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ObjectiveTo report the parent-reported behavioural outcomes of infants included in the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants study at 2 years’ corrected age (CA).DesignRandomised placebo-controlled trial.SettingDutch and Belgian neonatal intensive care units.PatientsInfants born InterventionInfants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190).Main outcome measuresParent-reported behavioural outcomes at 2 years’ CA assessed with the Child Behavior Checklist (CBCL 1½−5).ResultsParents completed the CBCL of 183 (70% (183/262)) infants (hydrocortisone group, n=96; placebo group, n=87). Multiple imputation was used to account for missing data. Infants with critically elevated T-scores (>55) were found in 22.9%, 19.1% and 29.4% of infants for total, internalising and externalising problems, respectively; these scores were not significantly different between groups (mean difference −1.52 (95% CI −4.00 to 0.96), −2.40 (95% CI −4.99 to 0.20) and −0.81 (95% CI −3.40 to 1.77), respectively). In the subscales, we found a significantly lower T-score for anxiety problems in the hydrocortisone group (mean difference −1.26, 95% CI −2.41 to –0.12).ConclusionThis study found high rates of behaviour problems at 2 years’ CA following very preterm birth, but these problems were not associated with hydrocortisone treatment initiated between 7 and 14 days after birth in ventilated preterm infants.Trial registration numberNTR2768; EudraCT 2010-023777-19.

Medically assisted reproduction (MAR) plays an increasingly important role in the realization of fertility intentions in advanced societies, yet the evidence regarding MAR-conceived children’s longer-term well-being remains inconclusive. Using register data on all Finnish children born in 1995–2000, we compared a range of social and mental health outcomes among MAR- and naturally conceived adolescents in population-averaged estimates, and within families who have conceived both through MAR and naturally. In baseline models, MAR-conceived adolescents had better school performance and the likelihood of school dropout, not being in education or employment, and early home-leaving were lower than among naturally conceived adolescents. No major differences were found in mental health and high-risk health behaviours. Adjustment for family sociodemographic characteristics attenuated MAR adolescents’ advantage in social outcomes, while increasing the risk of mental disorders. The higher probability of mental disorders persisted when comparing MAR adolescents to their naturally conceived siblings. On average, MAR adolescents had similar or better outcomes than naturally conceived adolescents, largely due to their more advantaged family backgrounds, which underscores the importance of integrating a sociodemographic perspective in studies of MAR and its consequences.

BackgroundRetinopathy of prematurity (ROP) and abnormal brain development share similar risk factors and mechanisms. There has been contrasting evidence on the association of ROP with adverse neurodevelopmental outcomes.ObjectiveWe analysed the association between ROP at levels of severity and treatment with all neurodevelopmental outcomes until adolescence.Data sourceWe followed PRISMA guidelines and searched Medline and Embase between 1 August 1990 and 31 March 2022.Study selection and participantsRandomised or quasi-randomised clinical trials and observational studies on preterm infants (Data extraction and synthesisWe included studies on ROP and any neurocognitive or neuropsychiatric outcomes.OutcomesThe primary outcomes were as follows: cognitive composite scores evaluated between the ages of 18 and 48 months by the Bayley Scales of Infant and Toddler Development (BSID) or equivalent; neurodevelopmental impairment (NDI; moderate to severe NDI or severe NDI), cerebral palsy, cognitive impairment; and neuropsychiatric or behavioural problems. The secondary outcomes were as follows: motor and language composite scores evaluated between the ages of 18 and 48 months by BSID or equivalent; motor/language impairment; and moderate/severe NDI as defined by the authors.ResultsIn preterm infants, “any ROP” was associated with an increased risk of cognitive impairment or intellectual disability [n = 83,506; odds ratio (OR): 2.56; 95% CI: 1.40–4.69; p = 0.002], cerebral palsy (n = 3,706; OR: 2.26; 95% CI: 1.72–2.96; p n = 81,439; OR: 2.45; 95% CI: 1.03–5.83; p = 0.04), or NDI as defined by authors (n = 1,930; OR: 3.83; 95% CI: 1.61–9.12; p = 0.002). Type 1 or severe ROP increased the risk of cerebral palsy (OR: 2.19; 95% CI: 1.23–3.88; p = 0.07), cognitive impairment or intellectual disability (n = 5,167; OR: 3.56; 95% CI: 2.6–4.86; p n = 5,500; OR: 2.76; 95% CI: 2.11–3.60; p p = 0.04], but not for cerebral palsy (aOR: 1.29; 95% CI: 0.65–2.56; p = 0.45). All outcomes were adjudged with a “very low” certainty of evidence.Conclusion and relevanceInfants with “any ROP” had higher risks of cognitive impairment or intellectual disability, cerebral palsy, and behavioural problems. Anti-VEGF treatment increased the risk of moderate cognitive impairment. These results support the association of ROP and anti-VEGF treatment with adverse neurodevelopmental outcomes.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42022326009.

