Evaluation of ADAM-12 as a Diagnostic Biomarker of Ectopic Pregnancy in Women with a Pregnancy of Unknown Location

Background

Ectopic pregnancy (EP) remains the most life-threatening acute condition in modern gynaecology. It remains difficult to diagnose early and accurately. Women often present at emergency departments in early pregnancy with a ‘pregnancy of unknown location’ (PUL) and diagnosis/exclusion of EP is challenging due to a lack of reliable biomarkers. Recent studies suggest that serum levels of a disintegrin and metalloprotease protein-12 (ADAM-12) can be used differentiate EP from viable intrauterine pregnancy (VIUP). Here we describe a prospective study evaluating the performance of ADAM-12 in differentiating EP from the full spectrum of alternative PUL outcomes in an independent patient cohort.

Methodology/Principal Findings

Sera were collected from 120 patients at their first clinical presentation with a PUL and assayed for ADAM-12 by ELISA. Patients were categorized according to final pregnancy outcomes. Serum ADAM-12 concentrations were increased in women with histologically-confirmed EP (median 442 pg/mL; 25%–75% percentile 232–783 pg/mL) compared to women with VIUP (256 pg/mL; 168–442 pg/mL) or miscarriage (192 pg/mL; 133–476 pg/mL). Serum ADAM-12 did not differentiate histologically-confirmed EP from spontaneously resolving PUL (srPUL) (416 pg/mL; 154–608 pg/mL). The diagnostic potential of ADAM-12 was only significant when ‘ambiguous’ PUL outcomes were excluded from the analysis (AROC = 0.6633; P = 0.03901).

Conclusions/Significance

When measured in isolation, ADAM-12 levels had limited value as a diagnostic biomarker for EP in our patient cohort. The development of a reliable serum biomarker-based test for EP remains an ongoing challenge.     

Oligohydramnios in Women with Preterm Prelabor Rupture of Membranes and Adverse Pregnancy and Neonatal Outcomes

Objective

To determine the association between the presence of oligohydramnios, determined as an amniotic fluid index ≤ 5 cm and the intra-amniotic inflammatory response, fetal inflammatory response and neonatal outcomes in actively managed preterm prelabor rupture of membranes (PPROM).

Methods

Women with singleton pregnancies complicated by PPROM at a gestational age of between 24+0 and 36+6 weeks were included in the study. Ultrasound assessments of the amniotic fluid index and evaluation of the amniotic fluid interleukin (IL)-6 levels were performed at admission. The umbilical cord blood IL-6 levels were evaluated after delivery.

Results

In total, 74 women were included. The women with oligohydramnios did not have different amniotic fluid IL-6 levels [with oligohydramnios: median 342 pg/mL, interquartile range (IQR) 110-1809 vs. without oligohydramnios: median 256 pg/mL, IQR 122–748; p = 0.71] or umbilical cord blood IL-6 levels (with oligohydramnios: median 8.2 pg/mL, IQR 3.8–146.9 vs. without oligohydramnios: median 5.9 pg/mL, IQR 2.1–27.9; p = 0.14) than those without oligohydramnios. No association between oligohydramnios and neonatal morbidity was found. A correlation between the amniotic fluid index and the interval from rupture of membranes to amniocentesis was observed (rho = −0.34; p = 0.003).

Conclusion

The presence of oligohydramnios is not associated with an adverse outcome in actively managed PPROM in singleton pregnancies in the absence of other complications.     

Ongoing Pregnancy Rates in Women with Low and Extremely Low AMH Levels. A Multivariate Analysis of 769 Cycles

Background

The ideal test for ovarian reserve should permit the identification of women who have no real chance of pregnancy with IVF treatments consequent upon an extremely reduced ovarian reserve. The aim of the current study was to evaluate pregnancy rates in patients with low AMH levels (0.2–1 ng/ml) and extremely low AMH levels (<0.2 ng/ml) and to determine the cumulative pregnancy rates following consecutive IVF treatments.

Methods

We conducted an historical cohort analysis at a tertiary medical center. Serum AMH levels were measured at initial clinic visit and prior to all following treatment cycles in 181 women (769 cycles) with an initial AMH level ≤1 ng/ml, undergoing IVF-ICSI. Main outcome measures were laboratory outcomes and pregnancy rates.

