Distinct protein patterns related to postnatal development in small for gestational age preterm infants.

BACKGROUND: Preterm infants, especially those born small for gestational age (SGA), are at risk of short-term and long-term health complications. Characterization of changes in circulating proteins postnatally in preterm infants may provide valuable fundamental insights into this population. Here, we investigated postnatal developmental patterns in preterm infants and explored protein signatures that deviate between SGA infants and appropriate for gestational age (AGA) infants using a mass spectrometry (MS)-based proteomics workflow. METHODS: Longitudinal serum samples obtained at postnatal days 0, 3, 7, 14, and 28 from 67 preterm infants were analyzed using unbiased MS-based proteomics. RESULTS: 314 out of 833 quantified serum proteins change postnatally, including previously described age-related changes in immunoglobulins, hemoglobin subunits, and new developmental patterns, e.g. apolipoproteins (APOA4) and terminal complement cascade (C9) proteins. Limited differences between SGA and AGA infants were found at birth while longitudinal monitoring revealed 69 deviating proteins, including insulin-sensitizing hormone adiponectin, platelet proteins, and 24 proteins with an annotated function in the immune response. CONCLUSIONS: This study shows the potential of MS-based serum profiling in defining circulating protein trajectories in the preterm infant population and its ability to identify longitudinal alterations in protein levels associated with SGA. IMPACT: Postnatal changes of circulating proteins in preterm infants have not fully been elucidated but may contribute to development of health complications. Mass spectrometry-based analysis is an attractive approach to study circulating proteins in preterm infants with limited material. Longitudinal plasma profiling reveals postnatal developmental-related patterns in preterm infants (314/833 proteins) including previously described changes, but also previously unreported proteins. Longitudinal monitoring revealed an immune response signature between SGA and AGA infants. This study highlights the importance of taking postnatal changes into account for translational studies in preterm infants.

Development of 24-hour rhythms in cortisol secretion across infancy: a systematic review and meta-analysis of individual participant data.

BACKGROUND: In adults, cortisol levels show a pronounced 24-hour rhythm with a peak in the early morning. It is unknown at what age this early-morning peak in cortisol emerges during infancy, hampering the establishment of optimal dosing regimens for hydrocortisone replacement therapy in infants with an inborn form of adrenal insufficiency. Therefore, we aimed to characterize daily variation in salivary cortisol concentration across the first year of life. METHODS: We conducted a systematic review followed by an individual participant data meta-analysis of studies reporting on spontaneous (i.e., not stress induced) salivary cortisol concentrations in healthy infants aged 0-1 year. A one-stage approach using linear mixed-effects modelling was used to determine the interaction between age and time of day on cortisol concentrations. FINDINGS: Through the systematic review, 54 eligible publications were identified, reporting on 29,177 cortisol observations. Individual participant data were obtained from 15 study cohorts, combining 17,079 cortisol measurements from 1,904 infants. The morning/evening cortisol ratio increased significantly from 1.7 (95% CI: 1.3-2.1) at birth to 3.7 (95% CI: 3.0-4.5) at 6-9 months (p < 0.0001). Cosinor analysis using all available data revealed the gradual emergence of a 24-hour rhythm during infancy. INTERPRETATION: The early-morning peak in cortisol secretion gradually emerges from birth onwards to form a stable morning/evening ratio from age 6-9 months. This might have implications for hydrocortisone replacement therapy in infants with an inborn form of adrenal insufficiency.

Neurodevelopmental outcomes of school-age children conceived after hysterosalpingography with oil-based or water-based iodinated contrast: long-term follow-up of a nationwide randomized controlled trial.