BackgroundRetinopathy of prematurity (ROP) and abnormal brain development share similar risk factors and mechanisms. There has been contrasting evidence on the association of ROP with adverse neurodevelopmental outcomes.ObjectiveWe analysed the association between ROP at levels of severity and treatment with all neurodevelopmental outcomes until adolescence.Data sourceWe followed PRISMA guidelines and searched Medline and Embase between 1 August 1990 and 31 March 2022.Study selection and participantsRandomised or quasi-randomised clinical trials and observational studies on preterm infants (

Very preterm (VPT) children and adolescents show executive, behavioural and socio-emotional difficulties that persists into adulthood. This study aims to assess the effectiveness of a mindfulness-based intervention (MBI) in improving these competencies in VPT young adolescents using a randomised controlled trial design. 56 young adolescents aged 10–14 years, born before 32 gestational weeks, were randomly assigned to an “intervention” or a “waiting” group and completed an 8-week MBI in a cross-over design. Executive, behavioural and socio-emotional competencies were assessed at three different time points via parent and self-reported questionnaires, neuropsychological testing and computerised tasks. The data were analysed using an intention-to-treat approach with linear regression modelling. Our findings show a beneficial effect of MBI on executive, behavioural and socio-emotional competencies in VPT young adolescents measured by parent questionnaires. Increased executive competencies were also observed on computerised task with enhanced speed of processing after MBI. Two subgroups of participants were created based on measures of prematurity, which revealed increased long-term benefits in the moderate-risk that were not observed in the high-risk subgroups of VPT young adolescents. MBI seems a valuable tool for reducing detrimental consequences of prematurity in young adolescents, especially regarding executive, behavioural and socio-emotional difficulties.Clinical Trial Registration ClinicalTrials, NCT04638101. Registered 20 November 2020—Retrospectively registered, https://clinicaltrials.gov/show/NCT04638101.

Background Deciding whether to resuscitate extremely preterm infants (EPIs) is clinically and ethically problematic. The aim of the study was to understand neonatologists’ clinical–ethical decision-making for resuscitation of EPIs. Methods We conducted a qualitative study in Belgium, following a constructivist account of the Grounded Theory. We conducted 20 in-depth, face-to-face, semi-structured interviews with neonatologists. Data analysis followed the qualitative analysis guide of Leuven. Results The main principles guiding participants’ decision-making were EPIs’ best interest and respect for parents’ autonomy. Participants agreed that justice as resource allocation should not be considered in resuscitation decision-making. The main ethical challenge for participants was dealing with the conflict between EPIs’ best interest and respect for parents’ autonomy. This conflict was most prominent when parents and clinicians disagreed about births within the gray zone (24–25 weeks). Participants’ coping strategies included setting limits on extent of EPI care provided and rigidly following established guidelines. However, these strategies were not always feasible or successful. Although rare, these situations often led to long-lasting moral distress. Conclusions Participants’ clinical–ethical reasoning for resuscitation of EPIs can be mainly characterized as an attempt to balance EPIs’ best interest and respect for parents’ autonomy. This approach could explain why neonatologists considered conflicts between these principles as their main ethical challenge and why lack of resolution increases the risk of moral distress. Therefore, more research is needed to better understand moral distress in EPI resuscitation decisions. Clinical Trial Registration: The study received ethical approval from the ethics committee of UZ/KU Leuven (S62867). Confidentiality of personal information and anonymity was guaranteed in accordance with the General Data Protection Regulation of 25 May 2018.

