Francisco J. Schneuer

Effects of maternal serum 25-hydroxyvitamin D concentrations in the first trimester on subsequent pregnancy outcomes in an Australian population

BACKGROUND Low serum 25-hydroxyvitamin D [25(OH)D] concentrations during pregnancy have been associated with adverse pregnancy outcomes in a few studies but not in other studies. OBJECTIVES We assessed the serum 25(OH)D concentration at 10-14 wk of pregnancy and its association with adverse pregnancy outcomes and examined the predictive accuracy. DESIGN In this nested case-control study, we measured serum 25(OH)D in 5109 women with singleton pregnancies who were attending first-trimester screening in New South Wales, Australia. Multivariate logistic regression was conducted to examine the association between low 25(OH)D concentrations and adverse pregnancy outcomes (small for gestational age, preterm birth, preeclampsia, gestational diabetes, miscarriage, and stillbirth). The predictive accuracy of models was assessed. RESULTS The median (IQR) 25(OH)D concentration for the total population was 56.4 nmol/L (43.3-69.8 nmol/L). Serum 25(OH)D concentrations showed significant variation by parity, smoking, weight, season of sampling, country of birth, and socioeconomic status. After adjustment for maternal and clinical risk factors, low 25(OH)D concentrations were not associated with most adverse pregnancy outcomes. The area under the receiver operating characteristic curve (AUC) and likelihood ratio for a composite of severe adverse pregnancy outcomes of 25(OH)D concentrations <25 nmol/L were 0.51 and 1.44, respectively, and, for risk factors alone, were 0.64 and 2.87, respectively. The addition of 25(OH)D information to maternal and clinical risk factors did not improve the ability to predict severe adverse pregnancy outcomes (AUC: 0.64; likelihood ratio: 2.32; P = 0.39). CONCLUSION Low 25(OH)D serum concentrations in the first trimester of pregnancy are not associated with adverse pregnancy outcomes and do not predict complications any better than routinely assessed clinical and maternal risk-factor information.

Association and Predictive Accuracy of High TSH Serum Levels in First Trimester and Adverse Pregnancy Outcomes

CONTEXT High serum levels of TSH have been associated with adverse pregnancy outcomes by some studies, and not by others. OBJECTIVE The aim of the study was to assess the association between high levels of TSH in the first trimester of pregnancy and adverse pregnancy outcomes; and to examine the predictive accuracy as a screening test. SETTING AND PARTICIPANTS Serum levels of TSH were measured in a cohort of 2801 women with a singleton pregnancy attending first trimester Down syndrome screening. Information on maternal and infant outcomes was obtained through record linkage to population-based birth and hospital data. Association between high TSH (>95th and >97.5th centiles) multiple of the median levels, and risk of adverse pregnancy outcomes was evaluated using multivariable logistic regression, and the predictive accuracy of models was assessed. MAIN OUTCOMES Rates of infants being small for gestational age (SGA), preterm birth, preeclampsia, miscarriage, and stillbirth were investigated. RESULTS High TSH multiple of the median levels were associated with SGA (<10th centile) [adjusted odds ratio (aOR), 1.71; 95% confidence interval (CI), 0.99-2.94]; preterm birth at less than 37 wk gestation (aOR, 2.59; 95% CI, 1.21-5.53); miscarriage (aOR, 3.66; 95% CI, 1.59-8.44); and a composite measure of any study outcome (aOR, 2.10; 95% CI, 1.23-3.59). The area under the receiver operator characteristic curves were 0.69 (95% CI, 0.65-0.73) for SGA; 0.56 (95% CI, 0.51-0.61) for preterm birth; 0.70 (95% CI, 0.61-0.79) for miscarriage; and 0.63 (95% CI, 0.60-0.65) for any adverse pregnancy outcome. CONCLUSIONS High TSH serum levels during the first trimester of pregnancy were associated with adverse pregnancy outcomes; however, the predictive accuracy was poor. Screening for high TSH levels in the first trimester would be of no benefit to identify women at risk.

First trimester screening of maternal placental protein 13 for predicting preeclampsia and small for gestational age: in-house study and systematic review