STUDY QUESTION: Does preconceptional exposure to oil-based iodinated contrast media during hysterosalpingography (HSG) impact children's neurodevelopment compared with exposure to water-based alternatives? SUMMARY ANSWER: Our study found no large-sized effects for neurodevelopment in children with preconceptional exposure to oil-based iodinated contrast media during HSG compared with water-based alternatives. WHAT IS KNOWN ALREADY: HSG is widely used as a diagnostic tool in the female fertility work-up. Tubal flushing with oil-based iodinated contrast has been shown to enhance fertility outcomes in couples with unexplained infertility, increasing the chances of pregnancy and live birth compared with water-based alternatives. However, oil-based contrast contains higher doses of iodine and has a longer half-life, and concerns exist that iodinated contrast media can affect women's iodine status and cause temporary (sub)clinical hypothyroidism in mothers and/or foetuses. Considering that thyroid hormones are vital to embryonal and foetal brain development, oil-based contrast media use could increase the risk of impaired neurodevelopment in children conceived shortly after HSG. Here we examine neurodevelopmental outcomes in school-aged children conceived after HSG. STUDY DESIGN, SIZE, DURATION: This is a long-term follow-up of the H2Oil trial in which oil-based or water-based contrast was used during HSG (Netherlands; 2012-2014; NTR3270). Of 369 children born <6 months after HSG in the study, we contacted the mothers of 140 children who gave consent to be contacted for follow-up. The follow-up study took place from January to July 2022 (NCT05168228). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: The study included 69 children aged 6-9 years who were conceived after HSG with oil-based (n = 42) or water-based contrast (n = 27). The assessments targeted intelligence (Wechsler Intelligence Scale for Children), neurocognitive outcomes (computerized neurocognitive tests), behavioural functioning (parent and teacher questionnaires), and academic performance. Linear regression models, adjusted for age, sex, and parental educational attainment were employed to compare groups. MAIN RESULTS AND THE ROLE OF CHANCE: School-aged children born to mothers after oil-based contrast HSG did not significantly differ from children born to mothers after water-based contrast HSG, in regards to intelligence, neurocognitive functioning, behavioural functioning, or academic performance, with the exception of better performance for visuomotor integration functions in children exposed to oil-based contrast preconception. After exploratory correction for multiple comparisons, none of the group differences was statistically significant. LIMITATIONS, REASONS FOR CAUTION: The small sample size of this follow-up study limited statistical power. This study provides evidence for the absence of large-sized differences between preconceptional exposure to the two contrast media types but does not rule out more subtle effects on neurodevelopment compared to naturally conceived children without preconceptional exposure to HSG. WIDER IMPLICATIONS OF THE FINDINGS: This study contributes to our knowledge about the long-term effects of different types of iodinated contrast media used in fertility work-up, indicating that choosing oil-based over water-based iodinated contrast media is unlikely to have major effect on the long-term neurodevelopmental outcomes of children conceived shortly after HSG. However, further research should focus on the overall safety of iodine exposure during HSG, comparing children conceived after HSG to those conceived naturally as both types of contrast contain high amounts of iodine. STUDY FUNDING/COMPETING INTEREST(S): The original H2Oil randomized controlled trial was an investigator-initiated study that was funded by the two academic hospitals now merged into the Amsterdam University Medical Centre. The current follow-up study (Neuro-H2Oil) is funded through a research grant awarded to the authors by the Amsterdam Reproduction & Development (AR&D) research institute. S.K. is funded by a AMC MD/PhD Scholarship from the Amsterdam UMC. S.K. reports holding voluntary roles in the civil society organizations Universities Allied for Essential Medicines and People's Health Movement. V.M. reports receiving travel and speaker fees as well as research grants from Guerbet, Merck and Ferring. K.D. reports receiving travel and speaker fees as well as research grants from Guerbet. BWM is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy, travel support and research funding from Merck, consultancy for Organon and Norgine, and holding stock from ObsEva. The other authors report no conflict of interest. TRIAL REGISTRATION NUMBER: NCT05168228.

Sulfate: a neglected (but potentially highly relevant) anion.

Sulfate is an important anion as sulfonation is essential in modulation of several compounds, such as exogens, polysaccharide chains of proteoglycans, cholesterol or cholesterol derivatives and tyrosine residues of several proteins. Sulfonation requires the presence of both the sulfate donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS) and a sulfotransferase. Genetic disorders affecting sulfonation, associated with skeletal abnormalities, impaired neurological development and endocrinopathies, demonstrate the importance of sulfate. Yet sulfate is not measured in clinical practice. This review addresses sulfate metabolism and consequences of sulfonation defects, how to measure sulfate and why we should measure sulfate more often.