Background We evaluated pubertal growth and pubertal timing of participants born preterm compared to those born at term. Methods In the ESTER Preterm Birth Study, we collected growth data and measured final height of men/women born very or moderately preterm (n = 52/55), late preterm (34– Results Age at PHV (years) and PHV (cm/year) were similar in all gestational age groups. Compared to term controls, insignificant differences in age at PHV were 0.1 (95% CI: −0.2 to 0.4) years/0.2 (−0.1 to 0.4) for very or moderately/late preterm born men and −0.0 (−0.3 to 0.3)/−0.0 (−0.3 to 0.2) for women, respectively. Being born small for gestational age was not associated with pubertal growth. Age at menarche or voice break was similar in all the gestational age groups. Conclusions Timing of pubertal growth and age at menarche or voice break were similar in participants born preterm and at term. Impact Pubertal growth and pubertal timing were similar in preterm and term participants in a relatively large cohort with a wide range of gestational ages. Previous literature indicates that small for gestational age is a risk for early puberty in term born children. This was not shown in preterm children. While our study had limited power for children born very preterm, all children born preterm were not at increased risk for early puberty.

STUDY QUESTION Is the health of singletons born after frozen embryo transfer (FET) comparable to that of singletons born after fresh embryo transfer (ET) until early adulthood? SUMMARY ANSWER The health of singletons born after FET does not differ from that of singletons born after fresh ET. WHAT IS KNOWN ALREADY The differences in perinatal outcomes of children born after FET and fresh ET are well known. FET is associated with an increased risk of large-for-gestational-age but diminished risks of preterm birth (PTB), small-for-gestational-age and decreased perinatal mortality compared to fresh ET. However, knowledge on the long-term health after FET is scarce. STUDY DESIGN, SIZE, DURATION This retrospective register-based cohort study compares singletons born after FET (n = 1825) between the years 1995 and 2006 to those born after fresh ET (n = 2933) and natural conception (NC, n = 31 136) with a mean follow-up time of 18–20 years. PARTICIPANTS/MATERIALS, SETTING, METHODS Singletons born after FET were compared to those born after fresh ET and NC regarding the frequencies of diagnoses in the main ICD-10 chapters (International Statistical Classification of Diseases and Related Health Problems, 10th revision), the number of outpatient visits and hospital admissions, and mortality. Adjustments were made for PTB, maternal age, parity, socioeconomic status based on mother’s occupation and offspring sex. The study combines data from the Finnish Medical Birth Register, the Finnish Care Register for Health Care (CRHC) and the Cause-of-Death Register at Statistics Finland. The Student’s T-test was used for continuous variables, and the Chi-square test was used for categorical variables. Cox regression was used to estimate crude and adjusted hazard ratios (HRs and aHRs, respectively). A general linear model was used to compare the means of outpatient visits, hospital admissions and lengths of hospital stays per person. MAIN RESULTS AND THE ROLE OF CHANCE No significant differences between the FET and fresh ET groups were found in the frequency of diagnoses in any of the ICD-10 chapters or in the parameters describing the need for hospital care. However, compared to the NC group, higher proportions in the FET group had outpatient visits in the hospital (93.5% vs 92.2%, aHR 1.23, 95% CI 1.17, 1.30) or hospital admissions (48% vs 46.5%, aHR 1.28, 95% CI 1.19, 1.37). Compared to the NC group, the FET group had elevated adjusted risks of diagnoses of infectious and parasitic diseases (aHR 1.24; 95% CI 1.11, 1.38), neoplasms (aHR 1.68; 95% CI 1.48, 1.91), diseases of the eye and adnexa, the ear or mastoid process (aHR 1.11; 95% CI 1.01, 1.21), the respiratory system (aHR 1.15; 95% CI 1.06, 1.23), the digestive system (aHR 1.17; 95% CI 1.05, 1.32), the skin or subcutaneous tissue (aHR 1.28; 95% CI 1.14, 1.43) and the genitourinary system (aHR 1.27; 95% CI 1.11, 1.45), as well as congenital malformations or chromosomal abnormalities (aHR 1.31; 95% CI 1.14, 1.50) and symptoms, signs or abnormal clinical or laboratory findings (aHR 1.25, 95% CI 1.16, 1.34). LIMITATIONS, REASONS FOR CAUTION Only hospital-based inpatient and outpatient care is covered by the CRHC register, excluding milder cases diagnosed elsewhere. We were not able to study the effect of ART treatments and subfertility separately in our setting. In addition, although our cohort is reasonably sized, even larger cohorts would be needed to reliably study rare outcomes, such as cancer. WIDER IMPLICATIONS OF THE FINDINGS For many ICD-10 chapters, we present the first published data on the long-term outcome of singletons born after FET. The results on FET versus fresh ET are reassuring, whereas the results on FET versus NC warrant further investigation. STUDY FUNDING/COMPETING INTEREST(S) Finnish government research funding was obtained for this study. Funding was also obtained from the Finnish Medical Society Duodecim, the Päivikki and Sakari Sohlberg Foundation, Orion Research Foundation, Finnish Society of Obstetrics and Gynaecology (research grants to A.M.T.) and Finnish government research funding. The funding sources were not involved in the planning or execution of the study. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER N/A.

