Extract and molecular-based early infant sensitization and associated factors-A PreventADALL study.

BACKGROUND: More knowledge about sensitization patterns in early infancy, including impact of molecular allergology, is needed to help predict future allergy development more accurately. OBJECTIVE: We aimed to determine the prevalence and patterns of allergic sensitization at 3 months of age, and explore possible associated factors. METHODS: From the Scandinavian antenatally recruited PreventADALL mother-child cohort, we included 1110 3-month infants with available serum. Sensitization was defined as s-IgE of ≥0.1 kUA /L by Phadiatop Infant® (ThermoFisher Scientific) including birch, cat, grass, dog, milk, egg, peanut and wheat. Further ImmunoCAP analyses to ovomucoid, casein, Ara h 1-3, omega-5-gliadin were performed in food extract s-IgE-positive children. Maternal sensitization was defined as s-IgE ≥ 0.35 kUA /L to Phadiatop® (inhalant allergen mix) and/or Fx5 (food allergen mix) at 18-week pregnancy. RESULTS: Overall 79 (7.3%) infants had specific sensitization, many with low s-IgE-levels (IQR 0.16-0.81 kUA /L), with 78 being sensitized to food extract allergens; 41 to egg, 27 to milk, 10 to peanut, and 25 to wheat. A total of 62/78 were further analysed, 18 (29%) had s-IgE to ovomucoid, casein, Ara h 1-3 and/or omega-5-gliadin. Eight infants (0.7%) were sensitized to inhalant allergens. Maternal sensitization to food allergens was associated with infant sensitization, odds ratio 3.64 (95% CI 1.53-8.68). CONCLUSION: Already at 3 months of age, 7% were sensitized to food, mostly without detectable s-IgE to food allergen molecules, and <1% to inhalant allergens. Maternal food sensitization was associated with infants' sensitization.

External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. METHODS: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. RESULTS: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%. CONCLUSIONS: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice. TRIAL REGISTRATION: PROSPERO ID: CRD42015029349 .

Childbirth after mid-urethral sling surgery: effects on long-term success and complications.

INTRODUCTION AND HYPOTHESIS: To evaluate long-term outcomes in women with one or more childbirths after mid-urethral sling (MUS) surgery and potential differences in outcomes based on mode of delivery. METHODS: A population-based cohort study using data from two national registries. Women registered with childbirth after MUS (case group) or without childbirth after MUS (control group), with equal follow-up time, underwent a structured telephone interview using a validated short-form urinary disease-specific questionnaire. Primary outcomes were current stress urinary incontinence (SUI) rate and change in cure rate. Secondary outcomes were effect of delivery mode, rates of repeat operations for SUI, complications, treatment satisfaction and urgency urinary incontinence rate. Childbirth as an independent risk factor for SUI recurrence was also evaluated. RESULTS: Seventy-two women with and 156 women without childbirth after MUS were included. Median follow-up time was 10 years for both groups. Subjective SUI cure rates were 82% (cases) and 75% (controls), respectively (p = 0.31). A significantly lower SUI cure rate was seen in the women with more than one childbirth after MUS (50% vs. 88% p = 0.006). No differences in primary or secondary outcomes were found between groups at follow-up, nor did mode of delivery affect outcomes. Childbirth after MUS was not an independent risk factor for subjective SUI recurrence (OR 0.8 CI 0.3-1.7). CONCLUSIONS: No differences in outcomes were seen between groups at follow-up independently of delivery mode. However, having more than one delivery after MUS seems to impact the continence status.

Gestational age reference ranges for umbilical cord blood lactate: An external validation study of post-date pregnancies.

A previous study published in 2008 by Wiberg et al demonstrated increasing umbilical cord blood lactate at delivery by gestational age in vigorous offspring (n = 10 169, gestational age 24-43 weeks). Based on these results the authors concluded that gestational age-independent umbilical cord lactate cut-off could give false-negative or false-positive diagnosis of lacticemia. To our knowledge, these findings have not been incorporated into clinical interpretations in delivery units. To perform an external validity study for the findings by Wiberg et al, we analyzed umbilical cord blood lactate levels according to gestational age in a post-date delivery study population at our large, tertiary obstetric unit. The parallel finding of our study to that of Wiberg et al highlights the importance of using available gestational age dependent reference ranges (eg as presented in Wiberg's publication), when interpreting umbilical cord blood lactate levels for fetal wellbeing.

