Objective
To determine the association between high-risk human papillomavirus (HR-HPV) and preeclampsia.
Methods
Retrospective cohort study of women with HR-HPV at entry to prenatal care compared with those with at least 2 normal pap smears. Preeclampsia was defined by clinical guidelines. Unadjusted and adjusted analyses were performed.
Results
Three hundred fourteen women with HR-HPV matched with 628 women with normal pap smears. Exposed HR-HPV patients were younger, had lower body mass index, systolic and diastolic blood pressure at entry to care, and more likely to be nulliparous and smokers. Exposed HR-HPV patients were more likely to develop preeclampsia (10.19% vs 4.94%; P = .004; adjusted odds ratio, 2.18; 95% confidence interval, 1.31–3.65). Women with HR-HPV were also more likely to deliver prematurely at less than 37 and less than 35 weeks.
Conclusion
HR-HPV is associated with an almost 2-fold increased risk of developing preeclampsia. This warrants a larger study, particularly when HPV infection can be prevented with vaccination.
Human papillomavirus (HPV) affects up to 80% of women in their lifetime. Although this infection is usually transient, the high-risk (HR), or oncogenic, types are more difficult to clear. In pregnancy, clearance of the virus may be even more difficult as HPV replication may be increased by progesterone and the ability to suppress infection is decreased because of a reduction in natural killer and helper T cells. This small, double stranded virus demonstrates a tropism for epithelial cells. However, infection of the placenta is possible and trophoblast cells appear to have the machinery for HPV replication.
Preeclampsia is a disease exclusive to pregnancy and remains a leading cause of maternal and fetal morbidity and mortality. Although the pathophysiology of preeclampsia is not completely understood, one proposed mechanism is abnormal placentation with reduced invasion of fetal trophoblasts. This ultimately results in the release of systemic factors that cause endothelial dysfunction and the clinical picture of elevated blood pressure and proteinuria. Whereas the association between HR-HPV and cervical dysplasia and cancer has been well established, it also appears to play a role in abnormal pregnancy outcomes. It is hypothesized that chronic cervicovaginal HPV infection leads to chronic inflammation that may predispose pregnancies to adverse outcomes. Trophoblasts have been shown to express HPV receptors and to be the primary target of HPV in spontaneously aborted products of conception by PCR amplification. HR-HPV subtypes 11, 16, 18, and 31 have also been shown to undergo complete life cycles and cause functional alterations in trophoblast cell lines including decreased viability and invasiveness. Trophoblasts mediate placental attachment to the uterus and are responsible for the establishment of low resistance maternal uterine circulation that supplies the placenta and subsequently provides nutrient and waste exchange between the fetal and maternal sides. HR-HPV trophoblast infection has been associated with increased rates of spontaneous abortion and preterm delivery. In addition, failed trophoblast invasion in early pregnancy may also lead to other adverse obstetric outcomes associated with placental dysfunction, such as preeclampsia.
Therefore, our objective was to determine whether HR-HPV infection in early pregnancy is associated with increased risk of preeclampsia.
Materials and Methods
We conducted a retrospective cohort review of women who delivered at the University of Texas Medical Branch from June 2009 to December 2011. This study was approved by the institutional review board (#11-329).
All patients who received prenatal care and delivered at University of Texas Medical Branch and had an adequate Papanicolaou smear during the index pregnancy were available for screening. We excluded women who delivered prior to 24 weeks, and those whose HR-HPV DNA testing was either unavailable or negative when that testing was clinically indicated based on their Papanicolaou smear result. Although preeclampsia may occur from 20 to 24 weeks as well, there were no patients in the HR-HPV group who delivered at this gestational age in the studied time period, and as the rate of preeclampsia at this gestational age is low, we would not expect the results to be significantly altered because of this exclusion. If patients had more than 1 pregnancy during the study period, only the first was included.
Our exposed HR-HPV group included women who were deemed to have a HR-HPV infection in pregnancy and included those whose Papanicolaou smear at entry to prenatal care was read either as low grade squamous intraepithelial lesions (LSIL), high grade squamous intraepithelial lesions (HSIL), or atypical squamous cells of undetermined significance (ASCUS) unable to rule out high grade lesions (ASCUS r/o HSIL). Patients with ASCUS on Papanicolaou smear were included in the exposed group if their HPV DNA testing was positive for high-risk types (including 16, 18, 31, 33, 35, 39, 45, 5, 52, 56, 58, 59, and 68). Papanicolaou smears were classified and patients were managed according to the performance of HPV DNA testing on patients with LSIL, HSIL, or ASCUS r/o HSIL Papanicolaou smear, as these are almost always associated with HR-HPV types.
The unexposed group included women who had 2 normal pap smears at entry to care of the index pregnancy and within 3 years of it. Relying on serial screening was deemed necessary because the sensitivity of a single cervical cytology test using liquid based cytology to detect abnormal cytology is 85%. Subjects in the unexposed group were matched to those in the HR-HPV group to within 2 days of the delivery date in a 2 to 1 ratio. Women were excluded from the unexposed group if they had any known history of abnormal Papanicolaou smears or cervical dysplasia.
