:1) using computer- generated cluster randomisation based on 92 geographical living area blocks as well as eight 3-month time blocks. Carers were instructed to apply the interventions on at least 4 days per week. Atopic dermatitis by age 12 months was the primary outcome, based on clinical investigations at 3, 6 and 12 months by investigators masked to group allocation. Atopic dermatitis was assessed after completing the 12-month investigations and diagnosed if either of the UK Working Party and Hanifin and Rajka (12 months only) diagnostic criteria were fulfilled. The primary efficacy analyses was done by intention-to-treat analysis on all randomly assigned participants. Food allergy results will be reported once all investigations at age 3 years are completed in 2020. This was a study performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment). The study is registered at clinicaltrials.gov, NCT02449850.
2697 women were recruited between Dec 9, 2014, and Oct 31, 2016, from whom 2397 newborn infants were enrolled from April 14, 2015, to April 11, 2017. Atopic dermatitis was observed in 48 (8%) of 596 infants in the no intervention group, 64 (11%) of 575 in the skin intervention group, 58 (9%) of 642 in the food intervention group, and 31 (5%) of 583 in the combined intervention group. Neither skin emollients nor early complementary feeding reduced development of atopic dermatitis, with a risk difference of 3·1% (95% CI –0·3 to 6·5) for skin intervention and 1·0% (–2·1 to 4·1) for food intervention, in favour of control. No safety concerns with the interventions were identified. Reported skin symptoms and signs (including itching, oedema, exanthema, dry skin, and urticaria) were no more frequent in the skin, food, and combined intervention groups than in the no intervention group.
Neither early skin emollients nor early complementary feeding reduced development of atopic dermatitis by age 12 months. Our study does not support the use of these interventions to prevent atopic dermatitis by 12 months of age in infants.
The study was funded by several public and private funding bodies: The Regional Health Board South East, The Norwegian Research Council, Health and Rehabilitation Norway, The Foundation for Healthcare and Allergy Research in Sweden-Vårdalstiftelsen, Swedish Asthma and Allergy Association's Research Foundation, Swedish Research Council—the Initiative for Clinical Therapy Research, The Swedish Heart-Lung Foundation, SFO-V at the Karolinska Institute, Freemason Child House Foundation in Stockholm, Swedish Research Council for Health, Working Life and Welfare—FORTE, Oslo University Hospital, the University of Oslo, and Østfold Hospital Trust.
Introduction
Increasing evidence suggests that cervical intraepithelial neoplasia, with or without subsequent treatment, is associated with preterm delivery. We aimed to explore the association ...between abnormal cervical cytology of different severity and the subsequent obstetric outcomes such as preterm delivery.
Material and methods
The historical register‐based cohort study comprised 19 822 women in the Western Region of Sweden who had at least one abnormal cervical cytology from 1978 to 2012 before the age of 45 and a subsequent singleton delivery. The reference group comprised 39 644 women with normal cervical cytology and a subsequent singleton delivery, matched by age and parity. Data were retrieved from the Swedish National Cervical Screening Registry, linked to the Swedish Medical Birth Register and Statistic Sweden. The study outcomes were spontaneous preterm delivery before 37 and 34 weeks, low birthweight (≤2500 g), small‐for‐gestational‐age, preterm premature rupture of membranes and neonatal mortality. Multivariable log binominal regression analyses were applied.
Results
Preterm delivery before 37 weeks was more common among women with abnormal cervical cytology compared with reference group: 6% vs 4.5%; adjusted relative risk 1.30 (95% confidence interval 1.21‐1.39). High vs low‐grade abnormal cervical cytology implied a higher risk: 7% vs 5.8% (P < 0.001). Early preterm delivery before 34 weeks, preterm premature rupture of membranes and low birthweight, but not small‐for‐gestational‐age and neonatal mortality, were significantly more common in women with abnormal cervical cytology compared with the reference group.
Conclusions
Abnormal cervical cytology may imply an increased risk of preterm delivery. Further studies are needed to investigate whether that risk is related to treatment.
Knowledge on prevalence and association of human papillomavirus (HPV) in third trimester placentae and adverse pregnancy outcomes is limited. We investigated the prevalence of placental HPV at ...delivery, explored urine HPV characteristics associated with placental HPV and whether placental HPV increased the risk adverse pregnancy outcomes.
Pregnant women were enrolled in the Scandinavian PreventADALL mother-child cohort study at midgestation. Human papillomavirus genotyping was performed on placental biopsies collected at delivery (n = 587) and first-void urine at midgestation and delivery (n = 556). Maternal characteristics were collected by questionnaires at gestational week 18 and 34. Adverse pregnancy outcomes were registered from chart data including hypertensive disorders of pregnancy, gestational diabetes mellitus and newborns small for gestational age. Uni- and multivariable regression models were used to investigate associations.
Placental HPV was detected in 18/587 (3 %). Twenty-eight genotypes were identified among the 214/556 (38 %) with midgestational urine HPV. Seventeen of the 18 women with placental HPV were midgestational HPV positive with 89 % genotype concordance. Midgestational high-risk-(HR)-HPV and high viral loads of Any- or HR-HPV were associated with placental HPV. Persisting HPV infection from midgestation to delivery was not associated with placental HPV. Adverse pregnancy outcomes were seen in 2/556 (0.4 %) of women with placental HPV.
In this general cohort of pregnant women, the prevalence of placental HPV was 3 %, and midgestational urinary HPV 38 %. High HPV viral load increased the risk for placental HPV infections. We observed no increased risk for adverse pregnancy outcomes in women with placental HPV.
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•Prevalence of third trimester placental HPV at delivery was low.•Genotype concordance between midgestational urine HPV and placental HPV at delivery was high.•Midgestational urine HR-HPV is associated with placental HPV at delivery.•High HPV viral load in midgestational urine is associated with placental HPV.•Few women had placental dysfunction syndromes and placental HPV at delivery.
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