The completeness and accuracy of the Norwegian Female Incontinence Registry.

INTRODUCTION: Medical quality registries have gained popularity as tools for monitoring the quality of medical treatments and they serve as data sources for research. The Norwegian Female Incontinence Registry (NFIR) was established in 1998 to monitor and improve the quality of surgery for women with stress and mixed urinary incontinence in Norway and to collect data for research. This study aimed to assess the completeness and accuracy of the Norwegian Female Incontinence Registry, and potential differences in data accuracy over time and according to surgical volume of the reporting hospitals. MATERIAL AND METHODS: A random selection of 300 women from a total of 20 610 operated for urinary incontinence between 1998 and 2016 reported to the Norwegian Female Incontinence Registry from 28 public hospitals were selected for validation. The database completeness was estimated for 2008-2017 by comparing surgical procedures registered both in the Norwegian Female Incontinence Registry and the Norwegian National Patient Registry. Historical data recorded in the Registry for 10 selected key variables were extracted and compared with the patients' individual medical records at the reporting hospitals as reference. The reviewers were blinded to the previously stored information. The intraclass correlation coefficient for continuous variables and Cohen's kappa for categorical variables were calculated. RESULTS: Primary source data on 285 of the 300 women selected from Norwegian Female Incontinence Registry were successfully retrieved. The completeness of the registry has increased from 61% in 2008 to 99% in 2017. The national coverage has increased from 12 reporting departments in 1998 to all 38 public departments performing female incontinence surgery in 2017. Excellent accuracy was found for both continuous variables (intraclass correlation coefficient >0.94) and categorical variables (Cohen's kappa >0.86). No differences in data accuracy were found comparing high-volume hospitals with low-volume hospitals, or when comparing data accuracy over time. CONCLUSIONS: The Norwegian Female Incontinence Registry is a reliable tool for quality assessment of incontinence surgery and research. The registry completeness has improved over time and now contains data on nearly all women undergoing incontinence surgery in Norway.

Impact of levator muscle avulsions on Manchester procedure outcomes in pelvic organ prolapse surgery.

INTRODUCTION: Levator ani muscle avulsions potentially increase recurrence after anterior colporrhaphies. We aimed at evaluating the impact of avulsions on anatomical and patient-reported outcomes 1 year after the Manchester procedure for primary anterior compartment pelvic organ prolapse. MATERIAL AND METHODS: Prospective cohort study of 189 women undergoing the Manchester procedure between October 2014 and January 2017. Avulsions were diagnosed by transperineal ultrasound. Women with and without avulsions were compared for 1-year postoperative outcomes; Pelvic Organ Prolapse Quantification measurements, subjective satisfaction (1-worse to 4-cured), failure (new prolapse treatment), response to validated questionnaires on pelvic floor distress and sexual function, and a composite outcome (subjectively cured and optimal anterior compartment outcome (stage 0-I)). Optimal mid-compartment outcome was defined as cervix ≥5 cm above the hymen. Factors potentially associated with poor anatomical outcomes (anterior compartment stage ≥II) or pelvic floor distress were analyzed using regression analyses. RESULTS: Fewer women with avulsions (present in 50.8%) obtained optimal mid-compartment outcomes (88.2% vs 77.1%; P = 0.05). The groups were otherwise similar in terms of mid-compartment reduction, anterior compartment results, failure rate, subjective satisfaction, pelvic floor/sexual symptoms, and combined optimal subjective and anatomical outcome. Only preoperative anterior compartment stage ≥III was associated with poor anatomical outcome (P < 0.01). A high preoperative symptom score was associated with a high postoperative symptom score (P < 0.001). CONCLUSIONS: Although fewer women with avulsions obtained optimal mid-compartment results, avulsions had no impact on other anatomical or symptomatic outcomes 1 year after the Manchester procedure for primary anterior compartment prolapse.