Results

Seventy patients undergoing 249 cycles had extremely low AMH levels (≤0.2 ng/ml), whereas 111 patients undergoing 520 cycles had low AMH levels (0.21–1.0 ng/ml). Number of oocytes retrieved per cycle, fertilized oocytes and number of transferred embryos were significantly lower in the extremely low AMH levels group compared to the low AMH levels (P<0.003). Crude ongoing pregnancy rates were 4.4% for both groups of patients. Among 48 cycles of women aged ≥42 with AMH levels of ≤0.2 ng/ml no pregnancies were observed. But, in patients with AMH levels of 0.2–1.0 ng/ml, 3 ongoing pregnancies out of 192 cycles (1.6%) were observed. However, in a multivariate regression analysis adjusted for age and cycle characteristics, no significant differences in ongoing pregnancy rates per cycle between the two groups were evident. Cumulative pregnancy rates of 20% were observed following five cycles, for both groups of patients.

Conclusions

Patients with extremely low AMH measurements have reasonable and similar pregnancy rates as patients with low AMH. Therefore, AMH should not be used as the criterion to exclude couples from performing additional IVF treatments.     

Reproductive Outcomes Following Ectopic Pregnancy: Register-Based Retrospective Cohort Study

Background

We aimed to compare reproductive outcomes following ectopic pregnancy (EP) versus livebirth, miscarriage, or termination in a first pregnancy.

Methods And Findings

A retrospective cohort study design was used. Scottish national data on all women whose first pregnancy occurred between 1981 and 2000 were linked to records of a subsequent pregnancy. The exposed cohort comprised women with an EP in their first pregnancy. There were three unexposed cohorts: women with livebirth, miscarriage, and termination of their first pregnancies. Any differences in rates of second pregnancy, livebirth, EP, miscarriage, or terminations and complications of a second ongoing pregnancy and delivery were assessed among the different exposure groups. A total of 2,969 women had an initial EP; 667,299 had a livebirth, 39,705 women miscarried, and 78,697 terminated their first pregnancies. Women with an initial EP had an increased chance of another pregnancy within 2 years (adjusted hazard ratio (AHR) 2.76 [95% CI 2.58–2.95]) or after 6 years (AHR 1.57 [95% CI 1.29–1.91]) compared to women with a livebirth. In comparison with women with an initial miscarriage, women who had an EP had a lower chance of a second pregnancy (AHR 0.53 [95% CI 0.50–0.56]). Compared to women with an initial termination, women with an EP had an increased chance of a second pregnancy (AHR 2.38 [95% CI 2.23–2.55]) within 2 years. Women with an initial EP suffered an increased risk of another EP compared to women with a livebirth (AHR 13.0 [95% CI 11.63–16.86]), miscarriage (AHR 6.07 [95% CI 4.83–7.62]), or termination (AHR 12.84 [95% CI 10.07–16.37]). Perinatal complications in a pregnancy following EP were not significantly higher than those in primigravidae or in women with a previous miscarriage or termination.

Conclusion

Women with an initial EP have a lower chance of conception than those who miscarry but an increased risk of a repeat EP in comparison with all three comparison groups. A major limitation of this study was the inability to separate women using contraception from those who were intending to conceive. Please see later in the article for the Editors'' Summary     

Reduction of Maternal Mortality with Highly Active Antiretroviral Therapy in a Large Cohort of HIV-Infected Pregnant Women in Malawi and Mozambique

Background

HIV infection is a major contributor to maternal mortality in resource-limited settings. The Drug Resource Enhancement Against AIDS and Malnutrition Programme has been promoting HAART use during pregnancy and postpartum for Prevention-of-mother-to-child-HIV transmission (PMTCT) irrespective of maternal CD4 cell counts since 2002.

Methods

Records for all HIV+ pregnancies followed in Mozambique and Malawi from 6/2002 to 6/2010 were reviewed. The cohort was comprised by pregnancies where women were referred for PMTCT and started HAART during prenatal care (n = 8172, group 1) and pregnancies where women were referred on established HAART (n = 1978, group 2).