Encephalopathy of prematurity (EoP) is a common cause of long‐term neurodevelopmental morbidity in extreme preterm infants. Diffuse white matter injury (dWMI) is currently the most commonly observed form of EoP. Impaired maturation of oligodendrocytes (OLs) is the main underlying pathophysiological mechanism. No therapies are currently available to combat dWMI. Intranasal application of mesenchymal stem cells (MSCs) is a promising therapeutic option to boost neuroregeneration after injury. Here, we developed a double‐hit dWMI mouse model and investigated the therapeutic potential of intranasal MSC therapy. Postnatal systemic inflammation and hypoxia‐ischemia led to transient deficits in cortical myelination and OL maturation, functional deficits and neuroinflammation. Intranasal MSCs migrated dispersedly into the injured brain and potently improved myelination and functional outcome, dampened cerebral inflammationand rescued OL maturation after dWMI. Cocultures of MSCs with primary microglia or OLs show that MSCs secrete factors that directly promote OL maturation and dampen neuroinflammation. We show that MSCs adapt their secretome after ex vivo exposure to dWMI milieu and identified several factors including IGF1, EGF, LIF, and IL11 that potently boost OL maturation. Additionally, we showed that MSC‐treated dWMI brains express different levels of these beneficial secreted factors. In conclusion, the combination of postnatal systemic inflammation and hypoxia‐ischemia leads to a pattern of developmental brain abnormalities that mimics the clinical situation. Intranasal delivery of MSCs, that secrete several beneficial factors in situ, is a promising strategy to restore myelination after dWMI and subsequently improve the neurodevelopmental outcome of extreme preterm infants in the future., Main Points Intranasal MSC therapy potently restores myelination after encephalopathy of prematurity.MSCs modify their secretome in situ to support OL maturation by upregulating valuable, beneficial growth factors and/or anti‐inflammatory cytokines.