The Manchester procedure: anatomical, subjective and sexual outcomes.

INTRODUCTION AND HYPOTHESIS: Classical native-tissue techniques for pelvic organ prolapse (POP) repairs, such as the Manchester procedure (MP), have been revitalized because of vaginal mesh complications. However, there are conflicting opinions regarding sufficient apical (mid-compartment) support by the MP and concerns about the risk of dyspareunia. The aims of this study were therefore to investigate anatomical and patient-reported outcomes 1 year after MP. METHODS: Prospective cohort study of 153 females undergoing an MP for anterior compartment POP between October 2014 and June 2016. Pre- and 1-year postoperative evaluations included POP-Q measurements and the questionnaires Pelvic Floor Distress Inventory Short Form 20 (PFDI-20) and POP/Urinary Incontinence Sexual Questionnaire (PISQ-12). RESULTS: At 1 year, 97% (148/153) attended the follow-up. Significant anatomical improvements (p < 0.01) were obtained in all compartments. Mean Ba was -1.1 (± 1.4), mean C -5.9 (± 1.7) and mean D -7.0 (± 1.2) at follow-up. Point C ≤ -5 was present in 81.1%. POP-Q stage 0-1 was obtained in 99.3% in the mid-compartment (C < -1), but only in 48.6% in the anterior compartment (Ba < -1). A significant reduction in symptom scores was obtained for PFDI-20 (p < 0.01) and PISQ-12 (p = 0.01). No significant changes were seen in dyspareunia rates (q.5, PISQ-12), but 5.6% reported de novo dyspareunia. Concerning POP symptoms, 96.0% reported being cured or significantly improved. CONCLUSIONS: The Manchester procedure provides adequate apical support, albeit inferior anatomical anterior compartment results, and 96.0% reported being subjectively cured or substantially better at 1-year follow-up, with no significant change in dyspareunia.

Levator ani defects and the severity of symptoms in women with anterior compartment pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: The aims of this study were to evaluate the prevalence of levator ani muscle (LAM) avulsions in a selected cohort of patients with primary anterior compartment pelvic organ prolapse (POP) and to assess whether LAM avulsions, as an independent factor, affect the degree of POP symptoms and sexual dysfunction. Additionally, clinical and demographic variables of women with and those without avulsions were compared. METHODS: We carried out a cross-sectional analysis of a prospective cohort study including 197 women scheduled for anterior compartment POP surgery. LAM avulsions were diagnosed on transperineal 4D ultrasound. Preoperative symptom severity and sexual dysfunction were evaluated using validated questionnaires (Pelvic Floor Disability Index [PFDI-20] and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-Short Form 12 [PISQ-12]). Linear regression was performed with avulsion as the main independent variable against total PFDI-20 and domain scores, bulge symptoms, and PISQ-12 score. Clinical and demographic variables for women with and without avulsions were compared using independent samples t test, Mann-Whitney U test or Chi-squared test. RESULTS: The prevalence of LAM avulsions was 50.3%. Avulsions were not associated with symptom severity or sexual dysfunction. "Chronic disease causing pain, fatigue or increased intra-abdominal pressure" was the only independent factor associated with all domains of the PFDI-20. Women with avulsions were younger at presentation, older at their first delivery, had lower BMI, and more often had a history of forceps delivery (p < 0.01). CONCLUSIONS: LAM avulsions were highly prevalent in this preoperative POP cohort. Avulsions were not associated with the severity of POP symptoms or sexual dysfunction. Women with avulsions seem to require fewer additional cofactors for developing POP.

Expression of L1CAM in curettage or high L1CAM level in preoperative blood samples predicts lymph node metastases and poor outcome in endometrial cancer patients.