Results

10,150 pregnancies were followed. Median (IQR) baseline values were age 26 years (IQR:23–30), CD4 count 392 cells/mm³ (IQR:258–563), Viral Load log₁₀ 3.9 (IQR:3.2–4.4), BMI 23.4 (IQR:21.5–25.7), Hemoglobin 10.0 (IQR: 9.0–11.0). 101 maternal deaths (0.99%) occurred during pregnancy to 6 weeks postpartum: 87 (1.1%) in group 1 and 14 (0.7%) in group 2. Mortality was 1.3% in women with <than 350 CD4 cells/mm³ and 0.7% in women with greater than 350 CD4s cells/mm³ [OR = 1.9 (CL 1.3–2.9) p = 0.001]. Mortality was higher in patients with shorter antenatal HAART: 22/991 (2.2%) if less than 30 days and 79/9159 (0.9%) if 31 days or greater [OR = 2.6 (CL 1.6–4.2) p<0.001]. By multivariate analysis, shorter antenatal HAART (p<0.001), baseline values for CD4 cell count (p = 0.012), hemoglobin (p = 0.02), and BMI (p<0.001) were associated with mortality. Four years later, survival was 92% for women with shorter antenatal HAART and 98% for women on established therapy prior to pregnancy, p = 0.001.

Conclusions

Antiretrovirals for PMTCT purposes have significant impact on maternal mortality as do CD4 counts and nutritional status. In resource-limited settings, PMTCT programs should provide universal HAART to all HIV+ pregnant women given its impact in prevention of maternal death.     

Maternal Serum Disintegrin and Metalloprotease Protein-12 in Early Pregnancy as a Potential Marker of Adverse Pregnancy Outcomes

Objectives

The aim of this study was to determine whether the concentration of disintegrin and metalloprotease protein12 (ADAM12) in first trimester maternal serum can be used as a marker for first-trimester complete spontaneous abortions, missed abortions, ectopic pregnancies and hydatidiform moles.

Methods

The maternal serum concentrations of ADAM12 were measured in the range of 5–9⁺⁶ weeks of gestation using an automated AutoDelfia immunoassay platform in 9 cases of complete spontaneous abortion, 27 cases of missed abortions, 56 cases of ectopic pregnancies, 12 cases of hydatidiform moles, and 100 controls. Logistic regression analysis was used to determine significant factors for predicting adverse pregnancy outcomes in early pregnancy. Screening performance was assessed using receiver operating characteristic curves.

Results

Two hundred and four women were enrolled in the study. In the control group, the level of ADAM12 increased with gestational age. The median ADAM12 levels in the spontaneous abortion (0.430 MoM), ectopic pregnancy (0.460 MoM) and hydatidiform mole (0.037 MoM) groups were lower than that in the control group, while the median ADAM12 level in the missed abortion group (1.062 MoM) was not significant from the controls (1.002 MoM). Logistic regression analysis demonstrated that the level of ADAM12 in maternal serum facilitated the detection of ectopic pregnancies (OR = 0.909; 95% CI = 0.841∼0.982) and complete spontaneous abortion (OR = 0.863; 95% CI = 0.787∼0.946).

Conclusions

In complete spontaneous abortion and ectopic pregnancy, ADAM12 maintained at low levels in early pregnancies, and there were significant differences compared to normal pregnancies. ADAM12 is a promising marker for the diagnosis of complete spontaneous abortion and ectopic pregnancy in symptomatic women, and under certain conditions, ADAM12 can diagnose ectopic pregnancy and spontaneous abortion before an ultrasonographic detection of the conditions.     

Maternal Serum Heme-Oxygenase-1 (HO-1) Concentrations in Early Pregnancy and Subsequent Risk of Gestational Diabetes Mellitus

Background

Heme oxygenase-1 (HO-1) concentrations have been recently reported to be elevated in impaired glucose tolerance and type 2 diabetes mellitus (T2DM). However, no study has examined the association between HO-1 concentrations and gestational diabetes mellitus (GDM).