Background: Adults born preterm (

Preterm birth carries a risk for adverse neurodevelopment. Cognitive dysfunctions, such as language disorders may manifest as atypical sound discrimination already in early infancy. As infant-directed singing has been shown to enhance language acquisition in infants, we examined whether parental singing during skin-to-skin care (kangaroo care) improves speech sound discrimination in preterm infants. Forty-five preterm infants born between 26 and 33 gestational weeks (GW) and their parents participated in this cluster-randomized controlled trial ( ID IRB00003181SK). In both groups, parents conducted kangaroo care during 33-40 GW. In the singing intervention group (n = 24), a certified music therapist guided parents to sing or hum during daily kangaroo care. In the control group (n = 21), parents conducted standard kangaroo care and were not instructed to use their voices. Parents in both groups reported the duration of daily intervention. Auditory event-related potentials were recorded with electroencephalogram at term age using a multi-feature paradigm consisting of phonetic and emotional speech sound changes and a one-deviant oddball paradigm with pure tones. In the multi-feature paradigm, prominent mismatch responses (MMR) were elicited to the emotional sounds and many of the phonetic deviants in the singing intervention group and in the control group to some of the emotional and phonetic deviants. A group difference was found as the MMRs were larger in the singing intervention group, mainly due to larger MMRs being elicited to the emotional sounds, especially in females. The overall duration of the singing intervention (range 15-63 days) was positively associated with the MMR amplitudes for both phonetic and emotional stimuli in both sexes, unlike the daily singing time (range 8-120 min/day). In the oddball paradigm, MMRs for the non-speech sounds were elicited in both groups and no group differences nor connections between the singing time and the response amplitudes were found. These results imply that repeated parental singing during kangaroo care improved auditory discrimination of phonetic and emotional speech sounds in preterm infants at term age. Regular singing routines can be recommended for parents to promote the development of the auditory system and auditory processing of speech sounds in preterm infants.

BACKGROUND: The mechanisms responsible for the associations between very preterm birth and a higher risk of poor cardiovascular and metabolic health in adult life are unknown. METHODS: Here, we compare the clinical and molecular phenotypes of healthy, normal-weight young adults (18-27 years), born very preterm (

Background:\ud Individuals born preterm are at risk of later developmental problems and long‐term morbidities. There is conflicting evidence regarding musculoskeletal pain in young adulthood. We investigated the prevalence of self‐reported musculoskeletal pain in young adults born across the range of preterm birth compared with a term‐born reference group.\ud \ud Methods:\ud From two Finnish birth cohorts, 184 individuals born early preterm (

AIM Prematurity has been shown to affect social competence in children and adults. Our aim was to evaluate profiles of self-reported social behaviours and loneliness in preterm- and term-born adolescents. METHODS Preterm (≤1500 g and, or

Background Very preterm (VPT) children and adolescents show executive, behavioural and socio-emotional difficulties that persist into adulthood. Despite the promising role of mindfulness-based intervention (MBI) in improving theses competences in children and adolescents, the effectiveness of an MBI has not been assessed in a VPT population so far. Aims To describe the protocol and to evaluate the feasibility and acceptability of a clinical trial on an 8-week MBI program to enhance executive and socio-emotional competences in a cohort of VPT young adolescents. Study design A randomised controlled trial (RCT) and a pre-post intervention designs. Participants 164 VPT young adolescents from 10 to 14 years old, born before 32 gestational weeks, without major intellectual, sensory or physical impairments, and attending mainstream school, were invited to participate in an 8-week MBI program. Outcome measures Completion rate of the study was recorded. Acceptability, satisfaction and attendance measures of the MBI were collected using self-reported questionnaires and registration of attendance. Results Of the 63 participants who were enrolled in the study (38.2% of families invited to participate), 52 (82.5%) completed all assessments. Acceptability was high as shown by the high attendance rate in the sessions and the feedback evaluation questionnaire. Conclusions Our findings suggest that an MBI is feasible to implement and show a high acceptability among participants. The use of an RCT design in our study constitutes the gold standard for testing the efficacy of such intervention in VPT young adolescents. If effective, the MBI program could potentially be a valuable tool for improving executive and socio-emotional competences in the vulnerable VPT population. Trial registration ClinicalTrials, NCT04638101 . Registered 19 November 2020 — retrospectively registered, https://clinicaltrials.gov/show/NCT04638101 .

