Interaction between interleukin-1 receptor 2 and Toll-like receptor 4, and cervical cytokines.

The objective was to assess the impact of genetic variation on cervical cytokine concentrations of interleukin (IL)-1α, IL-1ß, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α), and first, to determine if these variants interact with polymorphisms in Toll-like receptor 4 (TLR4) that were previously shown to associate with pro-inflammatory cervical cytokine concentrations, and second, to determine if findings are affected by bacterial vaginosis (BV). We examined 183 single nucleotide polymorphisms (SNPs) in 13 cytokine genes and receptors for associations with cervical cytokine levels in 188 African American and European American women. We tested for associations of gene-gene interactions between SNPs in TLR4 and cytokine gene and receptor polymorphisms with cervical pro-inflammatory cytokines. None of the single locus associations were significant after correction for multiple testing in either European Americans or African Americans. However, there were significant gene-gene interactions between IL-1R2 rs485127 and two SNPs in TLR4 (rs1554973 and rs7856729) with IL-1ß after correction for multiple testing. Our study demonstrates that interactions between TLR4 and IL-1R2 are associated with cervical pro-inflammatory cytokine concentrations. These results provide important insights into the possible regulatory mechanisms of the inflammatory response in the presence and absence of microbial disorders such as BV. Additionally, the observed differences in allele frequencies between African Americans and those of European descent may partially explain population disparity in pregnancy-related phenotypes that are cytokine concentration-dependent.

Cervical cancer and risk for delivery of small-for-gestational age neonates.

OBJECTIVE: To determine if cervical intraepithelial neoplasia grade 3 (CIN-3) and cervical cancer are associated with adverse obstetrical outcomes. METHODS: Women with diagnoses of CIN-3 and cervical cancer were first identified from the University of Pittsburgh Medical Center (UPMC) Network Cancer Registry by using respective ICD-3 codes. Identified records were then linked to the Magee Obstetrical Maternal and Infant (MOMI) database to identify women who subsequently delivered pregnancies at Magee-Womens Hospital. Women with cervical disease were compared with women without known disease to determine the impact of cervical disease on various maternal and neonatal outcomes. The latter group consisted of those women who delivered singleton pregnancies at our institution, as determined by the MOMI database, but who did not have any matching records in the UPMC Cancer Registry. Statistical significance was defined by a p value <0.05. RESULTS: We identified CIN-3 (n = 52) and cervical cancer patients (n = 83) who later had documented pregnancies delivered at Magee-Womens Hospital between 1989 and 2006. Women with cervical cancer and CIN-3 were at greater risk to deliver small-for-gestational age (SGA) neonates compared with women without known cervical disease (RR 1.54, 95% confidence interval [CI] 1.0-2.46). A secondary analysis of risk factors for SGA neonates demonstrated a significant association with cervical cancer (p = 0.04). After accounting for variables known to be risk factors for SGA, cervical cancer was associated with a 1.9-fold increased risk of a SGA delivery (OR 1.9, 95% CI 1.1-3.4). CONCLUSIONS: Cervical cancer is a risk factor for delivery of an SGA neonate in a subsequent pregnancy.

Lower urinary tract symptoms in women with pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: The objective of this study was to describe lower urinary tract symptoms (LUTS) and urinary incontinence (UI) symptoms in women with prolapse. METHODS: LUTS were measured with the urinary distress inventory (UDI) and UI symptoms with UDI and the Medical, Epidemiological and Social Aspects of Aging (MESA) in women with POPQ stage >or=I support. UI symptoms were classified as stress- or urge-only, stress-predominant or urge-predominant mixed, or mixed. Bladder function was assessed by urodynamics. Bi- and multivariable analyses were performed. RESULTS: Three hundred thirty-six women aged 62 +/- 13 years were characterized by UDI scores as having mixed 72% (n = 242), urge-only 24% (n = 80), and stress-only <1% (n = 1) UI symptoms. Of subjects with mixed UI symptoms, 57% (n = 137) were stress-predominant and 43% (n = 105) were urge-predominant. In multivariable regression models, advancing age and prolapse were associated with less reported distress related to stress UI symptoms. Prior hysterectomy was associated with higher total UDI scores. Similar findings were noted with MESA. CONCLUSIONS: Mixed UI symptoms are the predominant symptom type in women with POP.

Maternal vitamin D deficiency is associated with bacterial vaginosis in the first trimester of pregnancy.