Glucocorticoid signature of preterm infants developing bronchopulmonary dysplasia.

BACKGROUND: Systemic inflammation plays a key role in the development of bronchopulmonary dysplasia (BPD). Cortisol is known to dampen inflammation. However, adrenal function following preterm birth is characterized by insufficient cortisol levels for the degree of inflammation, and a relative abundancy of cortisol precursors. We investigated whether this pattern could contribute to the development of BPD in preterm infants born <30 weeks of gestation. METHODS: Cortisol, cortisone, 17-OH progesterone (17-OHP) and 11-deoxycortisol were measured in serum obtained at postnatal days 1, 3, 7, 14 and 28, using liquid-chromatography-tandem-mass-spectrometry. The presence of BPD was ascertained at 36 weeks postmenstrual age. RESULTS: Sixty-five infants were included for analysis, of whom 32 (49%) developed BPD. Preterm infants developing BPD, as compared to those without BPD, had higher levels of 17-OHP, 11-deoxycortisol and cortisone relative to cortisol in their first week of life, but not at birth or beyond day 7. CONCLUSION: Preterm infants developing BPD had higher levels of cortisol precursors and cortisone relative to cortisol in their first week of life than infants without BPD. These findings suggest that BPD is preceded by an activated hypothalamus-pituitary-adrenal axis that could not meet the high cortisol demands, which may predispose to inflammation and BPD. IMPACT: Relative adrenal insufficiency is common in the first weeks after preterm birth, resulting in insufficient cortisol production for the degree of inflammation and a relative abundance of cortisol precursors; Whether this pattern contributes to the development of bronchopulmonary dysplasia (BPD) is not fully elucidated, since most studies focused on cortisol levels; Preterm infants developing BPD had higher levels of cortisol precursors and cortisone relative to cortisol in the first week of life, suggestive of a hypothalamus-pituitary-adrenal-axis activation during BPD development which cannot meet the high cortisol demands in tissues; This glucocorticoid pattern is likely to dispose to inflammation and BPD.

Spontaneous haemoperitoneum in pregnancy: Nationwide surveillance and Delphi audit system.

OBJECTIVE: To evaluate the incidence, diagnostic management strategies and clinical outcomes of women with spontaneous haemoperitoneum in pregnancy (SHiP) and reassess the definition of SHiP. DESIGN: A population-based cohort study using the Netherlands Obstetric Surveillance System (NethOSS). SETTING: Nationwide, the Netherlands. POPULATION: All pregnant women between April 2016 and April 2018. METHODS: This is a case study of SHiP using the monthly registry reports of NethOSS. Complete anonymised case files were obtained. A newly introduced online Delphi audit system (DAS) was used to evaluate each case, to make recommendations on improving the management of SHiP and to propose a new definition of SHiP. MAIN OUTCOME MEASURES: Incidence and outcomes, lessons learned about clinical management and the critical appraisal of the current definition of SHiP. RESULTS: In total, 24 cases were reported. After a Delphi procedure, 14 cases were classified as SHiP. The nationwide incidence was 4.9 per 100 000 births. Endometriosis and conceiving after artificial reproductive techniques were identified as risk factors. No maternal and three perinatal deaths occurred. Based on the DAS, adequate imaging of free intra-abdominal fluid, and identifying and treating women with signs of hypovolemic shock could improve the early detection and management of SHiP. A revised definition of SHiP was proposed, excluding the need for surgical or radiological intervention. CONCLUSIONS: SHiP is a rare and easily misdiagnosed condition that is associated with high perinatal mortality. To improve care, better awareness among healthcare workers is needed. The DAS is a sufficient tool to audit maternal morbidity and mortality.

Prediction Models for Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review and Meta-Analysis.