STUDY QUESTION Do parental characteristics and treatment with ART affect perinatal outcomes in singleton pregnancies? SUMMARY ANSWER Both parental and ART treatment characteristics affect perinatal outcomes in singleton pregnancies. WHAT IS KNOWN ALREADY Previous studies have shown that singleton pregnancies resulting from ART are at risk of preterm birth. ART children are lighter at birth after correction for duration of gestation and at increased risk of congenital abnormalities compared to naturally conceived children. This association is confounded by parental characteristics that are also known to affect perinatal outcomes. It is unclear to which extent parental and ART treatment characteristics independently affect perinatal outcomes. STUDY DESIGN, SIZE, DURATION All IVF clinics in the Netherlands (n = 13) were requested to provide data on all ART treatment cycles (IVF, ICSI and frozen-thawed embryo transfers (FET)), performed between 1 January 2000, and 1 January 2011, which resulted in a pregnancy. Using probabilistic data-linkage, these data (n = 36 683) were linked to the Dutch Perinatal Registry (Perined), which includes all children born in the Netherlands in the same time period (n = 2 548 977). PARTICIPANTS/MATERIALS, SETTING, METHODS Analyses were limited to singleton pregnancies that resulted from IVF, ICSI or FET cycles. Multivariable models for linear and logistic regression were fitted including parental characteristics as well as ART treatment characteristics. Analyses were performed separately for fresh cycles and for fresh and FET cycles combined. We assessed the impact on the following perinatal outcomes: birth weight, preterm birth below 37 or 32 weeks of gestation, congenital malformations and perinatal mortality. MAIN RESULTS AND THE ROLE OF CHANCE The perinatal outcomes of 31 184 out of the 36 683 ART treatment cycles leading to a pregnancy were retrieved through linkage with the Perined (85% linkage). Of those, 23 671 concerned singleton pregnancies resulting from IVF, ICSI or FET. Birth weight was independently associated with both parental and ART treatment characteristics. Characteristics associated with lower birth weight included maternal hypertensive disease, non-Dutch maternal ethnicity, nulliparity, increasing duration of subfertility, hCG for luteal phase support (compared to progesterone), shorter embryo culture duration, increasing number of oocytes retrieved and fresh embryo transfer. The parental characteristic with the greatest effect size on birth weight was maternal diabetes (adjusted difference 283 g, 95% CI 228–338). FET was the ART treatment characteristic with the greatest effect size on birth weight (adjusted difference 100 g, 95% CI 84–117) compared to fresh embryo transfer. Preterm birth was more common among mothers of South-Asian ethnicity. Preterm birth was less common among multiparous women and women with ‘male factor’ as treatment indication (compared to ‘tubal factor’). LIMITATIONS, REASONS FOR CAUTION Due to the retrospective nature of our study, we cannot prove causality. Further limitations of our study were the inability to adjust for mothers giving birth more than once in our dataset, missing values for several variables and limited information on parental lifestyle and general health. WIDER IMPLICATIONS OF THE FINDINGS Multiple parental and ART treatment characteristics affect perinatal outcomes, with birth weight being influenced by the widest range of factors. This highlights the importance of assessing both parental and ART treatment characteristics in studies that focus on the health of ART-offspring, with the purpose of modifying these factors where possible. Our results further support the hypothesis that the embryo is sensitive to its early environment. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Foreest Medical School, Alkmaar, the Netherlands (grants: FIO 1307 and FIO 1505). B.W.M. reports grants from NHMRC and consultancy for ObsEva, Merck KGaA, iGenomics and Guerbet. F.B. reports research support grants from Merck Serono and personal fees from Merck Serono. A.C. reports travel support from Ferring BV. and Theramex BV. and personal fees from UpToDate (Hyperthecosis), all outside the remit of the current work. The remaining authors report no conflict of interests. TRIAL REGISTRATION NUMBER N/A.