Bacterial vaginosis (BV) is a highly prevalent vaginal infection that is associated with adverse pregnancy outcomes. Vitamin D exerts an influence on the immune system and may play a role in BV. The objective of this study was to examine the association between maternal vitamin D status and the prevalence of BV in early pregnancy. Women (n = 469) enrolled in a pregnancy cohort study at <16 wk underwent a pelvic examination and provided a blood sample for determination of serum 25-hydroxyvitamin D [25(OH)D]. BV was diagnosed using Gram-stained vaginal smears interpreted using the method of Nugent. Approximately 41% of women had BV (Nugent score 7-10) and 52% had a serum 25(OH)D concentration <37.5 nmol/L. The mean unadjusted serum 25(OH)D concentration was lower among BV cases (29.5 nmol/L; 95% CI: 27.1, 32.0) compared with women with normal vaginal flora (40.1 nmol/L; 95% CI: 37.0, 43.5; P < 0.001). BV prevalence decreased as vitamin D status improved (P < 0.001). Approximately 57% of the women with a serum 25(OH)D concentration <20 nmol/L had BV compared with 23% of women with a serum 25(OH)D concentration >80 nmol/L. There was a dose-response association between 25(OH)D and the prevalence of BV. The prevalence declined as 25(OH)D increased to 80 nmol/L, then reached a plateau. Compared with a serum 25(OH)D concentration of 75 nmol/L, there were 1.65-fold (95% CI: 1.01, 2.69) and 1.26-fold (1.01, 1.57) increases in the prevalence of BV associated with a serum 25(OH)D concentration of 20 and 50 nmol/L, respectively, after adjustment for race and sexually transmitted diseases. Vitamin D deficiency is associated with BV and may contribute to the strong racial disparity in the prevalence of BV.

Rectal colonization by group B Streptococcus as a predictor of vaginal colonization.

OBJECTIVE: The purpose of this article was to describe rectal colonization by group B Streptococcus (GBS) and its role in the prediction of vaginal colonization. STUDY DESIGN: In this prospective cohort of 1248 nonpregnant women, vaginal and rectal swabs for GBS culture were obtained at enrollment and at three 4-month intervals. Generalized estimating equations were used to identify factors that are associated with colonization. RESULTS: Eight hundred fourteen (65%) women had GBS colonization sometime during the observation period. Rectal GBS colonization was the strongest predictor of vaginal colonization (adjusted odds ratio, 14.3; 95% CI, 11.9-17.1). Recent sexual intercourse, vaginal colonization with yeast, and a vaginal Nugent score >/= 4 were also independent determinants of vaginal GBS colonization. Antimicrobial use decreased vaginal GBS colonization only among women who had no rectal colonization. CONCLUSION: GBS in the gastrointestinal tract is a risk factor for vaginal GBS. Sexual activity and abnormal vaginal microflora are independent determinants of vaginal GBS colonization.

Cervical cytokine network patterns during pregnancy: the role of bacterial vaginosis and geographic ancestry.

Few studies have examined the coordinated regulation of the extensive network of cytokines, chemokines, and growth factors involved in the immune response to bacterial vaginosis (BV) during pregnancy. We compared these patterns between women with (BV(+)) and without (BV(-)) bacterial vaginosis and between women of African and of European ancestry. This cohort included 83 Whites (28 BV(+) and 55 BV(-)) and 80 Blacks (41 BV(+) and 39 BV(-)). Pairwise correlations were determined for 28 factors that included cytokines, chemokines, and growth factors. In Whites, there were significantly more correlations involving immunoregulatory cytokines in BV(-) compared with BV(+) women. In Blacks, there were no significant differences in the correlation patterns between BV(+) and BV(-) women. Overall, in BV(-) women, there were no significant differences in the correlation patterns between Whites and Blacks. Conversely, in BV(+) women, Blacks have a stronger correlated response to infection than Whites. This indicates that Whites and Blacks have different correlated immune responses to BV that may at least partially explain the disparity observed in the prevalence of this disease.

First-trimester cervical inflammatory milieu and subsequent early preterm birth.