BACKGROUND: Several studies have identified L1 cell adhesion molecule (L1CAM) as a strong prognostic marker in endometrial cancer. To further underline the clinical usefulness of this biomarker, we investigated L1CAM as a predictive marker for lymph node metastases and its prognostic impact in curettage specimens and preoperative plasma samples. In addition, we aimed to validate the prognostic value of L1CAM in hysterectomy specimen. METHODS: Immunohistochemical staining of L1CAM was performed for 795 hysterectomy and 1134 curettage specimen from endometrial cancer patients. The L1CAM level in preoperative blood samples from 372 patients was determined using ELISA. RESULTS: Expression of L1CAM in curettage specimen was significantly correlated to L1CAM level in corresponding hysterectomy specimen (P<0.001). Both in curettage and preoperative plasma samples L1CAM upregulation was significantly associated with features of aggressive disease and poor outcome (P<0.001). The L1CAM was an independent predictor of lymph node metastases, after correction for curettage histology, both in curettage specimen (P=0.002) and plasma samples (P=0.048). In the hysterectomy samples L1CAM was significantly associated with poor outcome (P<0.001). CONCLUSIONS: We demonstrate that preoperative evaluation of L1CAM levels, both in curettage or plasma samples, predicts lymph node metastases and adds valuable information on patient prognosis.

Sling mobilization in the management of urinary retention after mid-urethral sling surgery.

OBJECTIVE: To compare intermittent catheterization, sling mobilization, and sling transection for treatment of urinary retention after mid-urethral sling surgery. METHODS: Data registered in the Norwegian Female Incontinence Registry from 1998 to 2013 were analyzed in this cohort study to compare subjective and objective outcomes after intermittent catheterization, sling mobilization, and sling transection as management of postoperative urinary retention after mid urethral sling surgery. Subjective outcomes were degree of symptom bother and the percentage of women stating "very satisfied" at the postoperative follow-up. The objective outcome was leakage at a cough-jump pad stress test. RESULTS: Intervention due to urinary retention was performed in 585 of 18,772 women (3.1%). Women who had their sling mobilized or had intermittent catheterization, scored better on all postoperative outcomes than those who had their sling transected (P < 0.001). Sling transection was more often needed after intermittent catheterization than after mobilization (P = 0.023). No outcome differences were found between intermittent catheterization only and sling mobilization only. Intention to treat analysis showed that women who underwent sling mobilization as the primary procedure significantly more often had a negative stress test (P = 0.033) and were more often "very satisfied" with the treatment (P = 0.006) than those who were primarily catheterized. CONCLUSIONS: Sling mobilization is a more successful treatment than intermittent catheterization or transection for urinary retention after mid-urethral sling surgery. CLINICAL TRIAL REGISTRATION: Clinical trial registration was not applicable because this study is based on an analysis of anonymous data from The Norwegian Female Incontinence Registry. Neurourol. Urodynam. 36:1091-1096, 2017. © 2016 Wiley Periodicals, Inc.

Episiotomy preferences, indication, and classification--a survey among Nordic doctors.

INTRODUCTION: Episiotomy performance impacts perineal health and rates of obstetric anal sphincter injuries (OASIS). Our objective was to assess self-reported episiotomy practice and opinions on clinical indication for episiotomy among Nordic physicians and to investigate potential misclassification. MATERIAL AND METHODS: A survey was conducted among doctors attending the 2012 Nordic obstetrical and gynecological conference. Participants were asked to draw an episiotomy on a photo of a perineum with a crowning fetal head similarly to their clinical practice if an episiotomy was clinically indicated, and to name the technique drawn. Differences in outcome measures were compared by country of practice and seniority. RESULTS: The majority of the 297 participants (47%) drew a lateral episiotomy according to our classification by incision point and angle, but as many as 64% of these 138 doctors misclassified this as mediolateral episiotomy. Only 20% drew a mediolateral episiotomy, the great majority classifying it accurately, but 8% misclassified their mediolateral cut as a lateral episiotomy. One-third of episiotomies were nonclassifiable. In general, doctors in Finland, Sweden, and Norway more often favored lateral episiotomies compared with doctors in Denmark and Iceland. There were significant differences between Finnish and Norwegian vs. Danish and Swedish doctors in perception of clinical indications for episiotomy. CONCLUSIONS: The great variation in self-reported episiotomy performance between Nordic physicians and large misclassification rates indicate that educational programs are warranted. Use of uniform classification and appropriate techniques may be crucial to investigate the role of episiotomies in preventing OASIS.