Many physical and psychological characteristics are influenced by prenatal development. Some studies have located links between low birth parameters and behavioural problems, with the latter in turn associated with educational progress, career success, overall health, and subsequent life events. However, few studies have investigated whether this association also applies to children in the normal birth growth range. This study thus investigates the relationship between normal-range birth length, weight, and behavioural problems at the age of seven. We use data from the Czech part of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) cohort, which provides comprehensive insight into a post-communist country undergoing a period of economic transition. Childhood behavioural problems were measured in 1,796 children using the Strengths and Difficulties Questionnaire. Associations were modelled using weighted logistic regression. Birth weight was found to be linked to the total difficulties score, hyperactivity, and peer relationship problems subscales in a fully adjusted model while birth length was not significantly associated with any subscale in the fully adjusted model. We thus conclude that normal-range birth weight is associated with behavioural problems. It can therefore be assumed that the odds of behavioural problems and their consequences can be mitigated by preventive programs targeting pregnant women and children with lower but still normal weight.

Research question Is the growth of term singletons born after frozen embryo transfer (FET) comparable to those born after fresh embryo transfer and natural conception up to 5 years of age? Design Observational cohort study in an academic medical centre and municipal child health clinics with repeated measurements carried out by medical professionals. Term singletons born after FET (n = 110) and fresh embryo transfer (n = 181) and their matched natural conception controls (n = 543) born in Oulu, Northern Finland, were included. Mean weights, lengths, heights and head circumferences at the ages of 4, 8 and 18 months and 3 and 5 years were compared. At 3 and 5 years, body mass indices were compared. Results Childhood growth did not differ between term singletons born after FET, fresh embryo transfer and natural conception, correcting for exact age at measurement and adjusting for maternal body mass index and paternal height. Conclusions Similar growth between children born after FET, fresh embryo transfer and natural conception offers reassurance of the safety and feasibility of the steadily increasing use of embryo cryopreservation in assisted reproduction.

Prematurity disrupts brain development during a critical period of brain growth and organization and is known to be associated with an increased risk of neurodevelopmental impairments. Investigating whole-brain structural connectivity alterations accompanying preterm birth may provide a better comprehension of the neurobiological mechanisms related to the later neurocognitive deficits observed in this population. Using a connectome approach, we aimed to study the impact of prematurity on neonatal whole-brain structural network organization at term-equivalent age. In this cohort study, twenty-four very preterm infants at term-equivalent age (VPT-TEA) and fourteen full-term (FT) newborns underwent a brain MRI exam at term age, comprising T2-weighted imaging and diffusion MRI, used to reconstruct brain connectomes by applying probabilistic constrained spherical deconvolution whole-brain tractography. The topological properties of brain networks were quantified through a graph-theoretical approach. Furthermore, edge-wise connectivity strength was compared between groups. Overall, VPT-TEA infants' brain networks evidenced increased segregation and decreased integration capacity, revealed by an increased clustering coefficient, increased modularity, increased characteristic path length, decreased global efficiency and diminished rich-club coefficient. Furthermore, in comparison to FT, VPT-TEA infants had decreased connectivity strength in various cortico-cortical, cortico-subcortical and intra-subcortical networks, the majority of them being intra-hemispheric fronto-paralimbic and fronto-limbic. Inter-hemispheric connectivity was also decreased in VPT-TEA infants, namely through connections linking to the left precuneus or left dorsal cingulate gyrus - two regions that were found to be hubs in FT but not in VPT-TEA infants. Moreover, posterior regions from Default-Mode-Network (DMN), namely precuneus and posterior cingulate gyrus, had decreased structural connectivity in VPT-TEA group. Our finding that VPT-TEA infants' brain networks displayed increased modularity, weakened rich-club connectivity and diminished global efficiency compared to FT infants suggests a delayed transition from a local architecture, focused on short-range connections, to a more distributed architecture with efficient long-range connections in those infants. The disruption of connectivity in fronto-paralimbic/limbic and posterior DMN regions might underlie the behavioral and social cognition difficulties previously reported in the preterm population.