OBJECTIVE: To review systematically and assess the accuracy of prediction models for bronchopulmonary dysplasia (BPD) at 36 weeks of postmenstrual age. STUDY DESIGN: Searches were conducted in MEDLINE and EMBASE. Studies published between 1990 and 2022 were included if they developed or validated a prediction model for BPD or the combined outcome death/BPD at 36 weeks in the first 14 days of life in infants born preterm. Data were extracted independently by 2 authors following the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (ie, CHARMS) and PRISMA guidelines. Risk of bias was assessed using the Prediction model Risk Of Bias ASsessment Tool (ie, PROBAST). RESULTS: Sixty-five studies were reviewed, including 158 development and 108 externally validated models. Median c-statistic of 0.84 (range 0.43-1.00) was reported at model development, and 0.77 (range 0.41-0.97) at external validation. All models were rated at high risk of bias, due to limitations in the analysis part. Meta-analysis of the validated models revealed increased c-statistics after the first week of life for both the BPD and death/BPD outcome. CONCLUSIONS: Although BPD prediction models perform satisfactorily, they were all at high risk of bias. Methodologic improvement and complete reporting are needed before they can be considered for use in clinical practice. Future research should aim to validate and update existing models.

Exhaled Volatile Organic Compounds for Early Prediction of Bronchopulmonary Dysplasia in Infants Born Preterm.

OBJECTIVE(S): To investigate the predictive performances of exhaled breath volatile organic compounds (VOCs) for development of bronchopulmonary dysplasia (BPD) in infants born preterm. METHODS: Exhaled breath was collected from infants born <30 weeks' gestation at days 3 and 7 of life. Ion fragments detected by gas chromatography-mass spectrometry analysis were used to derive and internally validate a VOC prediction model for moderate or severe BPD at 36 weeks of postmenstrual age. We tested the predictive performance of the National Institute of Child Health and Human Development (NICHD) clinical BPD prediction model with and without VOCs. RESULTS: Breath samples were collected from 117 infants (mean gestation 26.8 ± 1.5 weeks). Thirty-three percent of the infants developed moderate or severe BPD. The VOC model showed a c-statistic of 0.89 (95% CI 0.80-0.97) and 0.92 (95% CI 0.84-0.99) for the prediction of BPD at days 3 and 7, respectively. Adding the VOCs to the clinical prediction model in noninvasively supported infants resulted in significant improvement in discriminative power on both days (day 3: c-statistic 0.83 vs 0.92, P value .04; day 7: c-statistic 0.82 vs 0.94, P value .03). CONCLUSIONS: This study showed that VOC profiles in exhaled breath of preterm infants on noninvasive support in the first week of life differ between those developing and not developing BPD. Adding VOCs to a clinical prediction model significantly improved its discriminative performance.

Bronchopulmonary dysplasia is not related to neurofilament light for neuroaxonal damage in preterm infants.

BACKGROUND: Neurofilament light (NfL) has been identified as a biomarker for neuroaxonal damage in preterm infants, but its relation with bronchopulmonary dysplasia (BPD) has not been established. We hypothesized that BPD is associated with increased NfL levels at an early stage, indicative of early neuroaxonal damage. METHODS: We included preterm infants born <30 weeks of gestation for assessment of NfL levels from cord blood and blood obtained at postnatal days 3, 7, 14, and 28. We used linear regression analysis to compare NfL levels between infants with moderate/severe BPD and infants with no/mild BPD, and linear mixed model analysis to compare the effect of time on NfL levels between groups. RESULTS: Sixty-seven infants with a gestational age (GA) of 27 ± 1.3 weeks were included for analysis, of whom 19 (28%) developed moderate/severe BPD. Although NfL levels were higher at every time point in infants with BPD, statistical significance was lost after adjustment for GA, small for gestational age (SGA) and intraventricular hemorrhage (IVH). Groups did not differ in NfL change over time. CONCLUSIONS: The positive association between BPD and NfL in the first weeks of life could be explained by GA, SGA and IVH rather than by development of BPD. IMPACT: Neurofilament light chain (NfL) is a known biomarker for neuroaxonal damage. Biomarkers for brain damage during the first weeks of life in preterm infants developing BPD are lacking. NfL levels obtained during the first weeks of life did not differ between infants with and without BPD in analyses adjusted for GA, SGA, and IVH.

Biallelic variants in the SLC13A1 sulfate transporter gene cause hyposulfatemia with a mild spondylo-epi-metaphyseal dysplasia.