OBJECTIVE: Our objective was to explore the relation between the pro- and antiinflammatory cervical cytokine balance in early pregnancy and subsequent early preterm birth. STUDY DESIGN: In this prospective cohort of 218 pregnant women who were enrolled in the first trimester, we assayed cervical concentrations of interleukin-1alpha, -1beta, -6, -4, -10, and -13. Based on these cytokines, we categorized subjects into 1 of 3 strata: high proinflammatory/low antiinflammatory, high antiinflammatory/low proinflammatory, or balanced. The primary outcome of interest was preterm birth at < 34 weeks' gestation. RESULTS: Women in the high antiinflammatory/low proinflammatory stratum had a subsequent odds ratio for preterm birth < 34 weeks' gestation of 7.7 (95% CI, 4.9-9.1; P = .01), after adjustment for marital status, smoking, bacterial vaginosis, maternal race, and less than high school education. CONCLUSION: Women with a relatively hyporesponsive cervical inflammatory milieu in early pregnancy are at higher risk of subsequent early spontaneous preterm birth.

Maternal and fetal Toll-like receptor 4 genotype and chorionic plate inflammatory lesions.

OBJECTIVE: The objective of the study was to explore the relation between maternal and fetal genetic variation in Toll-like receptor 4 (TLR4) and chorionic plate inflammation STUDY DESIGN: In this prospective observational cohort of 109 women with singleton gestations, 13 tag single nucleotide polymorphisms (SNPs) were genotyped in the TLR4 gene. The diagnosis of chorionic plate inflammation was made by a single blinded perinatal pathologist. RESULTS: After adjustment for multiple comparisons, 1 maternal SNP (rs10759932) and 1 fetal SNP (rs1554973) in the TLR4 gene demonstrated highly significant association with chorionic plate inflammation. After adjustment for race, smoking, and bacterial vaginosis, carriage of these alleles was associated with chorionic plate inflammation (maternal rs1554973: odds ratio [OR] 5.2, 95% confidence interval, 3.2-6.4, P = .006; fetal rs10759932: OR 4.95, 95% confidence interval, 3.0-5.6, P = .005). There was no evidence of interaction between these 2 SNPs. CONCLUSION: Maternal and fetal genetic variation in TLR4 is strongly associated with chorionic plate inflammation. This maternal and fetal genotypic effect are independent of each other as well as other environmental covariates.

Genetic regulation of cervical antiinflammatory cytokine concentrations during pregnancy.

OBJECTIVE: The purpose of this study was to evaluate the contribution of maternal genotype to the concentration of interleukin (IL)-4, -10, and -13 in the cervix during the first trimester in the context of bacterial vaginosis and cigarette smoking. STUDY DESIGN: In this prospective cohort of 116 pregnant women, we examined 72 single nucleotide polymorphisms (SNPs) in 6 genes: IL-4, IL-4 receptor, IL-10, IL-10 receptor alpha, IL-10 receptor beta, and IL-13. RESULTS: Among black women, an IL-10 receptor beta SNP (rs6517158) demonstrated significant association with IL-10 concentration (P = .04), adjusted for bacterial vaginosis. Among white women, there were 4 SNPs in IL-10 receptor alpha with a highly significant association with IL-10 concentration, adjusted for bacterial vaginosis and smoking. CONCLUSION: Our data demonstrate a significant relation between cervical concentrations of IL-10 and SNPs in the IL-10 receptor alpha and beta genes. The contribution of genotype to IL-10 concentration is significant, even in the consideration of bacterial vaginosis and smoking.

Paternal race and preterm birth.

OBJECTIVE: The purpose of this study was to describe the contribution of paternal race and parental racial discordance to preterm birth STUDY DESIGN: We used a US natality cohort of 2,845,686 singleton births. Race was self-reported. Preterm birth was defined as a birth at <34 weeks of gestation. RESULTS: In considering white or black parents, black couples demonstrated greater odds of preterm birth (adjusted odds ratio, 2.4; 95% CI, 2.3-2.5) than white couples. Compared with white couples, black-white couples had increased odds of preterm birth. In black-white couples, the odds of preterm birth were greater if the mother was black (adjusted odds ratio, 1.7; 95% CI, 1.5-1.9) than if the father was black (adjusted odds ratio, 1.2; 95% CI, 1.1-1.3). CONCLUSION: Regardless of maternal race, paternal black race is associated with increased odds of preterm birth. Additionally, among white-black couples, the odds of preterm birth are greater if the mother is black than if the father is black. These data support the notion of a differential contribution of race on preterm birth depending on the parent of origin.

Episiotomy and increase in the risk of obstetric laceration in a subsequent vaginal delivery.