Methods

In a case-control study, nested within a prospective cohort of pregnant women (186 GDM cases and 191 women who remained eu-glycemic through pregnancy), we assessed the association of maternal serum HO-1 concentrations, measured in samples collected at 16 weeks gestation, on average, with subsequent risk of GDM. Maternal serum HO-1 concentrations were determined using ELISA. We fitted multivariate logistic regression models to derive estimates of odds ratios (ORs) and 95% confidence intervals (CIs).

Results

Median serum HO-1 concentrations in early pregnancy were lower in women who subsequently developed GDM compared with those who did not (1.60 vs. 1.80 ng/mL, p-value = 0.002). After adjusting for maternal age, race, family history of T2DM and pre-pregnancy body mass index, women with HO-1≥3.05 ng/mL (highest decile) experienced a 74% reduction of GDM risk (95% CI; 0.09–0.77) compared with women whose concentrations were<1.23 ng/mL (lowest quartile).

Conclusion

Serum HO-1 concentrations were inversely associated with subsequent GDM risk. These findings underscore the role of oxidative stress in the pathogenesis of GDM. Additional studies are warranted to confirm the clinical utility of serum HO-1 in diagnosis of GDM, particularly in the early pregnancy.     

Pregnancy Incidence and Correlates in a Clinical Trial Preparedness Study,North West Province South Africa

Introduction

Women in HIV prevention trials often must typically agree to avoid pregnancy. Regardless, some become pregnant. Screening tools predicting pregnancy risk could maximize trial safety and efficiency.

Objectives

We assessed incidence and correlates of pregnancy among women at high HIV risk.

Methods

We enrolled sexually-active, HIV-negative women into an observational cohort (2008–2011). At enrolment demographic, contraceptive, reproductive, pregnancy intention and behavioural data were collected. Women reported if one or both partners wanted or intended for the couple to become pregnant. We measured gender role beliefs using a locally validated eight-point index. We tested HIV and pregnancy, and inquired about sexually transmitted infection symptoms (STIs) at enrollment and monthly. HIV testing included behavioural counselling and condom provision, but did not specifically counsel women to avoid pregnancy. Cox proportional hazard modelling evaluated the associations with pregnancy. The multivariate model included the following variables “Recent pregnancy attempts”, “Gender Roles Beliefs”, ”Self-reported STIs” and “Age”.

Results

We screened 1068 women and excluded (24.6%, 263/1068) who did not report risk behaviour. Non-pregnant, non-sterilized women aged 18–35 (median = 21 years) enrolled (n = 438). Most women reported one partner (74.7%) and a prior live birth (84.6%). Median follow-up time was 6 months (range 0.7–15.5). Pregnancy incidence was 25.1 per 100 women-years (n = 57 pregnancies). Conservative beliefs on gender roles (Adjusted Hazard Ratio (aHR) 1.8; 95% confidence interval [CI] 1.1–2.9), recent pregnancy attempts (aHR 1.9; 95% CI 1.1–3.4) and baseline self-reported STI (aHR 2.5; 95% CI 1.4–4.4) were associated with increased incident pregnancy. Report of no pregnancy intention was associated with lowered pregnancy risk (aHR 0.3; 95% CI 0.1–0.7).

Conclusions

We identified new and confirmed existing factors that can facilitate screening for pregnancy risk.     

Asthma during Pregnancy in a Population-Based Study - Pregnancy Complications and Adverse Perinatal Outcomes

Background

Asthma is one of the most common chronic diseases, and prevalence, severity and medication may have an effect on pregnancy. We examined maternal asthma, asthma severity and control in relation to pregnancy complications, labour characteristics and perinatal outcomes.

Methods

We retrieved data on all singleton births from July 1, 2006 to December 31, 2009, and prescribed drugs and physician-diagnosed asthma on the same women from multiple Swedish registers. The associations were estimated with logistic regression.