OBJECTIVE To describe normative levels of PP13 in first trimester of pregnancy and determine the accuracy of PP13 in predicting preeclampsia and small for gestational age (SGA) infants. METHODS We measured PP13 in archived first trimester serum samples from an unselected maternal cohort of 2989 women. Associations of PP13 levels and diagnostic accuracy in predicting adverse pregnancy outcomes were assessed using multivariate logistic regression models. Due to inadequate number of cases we then conducted a systematic review and subsequent meta-analysis of predictive accuracy. Structured searches including all languages were completed in electronic databases and supplemented by cross-checking reference lists of relevant publications. Characteristics, data extraction and quality assessment of studies was conducted by independent assessors. RESULTS Overall, 2678 women were included in the in-house study with 71 (2.7%) preeclampsia cases, 5 (0.2%) early-onset preeclampsia (≤34 weeks) cases; and 191 (7.1%) and 41 (1.5%) infants SGA<10th and <3rd centile. Median (IQR) normative level of PP13 in unaffected pregnancies was 53.5 (37.7-71.8) pg/ml. The area under the receiver operating characteristic curve (AUC) for multivariate models was 0.72 (95%CI 0.66-0.78) for preeclampsia; 0.82 (95%CI 0.63-0.99) for early-onset preeclampsia; 0.73 (95%CI 0.69-0.77) for SGA<10th centile; and 0.83 (95%CI 0.78-0.88) for SGA<3rd centile. Eight studies were included in the systematic review, normative levels of PP13 were assessed in four studies but these were variable; and meta-analysis was performed on seven studies. Sensitivity rates of PP13 based on 5% fixed false positive rates were 24%, 45% and 26% for preeclampsia, for early-onset preeclampsia and SGA, respectively. There was no evidence of between-study heterogeneity. CONCLUSIONS First trimester PP13, in combination with maternal characteristics and other serum biomarkers was inadequate for screening purposes and predicting women at risk.

Prevalence, repairs and complications of hypospadias: an Australian population-based study

Objective To investigate hypospadias’ prevalence and trends, rate of surgical repairs and post-repair complications in an Australian population. Methods Hypospadias cases were identified from all live-born infants in New South Wales, Australia, during the period 2001–2010, using routinely collected birth and hospital data. Prevalence, trends, surgical procedures or repairs, hospital admissions and complications following surgery were evaluated. Risk factors for reoperation and complications were assessed using multivariate logistic regression. Results There were 3186 boys with hypospadias in 2001–2010. Overall prevalence was 35.1 per 10 000 live births and remained constant during the study period. Proportions of anterior, middle, proximal and unspecified hypospadias were 41.3%, 26.2%, 5.8% and 26.6%, respectively. Surgical procedures were performed in 1945 boys (61%), with 1718 primary repairs. The overall post-surgery complication rate involving fistulas or strictures was 13%, but higher (33%) for proximal cases. Complications occurred after 1 year post-repair in 52.3% of cases and up to 5 years. Boys with proximal or middle hypospadias were at increased risk of reoperation or complications, but age at primary repair did not affect the outcome. Conclusion One in 285 infants were affected with hypospadias, 60% required surgical repair or correction and one in eight experienced complications. The frequency of late complications would suggest that clinical review should be maintained for >1 year post-repair.

Angiopoietin 1 and 2 serum concentrations in first trimester of pregnancy as biomarkers of adverse pregnancy outcomes

OBJECTIVE To assess angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and the Ang-1/Ang-2 ratio levels in the first trimester of pregnancy, their association with adverse pregnancy outcomes, and their predictive accuracy. STUDY DESIGN This cohort study measured serum Ang-1 and Ang-2 levels in 4785 women with singleton pregnancies attending first trimester screening in New South Wales, Australia. Multivariate logistic regression models were used to assess the association and predictive accuracy of serum biomarkers with subsequent adverse pregnancy outcomes (small for gestational age, preterm birth, preeclampsia, miscarriage >10 weeks, and stillbirth). RESULTS Median (interquartile range) levels for Ang-1, Ang-2, and the Ang-1/Ang-2 ratio for the total population were 19.6 ng/mL (13.6-26.4), 15.5 ng/mL (10.3-22.7), and 1.21 (0.83-1.73), respectively. Maternal age, weight, country of birth, and socioeconomic status significantly affected Ang-1, Ang-2, and the Ang-1/Ang-2 ratio levels. After adjusting for maternal and clinical risk factors, women with low Ang-2 levels (<10th percentile) and high Ang-1/Ang-2 ratio (>90th percentile) had increased risk of developing most adverse pregnancy outcomes. Compared with the Ang-1/Ang-2 ratio alone, maternal and clinical risk factors had better predictive accuracy for most adverse pregnancy outcomes. The exception was miscarriage (Ang-1/Ang-2 ratio area under receiver operating characteristic curve = 0.70; maternal risk factors = 0.58). Overall, adding the Ang-1/Ang-2 ratio to maternal risk factors did not improve the ability of the models to predict adverse pregnancy outcomes. CONCLUSION Our findings suggest that the Ang-1/Ang-2 ratio in first trimester is associated with most adverse pregnancy outcomes, but do not predict outcomes any better than clinical and maternal risk factor information.