OBJECTIVE: To examine whether episiotomy at first vaginal delivery increases the risk of spontaneous obstetric laceration in the subsequent delivery. METHODS: A review was conducted of women with consecutive vaginal deliveries at Magee-Womens Hospital between 1995 and 2005, using the Magee Obstetrical Maternal and Infant database. The primary exposure of interest was episiotomy at first vaginal delivery. Multivariable polytomous logistic regression modeling of potential risk factors was used to estimate odds ratios (ORs) for obstetric laceration in the second vaginal delivery. RESULTS: A total of 6,052 patients were included, of whom 47.8% had episiotomy at first delivery. Spontaneous second-degree lacerations at the time of second delivery occurred in 51.3% of women with history of episiotomy at first delivery compared with 26.7% without history of episiotomy (P<.001). Severe lacerations (third or fourth degree) occurred in 4.8% of women with history of episiotomy at first delivery compared with 1.7% without history of episiotomy (P<.001). Prior episiotomy remained a significant risk factor for second-degree (OR 4.47, 95% confidence interval 3.78-5.30) and severe obstetric lacerations (OR 5.25, 95% confidence interval 2.96-9.32) in the second vaginal delivery after controlling for confounders. Based on these findings, for every four episiotomies not performed one second-degree laceration would be prevented. To prevent one severe laceration, performing 32 fewer episiotomies is required. CONCLUSION: Episiotomy at first vaginal delivery increases the risk of spontaneous obstetric laceration in the subsequent delivery. This finding should encourage obstetric providers to further restrict the use of episiotomy. LEVEL OF EVIDENCE: II.

Racial differences in cervical cytokine concentrations between pregnant women with and without bacterial vaginosis.

We have examined the association between cervical cytokine, chemokine and growth factor concentrations with bacterial vaginosis (BV) in pregnant white and black women. A nested case-control analysis was performed to examine 28 cervical cytokine, chemokine and growth factor concentrations in 83 white women (55 with normal flora and 28 with BV) and 81 black women (39 with normal flora and 42 with BV). White women with BV had significantly lower IP10 (P=0.001) and MCP1 (P=0.006) concentrations compared to women with normal flora. Black women with BV had higher IL-1alpha (P<0.001) concentrations than those with normal flora. In women with normal flora, whites had significantly higher levels of IL-1alpha (P=0.047), IL-6 (P=0.010), IL-10 (P=0.016) and PDGF-BB (P=0.010) than blacks. There were no significant concentration differences between white and black women with BV. These results demonstrate significant differences in cytokine and chemokine concentrations between women with and without BV. Ethnic differences in cytokine concentrations were also observed in women with normal flora, indicating that white and black women with normal flora have different cytokine levels, but respond to BV in a similar manner.

Paternal race and bacterial vaginosis during the first trimester of pregnancy.

OBJECTIVE: The purpose of this study was to determine the joint effects of maternal and paternal race on risk of bacterial vaginosis (BV) during the first trimester. STUDY DESIGN: In this cohort of black women and white women with singleton gestation at <13 weeks (n = 325), BV was diagnosed by vaginal pH and Gram stain. RESULTS: BV was less common among white women than black women. Paternal race modified the effect of maternal race on BV risk. BV risk was 2-fold greater among both white female-black male partners and black female-white male partners. BV risk was also 2-fold greater among black female-black male partners. Black race among both partners confers no additional risk than with 1 black partner. CONCLUSION: Paternal black race is an independent risk factor for BV during pregnancy and is as important a risk factor as maternal race. Studies of BV and adverse pregnancy outcomes should consider paternal race.

A delicate balance: risk factors for acquisition of bacterial vaginosis include sexual activity, absence of hydrogen peroxide-producing lactobacilli, black race, and positive herpes simplex virus type 2 serology.

BACKGROUND: The etiology of bacterial vaginosis (BV) is poorly understood, but better definition of the risk factors associated with its acquisition should improve our understanding of this complex disease entity. METHODS: A longitudinal cohort study of young sexually active women was conducted to identify variables associated with BV acquisition. Seven hundred seventy-three women without BV at enrollment were followed at 4-month intervals for 1 year. At each visit, demographic and behavioral interview data, a vaginal smear for the Gram stain diagnosis of BV, and a serum sample for detection of herpes simplex virus type 1 (HSV-1) and HSV-2 type-specific antibodies were collected. RESULTS: The overall incidence of BV acquisition was 36 cases/100 woman-years (223 acquisitions of BV during 619 woman-years of follow-up). Acquisition of BV was independently associated with black race, cigarette smoking, vaginal intercourse, receptive anal sex before vaginal intercourse, sex with an uncircumcised male partner, lack of vaginal H2O2-producing lactobacilli, and the detection of HSV-2 serum antibodies at the visit before BV acquisition. Longitudinal analyses revealed that HSV-2 serum antibodies were independently associated with loss of H2O2-producing lactobacilli. CONCLUSIONS: Our findings suggest that multiple and diverse risk factors can contribute to BV acquisition. They also illustrate why a more complete understanding of BV pathogenesis and the formulation of effective BV prevention strategies have been elusive. Further work will be needed to determine the specific effects of HSV-2 infection on vaginal flora composition and the acquisition of BV.