Results

In total, 266 045 women gave birth to 284 214 singletons during the study period. Maternal asthma was noted in 26 586 (9.4%) pregnancies. There was an association between maternal asthma and increased risks of pregnancy complications including preeclampsia or eclampsia (adjusted OR 1.15; 95% CI 1.06–1.24) and premature contractions (adj OR 1.52; 95% CI 1.29–1.80). There was also a significant association between maternal asthma and emergency caesarean section (adj OR 1.29; 95% CI 1.23–1.34), low birth weight, and small for gestational age (adj OR 1.23; 95% CI 1.13–1.33). The risk of adverse outcomes such as low birth weight increased with increasing asthma severity. For women with uncontrolled compared to those with controlled asthma the results for adverse outcomes were inconsistent displaying both increased and decreased OR for some outcomes.

Conclusion

Maternal asthma is associated with a number of serious pregnancy complications and adverse perinatal outcomes. Some complications are even more likely with increased asthma severity. With greater awareness and proper management, outcomes would most likely improve.     

Angiogenic factors in women ten years after severe very early onset preeclampsia

Background

Women with a history of mainly severe and early onset preeclampsia have an increased risk of future cardiovascular disease. During these complicated pregnancies increased levels of anti-angiogenic factors can be found. We hypothesize that women with a history of severe very early onset preeclampsia still have increased levels of these biomarkers years after this pregnancy, resulting in increased risk for cardiovascular disease.

Methods

Twenty women with severe early onset preeclampsia before 24 weeks'' gestation, who delivered between 1993–2003 in a tertiary referral centre and twenty matched controls with uncomplicated pregnancies and healthy term infants, were addressed for participation in the study. Venous plasma samples were analyzed for basic fibroblast growth factor (bFGF), placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFlt-1), vascular endothelial growth factor (VEGF), E- and P-selectin, soluble intercellular adhesion molecule-3 (sICAM-3) and thrombomodulin by ELISA.

Results

Sixteen case subjects and 18 control subjects consented participation. The median time interval index pregnancy to study was 9.4 and 9.7 years for cases and controls, respectively. Median levels for cases-controls (p-value) were not different; bFGF: 17.43–11.11 pg/mL (0.33), sFlt-1: 102.98–101.92 pg/ml (0.84), PLGF: 3.57–4.20 pg/mL (0.38), VEGF: 64.05–45.72 pg/mL (0.73), E-selectin: 5.11–4.68 ng/mL (0.20), P-selectin: 85.35–71.69 ng/mL (0.69), sICAM-3: 0.42–0.63 ng/mL (0.41) and Thrombomodulin: 0.92–0.93 ng/mL (0.59).

Conclusion

There were no differences in angiogenic biomarkers between women with a history of severe early onset preeclampsia versus uncomplicated pregnancy almost 10 years later, suggesting that these angiogenic factors will not contribute to the early detection of women at risk for future cardiovascular disease.     

Harnessing the Medicaid Analytic eXtract (MAX) to Evaluate Medications in Pregnancy: Design Considerations

Background

In the absence of clinical trial data, large post-marketing observational studies are essential to evaluate the safety and effectiveness of medications during pregnancy. We identified a cohort of pregnancies ending in live birth within the 2000–2007 Medicaid Analytic eXtract (MAX). Herein, we provide a blueprint to guide investigators who wish to create similar cohorts from healthcare utilization data and we describe the limitations in detail.

Methods

Among females ages 12–55, we identified pregnancies using delivery-related codes from healthcare utilization claims. We linked women with pregnancies to their offspring by state, Medicaid Case Number (family identifier) and delivery/birth dates. Then we removed inaccurate linkages and duplicate records and implemented cohort eligibility criteria (i.e., continuous and appropriate enrollment type, no private insurance, no restricted benefits) for claim information completeness.

Results

From 13,460,273 deliveries and 22,408,810 child observations, 6,107,572 pregnancies ending in live birth were available after linkage, cleaning, and removal of duplicate records. The percentage of linked deliveries varied greatly by state, from 0 to 96%. The cohort size was reduced to 1,248,875 pregnancies after requiring maternal eligibility criteria throughout pregnancy and to 1,173,280 pregnancies after further applying infant eligibility criteria. Ninety-one percent of women were dispensed at least one medication during pregnancy.

Conclusions

Mother-infant linkage is feasible and yields a large pregnancy cohort, although the size decreases with increasing eligibility requirements. MAX is a useful resource for studying medications in pregnancy and a spectrum of maternal and infant outcomes within the indigent population of women and their infants enrolled in Medicaid. It may also be used to study maternal characteristics, the impact of Medicaid policy, and healthcare utilization during pregnancy. However, careful attention to the limitations of these data is necessary to reduce biases.     