Angiogenic biomarkers in pregnancy: defining maternal and fetal health.

We review diagnostic and predictive roles of the angiogenic proteins placental growth factor, soluble fms-like tyrosine kinase 1, and soluble endoglin in preeclampsia, and their association with future cardiovascular disease, diabetes, and breast cancer. Specific patterns of these proteins represent preeclamptic prediction markers and combined with maternal and clinical characteristics, the predictive values increase. Women experiencing preeclampsia have increased risks of developing cardiovascular diseases and diabetes, and a decreased risk of breast cancer. High placental growth factor concentrations have, in elderly patients, been shown to predict cardiovascular events. Diabetes is also a risk factor for future cardiovascular disease. Diabetic vascular complications are associated with increased soluble endoglin concentrations, and vascular endothelial growth factor concentrations are correlated to HbA1c and fasting glucose. Hence dysregulation in angiogenic proteins may link preeclampsia and cardiovascular diseases, targeting women who could in future benefit from prophylactic programs to possibly prevent, delay or reduce cardiovascular disease.

Risk factors for long-term failure of the retropubic tension-free vaginal tape procedure.

AIMS: To investigate potential risk factors for long-term (10-year) subjective and objective failure of the retropubic tension-free vaginal tape procedure (TVT). METHODS: Secondary risk analysis was performed using data from a recently published multi-center study that were merged with additional preoperative and operative data individually stored in the Norwegian Female Incontinence Registry (NFIR). Subjective data from 483 women and objective data from 327 women were obtained 10 years after retropubic TVT surgery. A validated questionnaire was used for subjective outcome data and a stress test for objective outcome data. Uni- and multivariate logistic regression analyses were performed using preoperative and operative variables extracted from the NFIR. The outcomes were 10-year subjective failure defined as women stating not cured, and objective failure was defined as ≥1 g urinary leakage during stress testing. RESULTS: Age ≥56 years at the time of TVT surgery was associated with both long-term subjective failure (adjusted OR: 2.15, CI: 1.40-3.30) and long-term objective failure (adjusted OR: 2.81, CI: 1.30-6.09). Mixed incontinence was associated with subjective, but not objective failure if the urgency incontinence component was severe (adjusted OR: 2.33, CI: 1.27-4.28). Surgical complications occurring at or immediately following surgery were associated with both outcomes in the univariate analyses, but were only an independent risk factor for subjective failure in the multivariate analysis (adjusted OR: 3.02, CI: 1.53-5.95). CONCLUSIONS: Age ≥56 years, a severe preoperative urgency incontinence component and surgical complications seem to represent independent risk factors for long-term (10-year) failure.

Cytochrome P450 subfamily 2J polypeptide 2 expression and circulating epoxyeicosatrienoic metabolites in preeclampsia.

