Uncomplicated Monochorionic Diamniotic Twins and the Timing of Delivery

Cleary-Goldman and d'Alton discuss the implications of a new study in PLoS Medicine examining the risk of fetal death in uncomplicated monochorionic diamnotic twin pregnancies

Cross-Country Individual Participant Analysis of 4.1 Million Singleton Births in 5 Countries with Very High Human Development Index...

Background: Preterm birth is the most common single cause of perinatal and infant mortality, affecting 15 million infants worldwide each year with global rates increasing. Understanding of risk factors remains poor, and preventive interventions have only limited benefit. Large differences exist in preterm birth rates across high income countries. We hypothesized that understanding the basis for these wide variations could lead to interventions that reduce preterm birth incidence in countries with high rates. We thus sought to assess the contributions of known risk factors for both spontaneous and provider-initiated preterm birth in selected high income countries, estimating also the potential impact of successful interventions due to advances in research, policy and public health, or clinical practice. Methods: We analyzed individual patient-level data on 4.1 million singleton pregnancies from four countries with very high human development index (Czech Republic, New Zealand, Slovenia, Sweden) and one comparator U.S. state (California) to determine the specific contribution (adjusting for confounding effects) of 21 factors. Both individual and population-attributable preterm birth risks were determined, as were contributors to cross-country differences. We also assessed the ability to predict preterm birth given various sets of known risk factors. Findings: Previous preterm birth and preeclampsia were the strongest individual risk factors of preterm birth in all datasets, with odds ratios of 4.6–6.0 and 2.8–5.7, respectively, for individual women having those characteristics. In contrast, on a population basis, nulliparity and male sex were the two risk factors with the highest impact on preterm birth rates, accounting for 25–50% and 11–16% of excess population attributable risk, respectively (p < 0.001). The importance of nulliparity and male sex on population attributable risk was driven by high prevalence despite low odds ratios for individual women. More than 65% of the total aggregated risk of preterm birth within each country lacks a plausible biologic explanation, and 63% of difference between countries cannot be explained with known factors; thus, research is necessary to elucidate the underlying mechanisms of preterm birth and, hence, therapeutic intervention. Surprisingly, variation in prevalence of known risk factors accounted for less than 35% of the difference in preterm birth rates between countries. Known risk factors had an area under the curve of less than 0.7 in ROC analysis of preterm birth prediction within countries. These data suggest that other influences, as yet unidentified, are involved in preterm birth. Further research into biological mechanisms is warranted. Conclusions: We have quantified the causes of variation in preterm birth rates among countries with very high human development index. The paucity of explicit and currently identified factors amenable to intervention illustrates the limited impact of changes possible through current clinical practice and policy interventions. Our research highlights the urgent need for research into underlying biological causes of preterm birth, which alone are likely to lead to innovative and efficacious interventions

Down syndrome serum screening also identifies an increased risk for multicystic dysplastic kidney, two-vessel cord, and hydrocele

The FASTER trial compared 1st and 2nd trimester screening methods for aneuploidy. We examined relationships between maternal serum markers and common congenital anomalies in the pediatric outcome data set of 36,837 subjects

Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study

In an analysis of a cohort of pregnant women, Radek Bukowski and colleagues describe an association between taking folic acid supplements and a reduction in the risk of preterm birth

TSH and FT4 reference interval recommendations and prevalence of gestational thyroid dysfunction: quantification of current diagnostic approaches

Context Guidelines recommend use of population- and trimester-specific TSH and FT4 reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations. Methods We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using non-pregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines. Results The study population comprised 52,496 participants from 18 cohorts. Compared to the use of trimester-specific reference intervals, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction and non-pregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches. Conclusion Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable over- and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy

Risk factors for thyroid dysfunction in pregnancy: an individual participant data meta-analysis

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction

Rare chromosomal abnormalities: can they be identified using conventional first trimester combined screening methods?

Objective: To evaluate the performance of first trimester combined screening for the detection of rare chromosomal abnormalities, other than Trisomies 21, 18 or 13 or 45 × . Study design: A database containing 36,254 pregnancies was analyzed. These patients were recruited at 15 US centers and included singleton pregnancies from 10 3/7-13 6/7 weeks. All patients had a nuchal translucency (NT) scan and those without a cystic hygroma (N = 36,120) underwent a combined first trimester screening test ('FTS' - NT, PAPP-A and fbHCG). A risk cut-off of 1:300, which was used for defining high risk for Trisomy 21, was also used to evaluate the detection rate for rare chromosomal abnormalities using the combined FTS test. Results: 36,120 patients underwent combined FTS. Of these, 123 were found to have one of the following chromosomal abnormalities: Trisomy 21, Trisomy 18, Trisomy 13 or Turner syndrome. This study focuses on 40 additional patients who were found to have 'other' rare chromosomal abnormalities such as triploidy, structural chromosomal abnormalities, sex chromosome abnormalities or unusual chromosomal abnormalities (e.g. 47XX + 16), giving an incidence of 1.1 in 1000 for these rare chromosomal abnormalities. Of these 40 pregnancies, only 2 (5%) had an NT measurement of ≥3 mm. The detection rate for combined FTS, using a risk cut-off of ≥1:300, was 35 % (14 of 40 cases). Therefore, 65 % of cases of rarer fetal chromosomal abnormalities had a 'normal' combined FTS risk ( Conclusion: Traditional FTS methods are unable to identify the vast majority of rare chromosomal abnormalities. Our data do not support the potential detection of rare fetal chromosomal abnormalities as a reason to favour nuchal translucency-based first trimester screening over NIPT.</p

Rare chromosomal abnormalities: can they be identified using conventional first trimester combined screening methods?

Objective: To evaluate the performance of first trimester combined screening for the detection of rare chromosomal abnormalities, other than Trisomies 21, 18 or 13 or 45 × . Study design: A database containing 36,254 pregnancies was analyzed. These patients were recruited at 15 US centers and included singleton pregnancies from 10 3/7-13 6/7 weeks. All patients had a nuchal translucency (NT) scan and those without a cystic hygroma (N = 36,120) underwent a combined first trimester screening test ('FTS' - NT, PAPP-A and fbHCG). A risk cut-off of 1:300, which was used for defining high risk for Trisomy 21, was also used to evaluate the detection rate for rare chromosomal abnormalities using the combined FTS test. Results: 36,120 patients underwent combined FTS. Of these, 123 were found to have one of the following chromosomal abnormalities: Trisomy 21, Trisomy 18, Trisomy 13 or Turner syndrome. This study focuses on 40 additional patients who were found to have 'other' rare chromosomal abnormalities such as triploidy, structural chromosomal abnormalities, sex chromosome abnormalities or unusual chromosomal abnormalities (e.g. 47XX + 16), giving an incidence of 1.1 in 1000 for these rare chromosomal abnormalities. Of these 40 pregnancies, only 2 (5%) had an NT measurement of ≥3 mm. The detection rate for combined FTS, using a risk cut-off of ≥1:300, was 35 % (14 of 40 cases). Therefore, 65 % of cases of rarer fetal chromosomal abnormalities had a 'normal' combined FTS risk ( Conclusion: Traditional FTS methods are unable to identify the vast majority of rare chromosomal abnormalities. Our data do not support the potential detection of rare fetal chromosomal abnormalities as a reason to favour nuchal translucency-based first trimester screening over NIPT.</p