The Associations between Bridal Pregnancy and Obstetric Outcomes among Live Births in Korea: Population-Based Study

Objective

In East Asia the recently increased number of marriages in response to pregnancy is an important social issue. This study evaluated the association of marriage preceded by pregnancy (bridal pregnancy) with obstetric outcomes among live births in Korea.

Methods

In this population-based study, 1,152,593 first singleton births were evaluated from data registered in the national birth registration database from 2004 to 2008 in Korea. In the study population, the pregnancy outcomes among live births from the bridal pregnancy group (N = 62,590) were compared with the outcomes of the post-marital pregnancy group (N = 564,749), composed of women who gave birth after 10 months but before 24 months of marriage. The variables preterm birth (PTB; <37 weeks gestation) and low birth weight (LBW; <2.5 kg) were used to determine the primary outcome. The adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated after controlling for socio-demographic factors.

Results

The socio-demographic factors among the bridal pregnancy group were associated with a social disadvantage and particular risk factors. In the subgroup analyses of maternal age, differences in adverse pregnancy outcomes from bridal pregnancy were identified between women in the following age group: (i) ≤19, (ii) 20–39, and (iii) ≥40 years. After the multivariate analysis, the aORs for each age group were 1.47 (95% CI: 1.15–1.89), 1.76 (1.70–1.83), and 1.13 (0.77–1.66), respectively, for PTB and 0.92 (0.70–1.21), 1.60 (1.53–1.66), and 1.11 (0.71–1.74), respectively, for LBW. In the adjusted logistic regression models, bridal pregnancy was associated with PTB (1.76, 1.69–1.82) and LBW (1.53, 1.48–1.59).

Conclusion

Pregnancy outcomes among live births from bridal pregnancies are associated with higher risks for PTB and LBW in Korea.     

CB1 Expression Is Attenuated in Fallopian Tube and Decidua of Women with Ectopic Pregnancy

Background

Embryo retention in the Fallopian tube (FT) is thought to lead to ectopic pregnancy (EP), a considerable cause of morbidity. In mice, genetic/pharmacological silencing of cannabinoid receptor Cnr1, encoding CB1, causes retention of embryos in the oviduct. The role of the endocannabinoids in tubal implantation in humans is not known.

Methods and Findings

Timed FT biopsies (n = 18) were collected from women undergoing gynecological procedures for benign conditions. Endometrial biopsies and whole blood were collected from women undergoing surgery for EP (n = 11); management of miscarriage (n = 6), and termination of pregnancy (n = 8). Using RT-PCR and immunohistochemistry, CB1 mRNA and protein expression levels/patterns were examined in FT and endometrial biopsies. The distribution of two polymorphisms of CNR1 was examined by TaqMan analysis of genomic DNA from the whole blood samples. In normal FT, CB1 mRNA was higher in luteal compared to follicular-phase (p<0.05). CB1 protein was located in smooth muscle of the wall and of endothelial vessels, and luminal epithelium of FT. In FT from women with EP, CB1 mRNA expression was low. CB1 mRNA expression was also significantly lower (p<0.05) in endometrium of women with EP compared to intrauterine pregnancies (IUP). Although of 1359G/A (rs1049353) polymorphisms of CNR1 gene suggests differential distribution of genotypes between the small, available cohorts of women with EP and those with IUP, results were not statistically significant.

Conclusions

CB1 mRNA shows temporal variation in expression in human FT, likely regulated by progesterone. CB1 mRNA is expressed in low levels in both the FT and endometrium of women with EP. We propose that aberrant endocannabinoid-signaling in human FT leads to EP. Furthermore, our finding of reduced mRNA expression along with a possible association between polymorphism genotypes of the CNR1 gene and EP, suggests a possible genetic predisposition to EP that warrants replication in a larger sample pool.     