Sulfate is the fourth most abundant anion in human plasma but is not measured in clinical practice and little is known about the consequences of sulfate deficiency. Nevertheless, sulfation plays an essential role in the modulation of numerous compounds, including proteoglycans and steroids. We report the first patient with a homozygous loss-of-function variant in the SLC13A1 gene, encoding a renal and intestinal sulfate transporter, which is essential for maintaining plasma sulfate levels. The homozygous (Arg12Ter) variant in SLC13A1 was found by exome sequencing performed in a patient with unexplained skeletal dysplasia. The main clinical features were enlargement of joints and spondylo-epi-metaphyseal radiological abnormalities in early childhood, which improved with age. In addition, autistic features were noted. We found profound hyposulfatemia due to complete loss of renal sulfate reabsorption. Cholesterol sulfate was reduced. Intravenous N-acetylcysteine administration temporarily restored plasma sulfate levels. We conclude that loss of the SLC13A1 gene leads to profound hypersulfaturia and hyposulfatemia, which is mainly associated with abnormal skeletal development, possibly predisposing to degenerative bone and joint disease. The diagnosis might be easily missed and more frequent.

Long-term outcomes following antenatal exposure to low-dose aspirin: study protocol for the 4-year follow-up of the APRIL randomised controlled trial.

INTRODUCTION: The use of low-dose aspirin by pregnant women to prevent preterm pre-eclampsia is gradually increasing. The administration of aspirin during pregnancy improves perinatal outcome, which could translate into improved child outcome in the long term. However, antenatal exposure to aspirin could have adverse effects on child development that may manifest later in life. The aim of this follow-up study is to assess the long-term effects of antenatal exposure to low-dose aspirin compared with placebo on survival, (neuro)development, behaviour and general health at 4 years corrected age. METHODS AND ANALYSIS: This is a follow-up study of the Dutch double-blind randomised controlled APRIL trial which assessed the effectiveness of treatment with aspirin (80 mg daily) compared with placebo for the prevention of preterm birth in women with a previous spontaneous preterm birth. Treatment was initiated before 16 weeks of gestation and continued until 36 weeks or birth. We aim to follow-up all 379 children born to women who participated in the APRIL trial and survived the neonatal period, at the corrected age of 4 years. The main outcomes are (neuro)development as assessed by the Ages and Stages Questionnaire, and behaviour as assessed by the Strength and Difficulties Questionnaire. Additional outcomes include mortality, growth and general health from birth up to 4 years, and a composite outcome including mortality, abnormal (neuro)development and problem behaviour. Analyses will be performed by intention-to-treat using a superiority design. ETHICS AND DISSEMINATION: Institutional Review Board approval was obtained from the Medical Research Ethics Committee from Amsterdam Medical Center (no. W20 289#20.325). The results will be published in a peer-reviewed journal and presented at conferences. TRIAL REGISTRATION NUMBER: The APRIL trial (NTR5675, NL5553; EudraCT number 2015-003220-31) and the APRIL follow-up study (NL8950) are registered in the Dutch trial register. The study is funded by the Amsterdam Reproduction & Development research institute.

Identification of a Novel CYP11B2 Variant in a Family with Varying Degrees of Aldosterone Synthase Deficiency.

Isolated aldosterone synthase deficiency is a rare autosomal recessive disorder caused by pathogenic variants in CYP11B2, resulting in impaired aldosterone synthesis. We report on a neonate with isolated aldosterone synthase deficiency caused by a novel homozygous CYP11B2 variant Chr8:NM_000498.3:c.400G>A p.(Gly134Arg). The patient presented shortly after birth with severe signs of aldosterone deficiency. Interestingly, segregation analysis revealed that the patient's asymptomatic father was also homozygous for the CYP11B2 variant. Biochemical evaluation of the father indicated subclinical enzyme impairment, characterized by elevated aldosterone precursors. Apparently, this homozygous variant led to different clinical phenotypes in two affected relatives. In this manuscript we elaborate on the performed biochemical and genetic work-up and describe potential pitfalls of CYP11B2 sequencing due to its homology to CYP11B2.

Thyroid Function at Age Fifty After Prenatal Famine Exposure in the Dutch Famine Birth Cohort.