Risk factors for primary and subsequent anal sphincter lacerations: a comparison of cohorts by parity and prior mode of delivery.

OBJECTIVE: This study was performed to assess the effect of pregnancy, route of delivery, and parity on the risk of primary and subsequent anal sphincter laceration in women at first vaginal delivery (1st VD), vaginal birth after cesarean delivery (VBAC), or second vaginal delivery (2nd VD). METHODS: This retrospective cohort study used data from a perinatal database that included all deliveries at Magee-Womens Hospital from 1995 to 2002. Anal sphincter laceration was the primary outcome, defined as third- and fourth-degree perineal lacerations. The adjusted odds ratio (OR) for primary and subsequent anal sphincter laceration at delivery by risk group was estimated using logistic regression models and reported with 95% confidence intervals (CIs). RESULTS: We assessed 20,674 live, singleton, term deliveries at Magee-Womens Hospital from 1995 to 2002, including 13,183 with 1st VD, 6068 with 2nd VD, and 1423 with VBAC. Anal sphincter laceration occurred in 16% of women with 1st VD, 18% with VBAC, and 3% with 2nd VD. Multivariable logistic regression modeling for primary anal sphincter laceration showed that 1st VD had OR of 5.1 and 95% CI 4.4, 5.9, and VBAC had OR of 5.1, 95% CI 4.2, 6.2 when compared with the reference group with 2nd VD. Shown in order for 1st VD, VBAC, and 2nd VD, the following factors, adjusted for the other listed factors, were significantly related to anal sphincter laceration except as noted: forceps, ORs of 3.0, 2.6, 5.5; midline episiotomy, ORs of 2.7, 2.9, 2.9; infant birth weight 3500 g or more, ORs of 1.9, 1.9, 1.1, not significantly different from OR of 1.0; vacuum delivery, ORs of 1.7, 1.8, 1.5, not significantly different from OR of 1.0, and 2nd stage of labor 2 hours or longer, ORs of 1.8, 0.9, 0.9, last 2 not significantly different from OR of 1.0. Of women who had anal sphincter laceration in their first vaginal delivery, 7.2% (76 of 1054 women who had 2 pregnancies) had recurrent laceration in their second vaginal delivery, compared with 2.3% (123 of 5147) of women who had a primary anal sphincter laceration in their second vaginal delivery. Multivariable logistic regression modeling for recurrent anal sphincter laceration yielded the following significant factors: episiotomy, OR 8.5, 95% CI 4.1, 17.7; vertex malpresentation (primarily occiput posterior), OR 4.3, 95% CI 1.4, 12.6; shoulder dystocia, OR 2.7, 95% CI 1.2, 5.8; and infant birth weight 3500 g or greater, OR 1.7, 95% CI 1.1, 2.7. CONCLUSION: At this institution, women undergoing VBAC are at similarly high risk of anal sphincter laceration, compared with nulliparous women. Women with prior anal sphincter laceration are at 3 times increased risk for subsequent sphincter laceration, compared with women with prior vaginal delivery without sphincter laceration. Pregnancy by itself does not appear to be an important factor in decreasing the risk of anal sphincter laceration in subsequent deliveries.

Host immune consequences of asymptomatic Trichomonas vaginalis infection in pregnancy.

OBJECTIVE: The purpose of this study was to define the impact of asymptomatic trichomoniasis on lower genital tract neutrophil activation in pregnancy. STUDY DESIGN: In this nested cohort study, pelvic examination was performed on 65 asymptomatic pregnant women between 7 and 22 weeks' with vaginal pH > 4.4. Concentrations of cervical interleukin-8 and alpha-defensin were determined using enzyme-linked immunosorbent assay (ELISA). Trichomonas vaginalis was detected by culture. RESULTS: Median concentrations of vaginal fluid neutrophil defensins and cervical interleukin-8 were significantly greater among women with asymptomatic trichomoniasis (median defensins 18,622 ng/mL, median IL-8 9244 pg/mL) than their uninfected counterparts (median defensins 5144 ng/mL, median IL-8 2044 pg/mL) (P < .001). All women with asymptomatic trichomoniasis had detectable defensin and interleukin-8 concentrations. CONCLUSION: Asymptomatic trichomoniasis in pregnancy is accompanied by a state of neutrophil activation.