Women with Pregnancies Had Lower Adherence to 1% Tenofovir Vaginal Gel as HIV Preexposure Prophylaxis in CAPRISA 004, a Phase IIB Randomized-Controlled Trial

Background

Antiretroviral prophylaxis may be a critical strategy to reduce periconception HIV transmission. Maximizing the benefit of periconception pharmacologic HIV risk-reduction requires an understanding of the links between pregnancy and adherence to this prevention strategy.

Methods

We assessed study gel adherence among women with pregnancies compared to women without pregnancies enrolled in the CAPRISA 004 phase IIB trial of 1% vaginal tenofovir gel. Pregnancy was assessed with monthly urine tests. Adherence was measured monthly and defined as proportion of sex acts covered by two returned, used applicators based on pre- and post-coital dosing. High adherence was defined as a median adherence score of >80%, that is, more than 80% of sex acts were covered by two applications of study gel. A multivariate generalized estimating equations (GEE) model with a binomial distribution was used to assess covariates associated with high adherence (>80%) over time. Median adherence before and after pregnancy was compared using Wilcoxon signed rank test.

Results

Among 868 women, 53 had at least 1 pregnancy (4.06 per 100 woman years, 95% CI: 3.04, 5.31). Women with pregnancies had lower median adherence compared to women without pregnancies (50% [IQR: 45–83] vs. 60% [IQR: 50–100], p = 0.02). Women with pregnancies also had a 48% lower odds of high adherence compared to women without pregnancies when adjusting for confounders (aOR 0.52, 95%CI: 0.41–0.66, p<0.0001). Among women with pregnancies, adherence before and after pregnancy was not different (50% [IQR: 46–83] vs. 55% [IQR: 20–100], p = 0.68).

Conclusions

Women with pregnancies were less likely to have high adherence to study gel compared to women without pregnancies. Understanding these differences may inform findings from HIV prevention trials and future implementation of antiretroviral prophylaxis for at-risk women who choose to conceive. The protocol for the parent trial is registered on ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00441298","term_id":"NCT00441298"}}NCT00441298, http://www.clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00441298","term_id":"NCT00441298"}}NCT00441298.     

Cytomegalovirus Seroprevalence in Pregnant Women and Association with Adverse Pregnancy/Neonatal Outcomes in Jiangsu Province,China

Background

In this study, we aimed to determine the provincial population-based seroprevalence in pregnant women and to further explore the association of maternal CMV infection status and adverse pregnancy/neonatal/growth outcomes in Jiangsu, China.

Methods

In this case-control study, the sera from 527 pregnant women with adverse pregnancy/neonatal outcomes and 496 mothers of healthy infants in Jiangsu Province, collected at gestation age of 15–20 weeks, were tested for anti-CMV IgG, IgM and IgG avidity. Adverse pregnancy/neonatal outcomes were identified based on pregnancy/neonatal outcomes.

Results

The overall seroprevalence of anti-CMV IgG was 98.7%, with 99.4% and 98.0% in the case and control groups, respectively (P = 0.039). The prevalence of anti-CMV IgG+/IgM+, was higher in the case group than that in the control group (3.8% vs. 1.6%, P = 0.033). Anti-CMV IgG avidity assay showed that none in the control group were primarily infected, but five (0.9%) in the case group underwent primary infection (P = 0.084); all five infants of these women presented severe adverse neonatal/growth outcomes. Exact logistic regression analysis showed that anti-CMV IgG+/IgM+ was associated with adverse pregnancy/neonatal/growth outcomes (aOR = 2.44, 95% CI 1.01–6.48, P = 0.047). Maternal low education level and prior abnormal pregnancies also were risk factors for adverse pregnancy/neonatal outcomes.

Conclusions

In populations with very high prevalence of latent CMV infection, active maternal CMV infection during pregnancy might be a risk factor for adverse pregnancy/neonatal outcomes.     

Risk Factors for Venous Thromboembolism in 1.3 Million Pregnancies: A Nationwide Prospective Cohort

Objective

To quantify risk factors for venous thromboembolism during pregnancy and the puerperal period.

Design

In a nationwide prospective cohort study we followed pregnant and puerperal women in Denmark from 1995 to 2009 for venous thromboembolism. Information on risk factors and confounders was retrieved from national registries. The diagnosis of venous thromboembolism was confirmed through medical charts. We calculated adjusted incidence rates per 10,000 women years and used Poisson regression to estimate effects during pregnancy and the puerperal period.