Background: Early-life exposures during gestation may permanently alter thyroid physiology and health in adulthood. We investigated whether exposure to the Dutch Famine (1944-1945) in late, mid, or early gestation influences thyroid function (i.e., incidence of thyroid disease, thyroid autoantibodies, thyroid stimulating hormone (TSH), and free thyroxine (FT4) levels) in adulthood. We specifically assessed whether potential effects of famine differed for men and women. Methods: This study includes 910 men and women born as term singletons in the Wilhelmina Gasthuis in Amsterdam, the Netherlands, shortly before, during, or after the Dutch Famine. We evaluated medical histories for previous diagnosis or current treatment for thyroid dysfunction. At age 50 blood samples were drawn from 728 individuals for tests of thyroid function. We studied the prevalence of overt hypo- and hyperthyroidism and thyroid autoimmunity using medical histories, and measurements of TSH, FT4, anti-TPO and anti-TG, comparing participants exposed to famine at different pregnancy trimesters or born before or conceived after the famine. Additionally, we studied associations of TSH and FT4 levels with in utero famine exposure in a subsample of men and women free of thyroid disease that were exposed in late, mid, or early gestation. Results: There were no differences in thyroid dysfunction diagnosis or current treatment between participants at age 50 years who been exposed to famine during different periods of gestation and those born before or conceived after. There was no association between famine exposure and overt hypo- or hyperthyroidism or thyroid autoantibody positivity. Women who had been exposed to famine in mid gestation had slightly lower TSH levels than women who had not been exposed to famine prenatally (b=-0.06; 95%; CI=[-0.11,-0.02]; p<0.01). No differences in TSH levels were observed in men, and no differences in FT4 levels were observed in men or women. Conclusions: There are no differences in adult thyroid disease at age 50 years according to prenatal famine exposure. However, the lower TSH levels in women exposed to famine in the second trimester suggest that there may be sex-specific effects of famine exposure during a critical period of thyroid development on hypothalamic-pituitary-thyroid axis regulation in adulthood.

Low-Protein Infant Formula and Obesity Risk.

Infant formulas have been designed to mimic human milk for infants who cannot be breastfed. The overall goal is to establish similar functional outcomes to assure optimal growth, development, maturation of the immune system, and programming of the metabolic system. However, after decades of improving infant formula, growth patterns and body composition development are still different in formula-fed infants compared to breastfed infants, which could contribute to an increased risk of obesity among formula-fed infants. It has been hypothesized that the lower protein concentration of breast milk compared to infant formula influences infants' growth and body composition. Thus, several trials in formula-fed infants with different protein intake levels have been performed to test this hypothesis. In this review, we discuss the current evidence on low-protein infant formula and obesity risk, including future perspectives and implications.

Role of glucocorticoid metabolism in childhood obesity-associated hypertension.

Objective: Childhood obesity is associated with alterations in hypothalamus-pituitary-adrenal axis activity. We tested the hypothesis that multiple alterations in the metabolism of glucocorticoids are required for the development of hypertension in children who become overweight. Methods: Spot urine for targeted gas chromatography-mass spectrometry steroid metabolome analysis was collected from (1) overweight/hypertensive children (n = 38), (2) overweight/non-hypertensive children (n = 83), and (3) non-overweight/non-hypertensive children (n = 56). Results: The mean (± s.d.) age of participants was 10.4 ± 3.4 years, and 53% of them were male. Group 1 and group 2 had higher excretion rates of cortisol and corticosterone metabolites than group 3 (869 (interquartile range: 631-1352) vs 839 (609-1123) vs 608 (439-834) µg/mmol creatinine × m2 body surface area, P < 0.01, for the sum of cortisol metabolites), and group 1 had a higher excretion rate of naive cortisol than group 3. Furthermore, groups differed in cortisol metabolism, in particular in the activities of 11ß-hydroxysteroid dehydrogenases, as assessed from the ratio of cortisol:cortisone metabolites (group 2 < group 3), 5α-reductase (group 1 > group 2 or 3), and CYP3A4 activity (group 1 < group 2 or 3). Discussion: The sequence of events leading to obesity-associated hypertension in children may involve an increase in the production of glucocorticoids, downregulation of 11ß-hydroxysteroid dehydrogenase type 1 activity, and upregulation of 5α-reductase activity, along with a decrease in CYP3A4 activity and an increase in bioavailable cortisol.