BACKGROUND: Preeclampsia is a multisystem disorder of pregnancy, originating in the placenta. Cytochrome P450 (CYP)-dependent eicosanoids regulate vascular function, inflammation, and angiogenesis, which are mechanistically important in preeclampsia. METHODS AND RESULTS: We performed microarray screening of placenta and decidua (maternal placenta) from 25 preeclamptic women and 23 control subjects. The CYP subfamily 2J polypeptide 2 (CYP2J2) was upregulated in preeclamptic placenta and decidua. Reverse-transcription polymerase chain reaction confirmed the upregulation, and immunohistochemistry localized CYP2J2 in trophoblastic villi and deciduas at 12 weeks and term. The CYP2J2 metabolites, 5,6-epoxyeicosatrienoic acid (EET), 14,15-EET, and the corresponding dihydroxyeicosatrienoic acids, were elevated in preeclamptic women compared with controls in the latter two thirds of pregnancy and after delivery. Stimulating a trophoblast-derived cell line with the preeclampsia-associated cytokine tumor necrosis factor-α enhanced CYP2J2 gene and protein expression. In 2 independent rat models of preeclampsia, reduced uterine-perfusion rat and the transgenic angiotensin II rat, we observed elevated EET, dihydroxyeicosatrienoic acid, and preeclamptic features that were ameliorated by the CYP epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MsPPOH). Uterine arterial rings of these rats also dilated in response to MsPPOH. Furthermore, 5,6-EET could be metabolized to a thromboxane analog. In a bioassay, 5,6-EET increased the beating rate of neonatal cardiomyocytes. Blocking thromboxane synthesis reversed that finding and also normalized large-conductance calcium-activated potassium channel activity. CONCLUSIONS: Our data implicate CYP2J2 in the pathogenesis of preeclampsia and as a potential candidate for the disturbed uteroplacental remodeling, leading to hypertension and endothelial dysfunction.

Long-term follow-up of the retropubic tension-free vaginal tape procedure.

INTRODUCTION AND HYPOTHESIS: Retropubic tension-free vaginal tape (TVT) was introduced in 1996 as a new and innovative surgical approach in the treatment of stress urinary incontinence (SUI). In this study we evaluate the long-term objective and subjective outcomes in a non-selected patient population 10 years after the retropubic TVT procedure. METHODS: All women (603) operated on with retropubic TVT at four gynecological departments from September 1998 through December 2000 were identified, and those still alive (542) were invited to participate in this population-based prospective study. For subjective data a short-form urinary incontinence disease-specific questionnaire was used. For objective evaluation the women underwent a stress test. Data collected were merged with previously stored data in the Norwegian National Incontinence Registry Database. RESULTS: We included 483 women; 327 attended a clinical follow-up consultation and 156 had a telephone interview. Median duration of follow-up was 129 months. Objective cure rate was 89.9 %, subjective cure rate was 76.1 %, and 82.6 % of the patients stated they were "very satisfied" with their surgery (treatment satisfaction rate). Only 2.3 % of the women had undergone repeat SUI surgery. Subjective voiding difficulties were reported by 22.8 %, the majority describing slow stream or intermittency. De novo urgency incontinence increased significantly from 4.1 % 6-12 months after surgery to 14.9 % at the 10-year follow-up. CONCLUSIONS: Long-term objective and subjective outcome after retropubic TVT is excellent with a low number of re-operations even in a non-selected cohort of patients.

Serum amyloid A1 and pregnancy zone protein in pregnancy complications and correlation with markers of placental dysfunction.

BACKGROUND: Hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, and chronic hypertension), diabetes mellitus, and placental dysfunction confer an increased risk of long-term maternal cardiovascular disease. Preeclampsia is also associated with acute atherosis that involves lesions of uteroplacental spiral arteries, resembling early stages of atherosclerosis. Serum amyloid A1 is involved in hypercoagulability and atherosclerosis and may aggregate into amyloid-aggregations of misfolded proteins. Pregnancy zone protein may inhibit amyloid aggregation. Amyloid is involved in Alzheimer's disease and cardiovascular disease; it has been identified in preeclampsia, but its role in preeclampsia pathophysiology is unclear. OBJECTIVE: We hypothesized that serum amyloid A1 would be increased and pregnancy zone protein decreased in hypertensive disorders of pregnancy and diabetic pregnancies and that serum amyloid A1 and pregnancy zone protein would correlate with placental dysfunction markers (fetal growth restriction and dysregulated angiogenic biomarkers) and acute atherosis. STUDY DESIGN: Serum amyloid A1 is measurable in both the serum and plasma. In our study, plasma from 549 pregnancies (normotensive, euglycemic controls: 258; early-onset preeclampsia: 71; late-onset preeclampsia: 98; gestational hypertension: 30; chronic hypertension: 9; diabetes mellitus: 83) was assayed for serum amyloid A1 and pregnancy zone protein. The serum levels of angiogenic biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor were available for 547 pregnancies, and the results of acute atherosis evaluation were available for 313 pregnancies. The clinical characteristics and circulating biomarkers were compared between the pregnancy groups using the Mann-Whitney U, chi-squared, or Fisher exact test as appropriate. Spearman's rho was calculated for assessing correlations. RESULTS: In early-onset preeclampsia, serum amyloid A1 was increased compared with controls (17.1 vs 5.1 µg/mL, P<.001), whereas pregnancy zone protein was decreased (590 vs 892 µg/mL, P=.002). Pregnancy zone protein was also decreased in diabetes compared with controls (683 vs 892 µg/mL, P=.01). Serum amyloid A1 was associated with placental dysfunction (fetal growth restriction, elevated soluble fms-like tyrosine kinase-1 to placental growth factor ratio). Pregnancy zone protein correlated negatively with soluble fms-like tyrosine kinase-1 to placental growth factor ratio in all study groups. Acute atherosis was not associated with serum amyloid A1 or pregnancy zone protein. CONCLUSION: Proteins involved in atherosclerosis, hypercoagulability, and protein misfolding are dysregulated in early-onset preeclampsia and placental dysfunction, which links them and potentially contributes to future maternal cardiovascular disease.