Our primary outcome was preeclampsia, which was defined according to the American Congress of Obstetricians and Gynecologists guidelines as the presence of either a systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg on 2 occasions at least 6 hours apart, along with proteinuria (either ≥1+ on urine dipstick 4 hours apart or ≥300 mg in an adequately collected, timed urine sample after the 20th week of gestation). Our secondary outcomes included severity of preeclampsia, gestational age at onset, preterm delivery, and various other obstetric outcomes, which were defined according to the current guidelines of the American Congress of Obstetricians and Gynecologists.
Patients’ medical records were abstracted by reviewers blinded to the Papanicolaou smear result and group assignment. In addition, 20% of the charts were randomly selected and abstracted by a separate reviewer for validation.
Statistical methods
Statistical analyses were performed using SigmaPlot (Systat 11.0, Chicago, IL). After assessing for normality using Shapiro-Wilk test, continuous variables were compared with the use of the Student t test or Wilcoxon rank-sum test as appropriate. Categorical variables were compared with the χ 2 or Fisher exact test as appropriate. Logistic regression analysis was used to evaluate the association between HR-HPV status and preeclampsia after adjusting for demographic and clinical variables significantly different between the exposed and unexposed groups or known a priori to be associated with preeclampsia (age, nulliparity, smoking status, and blood pressure at entry to care). A 2-sided P value of less than .05 was considered to indicate statistical significance, and no adjustments were made for multiple comparisons.
On the basis of data from our center, we assumed the rate of preeclampsia in the unexposed group as 6%. Assuming a 5% type I error, 20% type II error and 2:1 ratio of unexposed to exposed subjects, 301 exposed and 602 unexposed subjects were needed to detect a 2-fold increase in the rate of preeclampsia in women with HR-HPV (from 6% to 12%).
Results
Of 9675 deliveries at our institution over the study time period, 563 (5.8%) had abnormal Papanicolaou smear results. Three hundred twenty nine women had ASCUS Papanicolaou smear results; however, their HR-HPV testing was either negative or not performed, and they were excluded. Three hundred fourteen were included in the exposed HR-HPV group, and were matched to 628 unexposed women. Demographic and obstetric characteristics of these patients are summarized in Table 1 . Women in the HR-HPV group were younger, more likely to be nulliparous, and Caucasian, and had lower body mass index and systolic and diastolic blood pressure at entry to care. They were also more likely to be smokers and less likely to have a history of preeclampsia in prior pregnancies.
| Characteristic | Exposed (HR-HPV) group n = 314 | Unexposed group (normal pap) n = 628 | P value |
|---|---|---|---|
| Age, y | 26 (22–29) | 27 (23–32) | < .001 |
| Nulliparity | 102 (32.5) | 115 (18.3) | < .001 |
| Ethnicity | .26 | ||
| White | 58 (18.47) | 87 (13.85) | |
| Hispanic | 220 (70.06) | 460 (73.25) | |
| Black | 35 (11.15) | 62 (9.87) | |
| Others | 1 (0.32) | 19 (3.03) | |
| Entry to care BMI, kg/m 2 | 25.78 (22.46–29.63) | 27.13 (23.53–31) | < .001 |
| Entry to care SBP, mm Hg | 111 (104–120) | 114 (106–122) | .02 |
| Entry to care DBP, mm Hg | 66 (60–73) | 68 (62–75) | < .001 |
| Chronic hypertension | 8 (2.55) | 26 (4.14) | .29 |
| Pregestational diabetes | 5 (1.59) | 15 (2.39) | .58 |
| Smoking | 48 (15.29) | 57 (9.08) | .006 |
| Twin pregnancy | 7 (2.23) | 12 (1.91) | .94 |
| History of preeclampsia | 5 (1.59) | 27 (4.3) | .049 |
Pregnancy outcomes of the 2 groups of the study are displayed in Tables 2 and 3 . Women with HR-HPV were more likely to develop preeclampsia compared with the unexposed group (10.19% vs 4.94%; P = .004), with an odds ratio (OR) of 2.18 (95% confidence interval [CI], 1.31–3.65). The association between HR-HPV and preeclampsia remained significant in the logistic regression model after adjusting for age, nulliparity, smoking status, and blood pressure at entry to care (adjusted OR, 2.29; 95% CI, 1.32–3.97). Although there was no difference in the gestational age at onset of preeclampsia, women with HR-HPV had a trend toward a higher risk of developing severe preeclampsia compared with the unexposed group (OR, 1.93; 95% CI, 0.96–3.87; P = .09; adjusted OR, 2.02; 95% CI, 0.95–4.3; P = .07). In addition, women with HR-HPV were more likely to deliver prematurely at less than 37 and less than 35 weeks ( Table 3 ). There were no differences in other measured obstetric outcomes.
| Variable | Exposed (HR-HPV) group n = 314 | Unexposed group (normal pap) n = 628 | P value |
|---|---|---|---|
| Gestational age at delivery, wks | 39.14 (38–40) | 39.14 (38.14–39.86) | .95 |
| Birthweight, g | 3295 (3012–3614) | 3285 (3005–3580) | .91 |
| Preeclampsia | 32 (10.19) | 31 (4.94) | .004 |
| Severe preeclampsia | 16 (5.1) | 17 (2.71) | .09 |
| Gestational age at onset of preeclampsia, wks | 37.14 (35.86–39) | 36.86 (34.57–39.57) | .88 |
| GDM | 17 (5.41) | 45 (7.17) | .37 |
| IUGR | 7 (2.23) | 9 (1.43) | .53 |
| Cesarean delivery | 75 (32.05) | 191 (38.82) | .08 |
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