Heritability of Urinary Amines, Organic Acids, and Steroid Hormones in Children.

Variation in metabolite levels reflects individual differences in genetic and environmental factors. Here, we investigated the role of these factors in urinary metabolomics data in children. We examined the effects of sex and age on 86 metabolites, as measured on three metabolomics platforms that target amines, organic acids, and steroid hormones. Next, we estimated their heritability in a twin cohort of 1300 twins (age range: 5.7-12.9 years). We observed associations between age and 50 metabolites and between sex and 21 metabolites. The monozygotic (MZ) and dizygotic (DZ) correlations for the urinary metabolites indicated a role for non-additive genetic factors for 50 amines, 13 organic acids, and 6 steroids. The average broad-sense heritability for these amines, organic acids, and steroids was 0.49 (range: 0.25-0.64), 0.50 (range: 0.33-0.62), and 0.64 (range: 0.43-0.81), respectively. For 6 amines, 7 organic acids, and 4 steroids the twin correlations indicated a role for shared environmental factors and the average narrow-sense heritability was 0.50 (range: 0.37-0.68), 0.50 (range; 0.23-0.61), and 0.47 (range: 0.32-0.70) for these amines, organic acids, and steroids. We conclude that urinary metabolites in children have substantial heritability, with similar estimates for amines and organic acids, and higher estimates for steroid hormones.

Long-term health outcomes of children born to mothers with hyperemesis gravidarum: a systematic review and meta-analysis.

OBJECTIVE: Hyperemesis gravidarum is characterized by severe nausea and vomiting in pregnancy, frequently resulting in severe maternal nutritional deficiency. Maternal undernutrition is associated with adverse offspring health outcomes. Whether hyperemesis gravidarum permanently affects offspring health remains unclear. This review aimed to evaluate the effects of maternal hyperemesis gravidarum on offspring health. DATA SOURCES: MEDLINE and Embase were searched from inception to September 6, 2021. STUDY ELIGIBILITY CRITERIA: Studies reporting on health at any age beyond the perinatal period of children born to mothers with hyperemesis gravidarum were included. METHODS: Two reviewers independently selected studies and extracted data. The Newcastle-Ottawa Quality Assessment Scale was used to assess risk of bias. We conducted a narrative synthesis and meta-analysis where possible. In meta-analyses with high heterogeneity (I2>75%), we did not provide a pooled odds ratio. RESULTS: Nineteen studies were included in this systematic review (n=1,814,785 offspring). Meta-analysis (n=619, 2 studies: 1 among adolescents and 1 among adults) showed that hyperemesis gravidarum was associated with anxiety disorder (odds ratio, 1.74; 95% confidence interval, 1.04-2.91; I2, 0%) and sleep problems in offspring (odds ratio, 2.94; 95% confidence interval, 1.25-6.93; I2, 0%). Hyperemesis gravidarum was associated with testicular cancer in male offspring aged up to 40 years on meta-analysis (5 studies, n=20,930 offspring), although heterogeneity was observed on the basis of a wide 95% prediction interval (odds ratio, 1.60; 95% confidence interval, 1.07-2.39; I2, 0%; 95% prediction interval, 0.83-3.08). All 6 studies reporting on attention deficit (hyperactivity) disorder and autism spectrum disorder reported an increase among children of mothers with hyperemesis gravidarum in comparison with children of unaffected mothers. Meta-analysis showed high heterogeneity, precluding us from reporting a pooled odds ratio. Most studies reporting on cognitive and motor problems found an increase among hyperemesis gravidarum-exposed children. One study investigated brain structure and found smaller cortical volumes and areas among children from hyperemesis gravidarum-affected pregnancies than among those from unaffected pregnancies. Studies evaluating anthropometry and cardiometabolic disease risk of hyperemesis gravidarum-exposed children had inconsistent findings. CONCLUSION: Our systematic review showed that maternal hyperemesis gravidarum is associated with small increases in adverse health outcomes among children, including neurodevelopmental disorders, mental health disorders, and possibly testicular cancer, although evidence is based on few studies of low quality.

