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BackgroundThe age at onset of the association between poverty and poor health is not understood. Our hypothesis was that individuals from highest household income (HI), compared to those with lowest HI, will have increased fetal size in the second and third trimester and birth.Methods.Second and third trimester fetal ultrasound measurements and birth measurements were obtained from eight cohorts. Results were analysed in cross-sectional two-stage individual patient data (IPD) analyses and also a longitudinal one-stage IPD analysis.ResultsThe eight cohorts included 21 714 individuals. In the two-stage (cross-sectional) IPD analysis, individuals from the highest HI category compared with those from the lowest HI category had larger head size at birth (mean difference 0.22 z score (0.07, 0.36)), in the third trimester (0.25 (0.16, 0.33)) and second trimester (0.11 (0.02, 0.19)). Weight was higher at birth in the highest HI category. In the one-stage (longitudinal) IPD analysis which included data from six cohorts (n=11 062), head size was larger (mean difference 0.13 (0.03, 0.23)) for individuals in the highest HI compared with lowest category, and this difference became greater between the second trimester and birth. Similarly, in the one-stage IPD, weight was heavier in second highest HI category compared with the lowest (mean difference 0.10 (0 .00, 0.20)) and the difference widened as pregnancy progressed. Length was not linked to HI category in the longitudinal model.ConclusionsThe association between HI, an index of poverty, and fetal size is already present in the second trimester.

BACKGROUND: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. METHODS: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT(4)), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. FINDINGS: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT(4) concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT(4) concentrations were not associated with the outcomes measured. INTERPRETATION: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies. FUNDING: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research.

Background: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright's hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. Methods: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. Results: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. Conclusions: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes. The study was supported by funding from a research project grant (PI13/00467) from the Instituto de Salud Carlos III (Carlos III Institute of Health) of the Ministry of Economy and Competitiveness (Spain), co-financed by the European Regional Development Fund, and the Department of Health of the Basque Government (GV2014111017). AP is partly supported by the University of the Basque Country (Ref: 48198). GPN is partly supported by the I3SNS Program of the Spanish Ministry of Health (CP03/0064; SIVI 1395/09).

OBJECTIVE:To investigate whether circulating 25-hydroxyvitamin D3 [25(OH)D3] concentration in pregnancy is associated with neuropsychological development in infants.METHODS:The Spanish population-based cohort study INfancia y Medio Ambiente Project recruited pregnant women during the first trimester of pregnancy between November 2003 and February 2008. Completed data on 1820 mother-infant pairs were used. Maternal plasma 25(OH)D3 concentration was measured by high-performance liquid chromatography in pregnancy (mean 13.5±2.1 weeks of gestation). Offspring mental and psychomotor scores were assessed by trained psychologists at age 14 months (range, 11–23) by using the Bayley Scales of Infant Development. β-Coefficients with 95% confidence intervals (CIs) of mental and psychomotor scores associated with continuous or categorical concentrations of maternal plasma 25(OH)D3 were calculated by using linear regression analysis.RESULTS:The median plasma value of 25(OH)D3 in pregnancy was 29.6 ng/mL (interquartile range, 21.8–37.3). A positive linear relationship was found between circulating concentrations of maternal 25(OH)D3 concentrations in pregnancy and mental and psychomotor scores in the offspring. After adjustment for potential confounders, infants of mothers with 25(OH)D3 concentrations in pregnancy >30 ng/mL showed higher mental score (β = 2.60; 95% CI 0.63–4.56) and higher psychomotor score (β = 2.32; 95% CI 0.36–4.28) in comparison with those of mothers with 25(OH)D3 concentrations CONCLUSIONS:Higher circulating concentration of maternal 25(OH)D3 in pregnancy was associated with improved mental and psychomotor development in infants.