Results

We studied 1,297,037 pregnancies and related puerperal periods, during which there were 748 venous thromboembolisms. The incidence rate for venous thromboembolism during a pregnancy with and without hospitalization for hyperemesis was 15.2/10,000 yr and 6.3/10,000 yr, respectively, (adjusted rate ratio: 2.5 (95%-confidence interval; 1.4–4.5)). The incidence rate among women with multiple pregnancies was 18.2/10,000 yr and 6.3/10,000 yr in singletons (adjusted rate ratio: 2.8 (1.9–4.2)). Increased risk was found with hospitalization during pregnancy or the puerperal period with incidence rates of 42.1/10.000 and 54.7/10.000, respectively, (rate ratios: 12.2 (8.7–17) and 5.9 (4.0–8.8)). Women hospitalized with infections during pregnancy had incidence rates of 25.9/10,000 yr and 29.3/10,000 yr during pregnancy and the puerperal period, respectively, and of 62.7/10,000 yr if hospitalized with infection in the puerperal period. Puerperal venous thromboembolism was associated with hospitalization for preeclampsia and intrauterine growth restriction/fetal death with incidence rates of 45.8/10,000 yr and 18.3/10,000 yr, respectively (rate ratio: 5.0 (3.1–7.8) and 1.9 (0.9–4.4)). Additionally puerperal venous thromboembolism was associated with obesity, elective and acute caesarean sections and major postpartum bleeding with incidence rates of 25.5/10,000 yr, 23.2/10,000 yr, 34.0/10,000 yr and 20.3/10,000 yr, respectively (rate ratios 1.7 (1.1–2.7), 2.1 (1.4–3.1), 3.0 (2.3–4.0) and 1.4 (1.0–2.1)).

Conclusions

Important risk factors for venous thromboembolism during pregnancy or the puerperal period were hospitalization, infection, hyperemesis, multiple pregnancies, preeclampsia, obesity, caesarean section, major postpartum bleeding, and intrauterine growth restriction or fetal death.     

Background Rates of Adverse Pregnancy Outcomes for Assessing the Safety of Maternal Vaccine Trials in Sub-Saharan Africa

Background

Maternal immunization has gained traction as a strategy to diminish maternal and young infant mortality attributable to infectious diseases. Background rates of adverse pregnancy outcomes are crucial to interpret results of clinical trials in Sub-Saharan Africa.

Methods

We developed a mathematical model that calculates a clinical trial''s expected number of neonatal and maternal deaths at an interim safety assessment based on the person-time observed during different risk windows. This model was compared to crude multiplication of the maternal mortality ratio and neonatal mortality rate by the number of live births. Systematic reviews of severe acute maternal morbidity (SAMM), low birth weight (LBW), prematurity, and major congenital malformations (MCM) in Sub-Saharan African countries were also performed.

Findings

Accounting for the person-time observed during different risk periods yields lower, more conservative estimates of expected maternal and neonatal deaths, particularly at an interim safety evaluation soon after a large number of deliveries. Median incidence of SAMM in 16 reports was 40.7 (IQR: 10.6–73.3) per 1,000 total births, and the most common causes were hemorrhage (34%), dystocia (22%), and severe hypertensive disorders of pregnancy (22%). Proportions of liveborn infants who were LBW (median 13.3%, IQR: 9.9–16.4) or premature (median 15.4%, IQR: 10.6–19.1) were similar across geographic region, study design, and institutional setting. The median incidence of MCM per 1,000 live births was 14.4 (IQR: 5.5–17.6), with the musculoskeletal system comprising 30%.

Interpretation

Some clinical trials assessing whether maternal immunization can improve pregnancy and young infant outcomes in the developing world have made ethics-based decisions not to use a pure placebo control. Consequently, reliable background rates of adverse pregnancy outcomes are necessary to distinguish between vaccine benefits and safety concerns. Local studies that quantify population-based background rates of adverse pregnancy outcomes will improve safety assessment of interventions during pregnancy.