Fetal thoracic circumference in mid-pregnancy and infant lung function.

BACKGROUND AND AIM: Impaired lung function in early infancy is associated with later wheeze and asthma, while fetal thoracic circumference (TC) predicts severity of neonatal lung hypoplasia. Exploring fetal origins of lung function in infancy, we aimed to determine if fetal TC in mid-pregnancy was associated with infant lung function. METHODS: From the prospective Scandinavian general population-based PreventADALL mother-child birth cohort, all 851 3-month-old infants with tidal flow-volume measurements in the awake state and ultrasound fetal size measures at 18 (min-max 16-22) weeks gestational age were included. Associations between fetal TC and time to peak tidal expiratory flow to expiratory time (tPTEF /tE ) were analyzed in linear regression models. To account for gestational age variation, we adjusted TC for simultaneously measured general fetal size, by head circumference (TC/HC), abdominal circumference (TC/AC), and femur length (TC/FL). Multivariable models were adjusted for maternal age, maternal asthma, pre-pregnancy body mass index, parity, nicotine exposure in utero, and infant sex. RESULTS: The infants (47.8% girls) were born at mean (SD) gestational age of 40.2 (1.30) weeks. The mean (SD) tPTEF /tE  was 0.39 (0.08). The mean (SD) TC/HC was 0.75 (0.04), TC/AC 0.87 (0.04), and TC/FL 4.17 (0.26), respectively. Neither TC/HC nor TC/AC were associated with infant tPTEF /tE while a week inverse association was observed between TC/FL and tPTEF /tE  ( ß ^ $\hat{\beta }$ = -0.03, 95% confidence interval [-0.05, -0.007], p = 0.01). CONCLUSION: Mid-pregnancy fetal TC adjusted for fetal head or abdominal size was not associated with tPTEF /tE in healthy, awake 3-month-old infants, while a weak association was observed adjusting for fetal femur length.

Effects of external cephalic version for breech presentation at or near term in high-resource settings: A systematic review of randomized and non-randomized studies.