In a previous study on single umbilical artery (SUA) and its association with congenital defects, we observed a serendipitous association between isolated skin anomalies and the presence of SUA. Although this could be a spurious association, we considered that it deserved to be studied in detail. The aim of this study was to investigate, in an epidemiological setting, whether this association has any biological meaning or if it occurs just by chance. Using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), we analyzed "angiomas" (including all type of capillary skin marks, since it is not possible to distinguish it during the first 3 days of life), and nevi because they are the only defects detected in newborn infants as isolated skin defects. In the ECEMC methodology, infants with nevi or angiomas as the only congenital defect are considered as cases when they present with only one of these skin marks measuring at least 1 cm in diameter and within the first 3 days of life, or when they have three or more such marks of any size. A total sample of 1,832 consecutive newborn infants with isolated congenital skin marks was identified: 871 with nevi, 958 with angiomas, and 3 with both. Newborn infants with SUA and isolated angiomas displayed higher birth measurements, and older maternal and paternal ages than newborn infants with angiomas and three umbilical vessels. Similar results were observed when infants with angiomas and SUA were compared with control infants either with or without SUA. These associations were not observed in newborn infants with nevi with or without SUA or for control infants with or without SUA. The distribution of the angiomas by body areas, and sex preferences were also analyzed. After evaluating the limitations and advantages of the present study, the results suggest that newborn infants with angiomas (irrespective of their type), SUA, and higher centile measurements may have one of the syndromes that exhibit this type of skin mark. Although this observation requires confirmation, we do suggest close attention to newborns with these three signs.

Objectives: We examined the use of low (= 1000 mu g/day) among pregnant women in Spain, and explored factors associated with the use of these non-recommended dosages. Design: Population-based cohort study. Setting: Spain. Participants: We analysed data from 2332 pregnant women of the INMA study, a prospective mother-child cohort study in Spain. Main outcome measures: We assessed usual dietary folate and the use of FAS from preconception to the 3rd month (first period) and from the 4th to the 7th month (second period), using a validated food frequency questionnaire. We used multinomial logistic regression to estimate relative risk ratios (RRRs). Results: Over a half of the women used low dosages of FAS in the first and second period while 29% and 17% took high dosages of FAS, respectively. In the first period, tobacco smoking (RRR=1.63), alcohol intake (RRR=1.40), multiparous (RRR=1.44), unplanned pregnancy (RRR=4.20) and previous spontaneous abortion (RRR=0.58, lower use of high FAS dosages among those with previous abortions) were significantly associated with low FAS dosages. Alcohol consumption (RRR=1.42), unplanned pregnancy (RRR=2.66) and previous spontaneous abortion (RRR=0.68) were associated with high dosage use. In the second period, only tobacco smoking was significantly associated with high FAS dosage use (RRR=0.67). Conclusions: A high proportion of pregnant women did not reach the recommended dosages of FAS in periconception and a considerable proportion also used FAS dosages >= 1000 mu g/day. Action should be planned by the Health Care System and health professionals to improve the appropriate periconceptional use of FAS, taking into consideration the associated factors., This study was funded by grants from Instituto de Salud Carlos III and Spanish Ministry of Health (Red INMA G03/176; CB06/02/0041; FIS 97/0588; 00/0021-2, PI061756; PS0901958; FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314; 09/02647; FIS-PI041436, FIS-PI081151, FIS-PI06/0867; FIS-PS09/00090, FIS-PI042018, FIS-PI09 02311, FIS PI11/01007, FISPI13/02429) Universidad de Oviedo, Conselleria de Sanitat Generalitat Valenciana, Generalitat de Catalunya-CIRIT 1999SGR 00241, Department of Health of the Basque Government (2005111093 and 2009111069) and the Provincial Government of Guipuzcoa (DFG06/004 and DFG08/001).

Aim. To present data on prenatal diagnosis of six major cardiac malformations in low-risk European populations. Methods. Data from 12 Eurocat registries on congenital malformations. All registries have multiple sources of information and use the same methods of data collection and coding. The six cardiac malformations included were hypoplastic left heart, tricuspid atresia, single ventricle, Tetralogy of Fallot, transposition of great arteries and common A-V-canal. Results. There were significant differences in the proportion of cases diagnosed prenatally, with the highest detection rate in France (91% for single ventricle in Paris) and the lowest detection rate in countries without prenatal ultrasound screening (no cases diagnosed prenatally in the Danish registry area). Prenatal detection rate was significantly higher for the three malformations affecting the size of the ventricles (hypoplastic left heart, tricuspid atresia, single ventricle) compared to the other three malformations (46% versus 24%, p Conclusion. There are significant regional differences in prenatal detection rate of major cardiac malformations in Europe.