Age at surgery and outcomes of an undescended testis

BACKGROUND: Undescended testis (UDT) is the most common genital anomaly in boys. Current guidelines recommend surgery before 12 months of age to maximize fertility and potentially reduce the risk of future malignancy. We investigated the prevalence of UDT and examined rates of surgery and age at surgery in an Australian population. METHODS: UDT was identified from all live-born infants in New South Wales, Australia, from 2001 to 2011 using routinely collected record-linked birth and hospital data. The prevalence of UDT, surgery rates, age at surgery, postsurgical outcomes, and risk factors for surgery performed later than the recommended age were evaluated. RESULTS: There were 10 875 (2.1%) boys with a recorded diagnosis of UDT. Corrective surgery was performed in 4980 (45.8%), representing a cumulative prevalence of 9.6 per 1000 male births. Five percent of surgeries were orchidectomies, and 9% of boys had revision surgery. Median age at surgery was 16.6 months (interquartile range 11.8 to 31.0 months), decreasing from 21 months for boys born in 2001 to 13 months for boys born in 2010. Among those boys having surgery before 36 months (n = 3897), 67% had corrective surgery after the recommended 12 months of age; socioeconomic disadvantage, regional/remote area of residence, and lack of private health insurance were risk factors for having corrective surgery after 12 months. CONCLUSIONS: One in 50 boys born are diagnosed with UDT; two-thirds had no report of corrective surgery. The age at surgery is decreasing; however, two-thirds of surgeries are performed after 12 months of age.

Genetic and environmental factors in the aetiology of hypospadias

This article reviews the current evidence and knowledge of the aetiology of hypospadias. Hypospadias remains a fascinating anomaly of the male phallus. It may be an isolated occurrence or part of a syndrome or field defect. The increasing use of assisted reproductive techniques and hormonal manipulation during pregnancy may have been associated with an apparent rise in the incidence of hypospadias. Genetic studies and gene analysis have suggested some defects that could result in hypospadias. New light has also been thrown on environmental factors that could modulate candidate genes, causing altered development of the male external genitalia.

First trimester screening of serum soluble fms-like tyrosine kinase-1 and placental growth factor predicting hypertensive disorders of pregnancy

OBJECTIVE To assess the accuracy of first trimester soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in predicting pregnancy hypertension and pre-eclampsia; and compare with the accuracy of routinely collected maternal and clinical risk factors. STUDY DESIGN In this population-based cohort study, serum sFlt-1 and PlGF levels were measured in first trimester in 2,681 women with singleton pregnancies in New South Wales, Australia. MAIN OUTCOME MEASURES Prediction of pregnancy hypertension and pre-eclampsia. RESULTS There were 213 (7.9%) women with pregnancy hypertension, including 68 (2.5%) with pre-eclampsia. The area under the curve (AUC) for both sFlt-1 and PlGF was not different from chance, but combined was 0.55 (P=0.005). Parity and previous diagnosed hypertension had better predictive accuracy than serum biomarkers (AUC=0.64, P<0.001) and the predictive accuracy for all maternal and clinical information was fair (AUC=0.70, P<0.001 for pregnancy hypertension and AUC=0.74, P<0.001 for pre-eclampsia). Adding sFlt-1 and PlGF to maternal risk factors did not improve the ability of the models to predict pregnancy hypertension or pre-eclampsia. CONCLUSIONS Maternal first trimester serum concentrations of sFlt-1 and PlGF do not predict hypertensive disorders in pregnancy any better than routinely collected clinical and maternal risk factor information. Screening for sFlt-1 and PlGF levels in early pregnancy would not identify those pregnancies at-risk.

The impact of general anesthesia on child development and school performance: a population‐based study

There has been considerable interest in the possible adverse neurocognitive effects of exposure to general anesthesia and surgery in early childhood.

Early Childhood Development of Boys with Genital Anomalies

BACKGROUND Male genital anomalies often require surgery in early life to address functional and cosmetic consequences. However, there has been little assessment of developmental outcomes of affected boys. METHODS We conducted a population-based cohort study of all boys born in New South Wales, Australia, and undergoing school-entry developmental assessment in 2009 or 2012. Health and developmental information was obtained by means of record-linkage of birth, hospital and Australian Early Development Census data. Boys with hypospadias or undescended testis (UDT) were compared with those without. Developmental outcomes were assessed in five domains (physical health, emotional maturity, communication, cognitive skills, and social competence), and boys were categorized as vulnerable (<10th centile of national scores), developmentally high risk (DHR; vulnerable in 2+ domains), and special needs. RESULTS We included 420 boys with hypospadias, 873 with UDT, and 77,176 unaffected boys. There was no difference in the proportion of boys developmentally vulnerable in any domain or DHR between boys with hypospadias (DHR: n = 49; 13.1%; p = 0.9), UDT (n = 116; 15.2%; p = 0.06), and unaffected boys (n = 9278; 12.9%). Compared with unaffected boys (n = 4826; 6.3%), boys with hypospadias (n = 43; 10.2%; p < 0.001) or UDT (n = 105; 12.0%; p < 0.001) were more likely to have special needs. Stratified analyses revealed that only boys with UDT and coexisting anomalies had increased risk of being DHR (odds ratio: 2.65; 95% confidence interval, 1.61-4.36) or special needs (odds ratio: 2.91; 95% confidence interval, 2.00-4.22). CONCLUSION We found no increased risk of poor development among boys with hypospadias or UDT. However, boys with UDT and coexisting anomalies were more likely to have poorer development and special needs. Birth Defects Research 109:535-542, 2017.