Cervical anti-inflammatory cytokine concentrations among first-trimester pregnant smokers.

OBJECTIVE: Anti-inflammatory cytokines play a role in the lower genital tract immune defense. We examined the impact of cigarette smoking in pregnancy on the detection of the 3 most important anti-inflammatory cytokines (interleukin-4, -10, and -13) in the cervix. STUDY DESIGN: One hundred fourteen gravid women from 4 to 16 weeks of gestation without bacterial vaginosis or sexually transmitted disease were queried regarding demographic factors and smoking. Concentrations of cytokines were determined with a multiplex assay for cervical swabs. RESULTS: There was a positive linear relationship between the number of cigarettes that were smoked per day and cervical concentrations of interleukin-4, -10, and -13 (P < .001 for each). Median concentrations of interleukin-4 and -10 were greater among women who smoked > or = 20 cigarettes per day than among non-smokers or less heavy smokers (P < .05 for both). There was no difference in concentrations of proinflammatory cytokines between smokers and non-smokers. CONCLUSION: Cigarette smoking in pregnancy is associated with an increase of cervical anti-inflammatory cytokines without a commensurate increase of proinflammatory cytokines. This may have important impact on the host response to infection.

Knowledge about sexually transmitted diseases in women among primary care physicians.

OBJECTIVES: Little is known about sexually transmitted disease (STD) knowledge of primary care providers. The objectives of this study were to determine the knowledge about the management of STDs among primary care physicians and to identify physician characteristics associated with possession of STD knowledge. STUDY: A self-administered questionnaire was mailed to a random sample of 1600 obstetrician/gynecologists, pediatricians, family physicians, and internists practicing in Pennsylvania. Information on physician and patient demographics was gathered, and we assessed knowledge and practice patterns concerning the management of STDs in young women. RESULTS: Physician knowledge regarding the evaluation and management of women with or at risk for STDs was associated with female gender (odds ratio [OR]: 2.1; 95% confidence interval [CI]: 1.4-3.2), age < or =40 (OR: 2.3; 95% CI: 1.4-3.6), and metropolitan practice location (OR: 1.7; 95% CI: 1.1-2.6). Familiarity with the Center for Disease Control and Prevention's (CDC's) STD treatment guidelines was independently associated with STD knowledge (OR: 2.0; 95% CI: 1.2, 3.3). Physicians with good STD knowledge were more likely to report routinely screening at-risk women for Chlamydia trachomatis (OR: 3.9; 95% CI: 2.3-6.8). CONCLUSIONS: Inadequacies in physician knowledge may serve as a barrier to the appropriate diagnosis and treatment of STDs. Interventions to improve STD management practices should include continuing medical education and distribution of CDC's STD treatment guidelines to primary care providers.

Second pregnancy outcomes following preeclampsia in a first pregnancy.

OBJECTIVES: We compared second pregnancy outcomes among women with and without preeclampsia in their first pregnancies who all had second pregnancies without preeclampsia. METHODS: One hundred thirty women with and 6148 without preeclampsia in their first pregnancies, who all had nonpreeclamptic second pregnancies, were included. Outcomes, including delivery gestational age, birthweight, small-for-gestational-age (SGA), and preterm delivery were compared. RESULTS: Overall, second pregnancy outcomes were not different between women with and without preeclampsia in their first pregnancy. However, when women were stratified by gestational timing of preeclampsia, women with preeclampsia at < 34 weeks (N = 22) had smaller infants and delivered earlier in their second nonpreeclamptic pregnancy compared to women with later preeclampsia (N = 108) or no preeclampsia in the first pregnancy. Women with early preeclampsia also had an increased risk of prematurity (< 37 weeks) in second pregnancies that persisted after controlling for confounding factors [Odds ratio (OR = 3.2)]. DISCUSSION: Second, nonpreeclamptic pregnancy outcomes are different between women with previous early preeclampsia and controls but not between late preeclampsia and controls. These findings support other epidemiological data indicating differences between early and late onset preeclampsia as well as a potential relationship of preeclampsia and spontaneous preterm birth.