Long-term health and neurodevelopment in children after antenatal exposure to low-dose aspirin for the prevention of preeclampsia and fetal growth restriction: A systematic review of randomized controlled trials.

OBJECTIVE: To evaluate the long-term effects of antenatal aspirin exposure on child health and neurodevelopmental outcome beyond the perinatal period. STUDY DESIGN: PubMed, Embase.com, the Cochrane Library and Web of Science were systematically searched from inception through 5 November 2020. We performed a cited-reference search and ClinicalTrials.gov was searched on 20 October 2020 to identify trial results that were not reported elsewhere. We included randomized controlled trials reporting on health-related outcomes in children (aged > 28 days) exposed to aspirin versus placebo or no treatment during pregnancy. Studies with any dose or duration of aspirin use were included. We excluded studies evaluating other antiplatelet agents or non-steroidal inflammatory drugs. Two authors independently performed study selection, data extraction and quality assessment. Quality assessment was performed using the Cochrane RoB2 tool for the original randomized controlled trials and the QUIPS for the follow-up studies. Results are presented as relative risks (RR) with 95% confidence intervals (95%CI). RESULTS: The search yielded 6,907 unique records. Two studies were included, containing 4,168 children at age 12 months and 5,153 children at 18 months. Children were exposed to aspirin 50-60 mg versus placebo or no treatment. At 12 months, post-neonatal mortality was lower after allocation to aspirin (0.2% versus 0.5%; RR 0.28, 95%CI 0.08-0.99) in a single study. At 18 months, fewer children were found to have (gross and fine) motor problems (RR 0.49, 95%CI 0.26-0.91) after antenatal aspirin exposure in one study. No differences were found in mortality rate; the proportion of children with a short stature or low weight; or respiratory, hearing or visual problems at 18 months. Both included studies had a high risk of bias. CONCLUSION: The two included studies showed evidence of potential benefit of antenatal low-dose aspirin on mortality and neurodevelopment up to the age of 18 months. Our findings support the current application of low-dose aspirin in pregnant women at risk for preeclampsia and fetal growth restriction. However, further follow-up research of children who were exposed to low-dose aspirin during pregnancy is of utmost importance to exclude potential long-term harm.

Long-term follow-up of children exposed in-utero to progesterone treatment for prevention of preterm birth: study protocol of the AMPHIA follow-up.

INTRODUCTION: Preterm birth is one of the main problems in obstetrics, and the most important cause of neonatal mortality, morbidity and neurodevelopmental impairment. Multiple gestation is an important risk factor for preterm birth, with up to 50% delivering before 37 weeks. Progesterone has a role in maintaining pregnancy and is frequently prescribed to prevent (recurrent) preterm birth and improve pregnancy outcomes in high-risk patients. However, little is known about its long-term effects in multiple gestations. The objective of this follow-up study is to assess long-term benefits and harms of prenatal exposure to progesterone treatment in multiple gestations on child development. METHODS AND ANALYSIS: This is a follow-up study of a multicentre, double-blind, placebo-controlled randomised trial (AMPHIA trial, ISRCTN40512715). Between 2006 and 2009 women with a multiple gestation were randomised at 16-20 weeks of gestation to weekly injections 250 mg 17α-hydroxyprogesterone caproate or placebo, until 36 weeks of gestation or delivery. The current long-term follow-up will assess all children (n=1355) born to mothers who participated in the AMPHIA trial, at 11-14 years of age, with internationally validated questionnaires, completed by themselves, their parents and their teachers. MAIN OUTCOMES ARE CHILD COGNITION AND BEHAVIOUR: Additional outcomes are death (perinatal and up to age 14), gender identity, educational performance and health-related problems. We will use intention-to-treat analyses comparing experimental and placebo group. To adjust for the correlation between twins, general linear mixed-effects models will be used. ETHICS AND DISSEMINATION: Amsterdam UMC MEC provided a waiver for the Medical Research Involving Human Subjects Act (W20_234#20.268). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders, patients and participants. This protocol is published before analysis of the results. TRIAL REGISTRATION NUMBER: NL8933.