INTRODUCTION: External cephalic version (ECV) for breech presentation involves manual manipulation of the fetus from breech to cephalic presentation at or near term, in an attempt to avoid breech birth. This systematic review summarizes the literature on the effects of ECV at or near term on pregnancy outcomes in high-resource settings. METHODS: The MEDLINE, Embase, CINAHL, Cochrane Library, MIDIRS, and SweMED+ databases were searched for relevant articles published through April 2019, with no limitation on publication date. Clinical trials comparing the effects of ECV at ≥36 weeks, with or without tocolysis, with that of no ECV, conducted in northern, western, and central Europe, the USA, Canada, Australia, and New Zealand were eligible for inclusion. RESULTS: Nine articles reporting on 184704 breech pregnancies were included. Pooled data showed that ECV attempts reduced the failure to achieve vaginal cephalic birth (risk ratio, RR=0.56; 95% CI: 0.45-0.71), caesarean section performance (RR=0.57; 95% CI: 0.50-0.64), and non-cephalic presentation at birth (RR=0.45; 95% CI: 0.29-0.68) compared with no ECV. ECV attempts also increased the incidence of Apgar score <7 at 5 minutes (RR=1.29; 95% CI: 1.10-1.52). CONCLUSIONS: Women for whom ECV is attempted at or near term are at reduced risk of caesarean section, non-cephalic presentation at term, and failure to achieve vaginal cephalic birth. Compared with no ECV, attempted ECV was also associated with a slightly increased risk of a low Apgar score at 5 minutes. The evidence is limited by the scarcity of high-quality research and the presence of risks of bias.

Galectin-3 deficiency in pregnancy increases the risk of fetal growth restriction (FGR) via placental insufficiency.

Fetal growth restriction (FGR) is the most common pregnancy complication in developed countries. Pregnancies affected by FGR, frequently concur with complications and high risk of neonatal morbidity and mortality. To date, no approved treatment is available for pregnant women affected with FGR. The objective of this study was to investigate the contribution of galectin-3 (gal-3), a ß-galactoside binding protein involved in pregnancy, placental function and fetal growth. We demonstrated that lack of gal-3 during mouse pregnancy leads to placental dysfunction and drives FGR in the absence of a maternal preeclampsia syndrome. Analysis of gal-3 deficient dams revealed placental inflammation and malperfusion, as well as uterine natural killer cell infiltration with aberrant activation. Our results also show that FGR is associated with a failure to increase maternal circulating gal-3 levels during the second and third trimester in human pregnancies. Placentas from human pregnancies affected by FGR displayed lower gal-3 expression, which correlated with placental dysfunction. These data highlight the importance of gal-3 in the promotion of proper placental function, as its absence leads to placental disease and subsequent FGR.

Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. OBJECTIVES: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. DESIGN: This was an individual participant data meta-analysis of cohort studies. SETTING: Source data from secondary and tertiary care. PREDICTORS: We identified predictors from systematic reviews, and prioritised for importance in an international survey. PRIMARY OUTCOMES: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia. ANALYSIS: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I2 and τ2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. RESULTS: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. LIMITATIONS: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. CONCLUSION: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. FUTURE WORK: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015029349. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Pre-eclampsia, a condition in pregnancy that results in raised blood pressure and protein in the urine, is a major cause of complications for the mother and baby. WHAT IS NEEDED?: A way of accurately identifying women at high risk of pre-eclampsia to allow clinicians to start preventative interventions such as administering aspirin or frequently monitoring women during pregnancy. WHERE ARE THE RESEARCH GAPS?: Although over 100 tools (models) have been reported worldwide to predict pre-eclampsia, to date their performance in women managed in the UK NHS is unknown. WHAT DID WE PLAN TO DO?: We planned to comprehensively identify all published models that predict the risk of pre-eclampsia occurring at any time during pregnancy and to assess if this prediction is accurate in the UK population. If the existing models did not perform satisfactorily, we aimed to develop new prediction models. WHAT DID WE FIND?: We formed the International Prediction of Pregnancy Complications network, which provided data from a large number of studies (78 studies, 25 countries, 125 researchers, 3,570,993 singleton pregnancies). We were able to assess the performance of 24 out of the 131 models published to predict pre-eclampsia in 11 UK data sets. The models did not accurately predict the risk of pre-eclampsia across all UK data sets, and their performance varied within individual data sets. We developed new prediction models that showed promising performance on average across all data sets, but their ability to correctly identify women who develop pre-eclampsia varied between populations. The models were more clinically useful when used in the care of first-time mothers pregnant with one child, compared to a strategy of treating them all as if they were at high-risk of pre-eclampsia. WHAT DOES THIS MEAN?: Before using the International Prediction of Pregnancy Complications models in various populations, they need to be adjusted for characteristics of the particular population and the setting of application.