Research question What ethical implications, issues and concerns play a role in conducting follow-up studies of children born after assisted reproductive technologies (ART)? Design Literature study and relevant experiences of academic medical centres in Brussels, Belgium, and Maastricht, the Netherlands were used to identify and analyse the most pertinent ethical implications, issues and concerns. Results According to recommendations from the European Society of Human Reproduction and Embryology, follow-up (ideally long term) of children conceived through medically assisted reproduction (MAR) should be an integral part of introducing new ART. With potentially risky new ART on the horizon, these recommendations need to be taken more seriously. Apart from practical barriers, such as funding, challenges for follow-up include securing active involvement of families of children conceived through MAR, starting with parents of young children, and ideally involving consenting adolescents and adults during a large part of their lives, possibly even into the next generation. Conclusions From an ethical viewpoint, the most pertinent issues include the proportionality of the inevitable burdens and risks for families of children conceived through MAR, and the implications of the principle of respect for autonomy. The proportionality requirement is most critical when it concerns incompetent children, who should not be included in research with more than minimal burdens and risks if there is no reasonable expectation of benefit for themselves. With respect for autonomy, we argue that, when seeking voluntary consent for participating in follow-up studies that meet the condition of proportionality, professionals may encourage members of families of children conceived through MAR to partake in follow-up research.

Objective: The impact of pediatric intestinal failure (IF) on neurodevelopment beyond infancy has not been systematically studied. Our aim was to evaluate cognitive and motor impairment and to identify risk factors for adverse outcomes among children with IF. Methods: We conducted a cross-sectional single-center study at the Helsinki University Children's Hospital. Patients with IF with >60 days of parental nutrition (PN) dependency aged between 3 and 16 years (n = 40) were invited to participate. The cognitive and motor skills were evaluated using validated tests: Wechsler Preschool and Primary Scale of Intelligence, 3rd edition, Wechsler Intelligence Scale for Children, 4th edition, and Movement Assessment Battery for Children, 2nd edition. Results: All the patients attending the study tests (n = 30, males = 24) were included. Their median age, gestational age, and birth weight was 7.5 (range 3-16) years, 35 (interquartile range [IQR] 28-38) weeks and 2238 (IQR 1040-3288) grams, respectively. Median duration of PN was 13 (IQR 5-37) months and 9 patients were currently on PN. Median intelligence quotient was 78 (IQR 65-91) and 10 (35%) patients had an intelligence quotient under 70 (-2 standard deviation). Significant motor impairment was detected in 10 patients (36%) and milder difficulties in 8 (28%). Adverse cognitive outcome was associated with neonatal short bowel syndrome, number of interventions under general anesthesia, and length of inpatient status, whereas adverse motor outcome was associated with prematurity. Conclusion: Clinically significant cognitive and motor impairments are alarmingly common among neonatal patients with IF. We recommend early neurodevelopmental follow-up for all children with IF.

Purpose: To gain insight into the patient characteristics of surgically treated hydrocephalus in the Netherlands, we report the first data from the Dutch Quality Registry NeuroSurgery (QNRS) database for infants with hydrocephalus requiring surgical intervention. Methods: We used the prospectively gathered database concerning infants ≤ 2 years of age surgically treated for hydrocephalus. We report data from start of registry, concerning etiology, age, and treatment of patients registered. We compared data with the Hydrocephalus Clinical Research Network (HCRN), a multicenter network of pediatric neurosurgical institutions in North America. Results: A total of 359 operated infants was registered in the period from 2010 to 2017. A drop in patients registered was seen in 2015, possibly due to revisions of the database. Most infants were operated on between 1 and 6 months of age. Cause of hydrocephalus was predominantly intracranial hemorrhage, followed by congenital causes. The proportion of infants with aqueduct stenosis and myelomeningocele as cause of hydrocephalus stayed relatively stable during this period of registration. Initial shunting was performed in 40% and reservoir/ETV as initial treatment was done in 60%. In both groups, 50% needed revision surgery. Conclusions: The first data concerning surgically treated pediatric hydrocephalus from a prospectively collected Dutch register are presented, showing similar results when comparing to the HCRN database.

Critical for organismal survival, pain evokes strong physiological and behavioral responses in various sentient species. Clinical and preclinical (animal) studies markedly increase our understanding of biological consequences of developmental (early-life) adversity, as well as acute and chronic pain. However, the long-term effects of early-life pain exposure on human and animal emotional responses remain poorly understood. Here, we discuss experimental models of nociception in rodents and zebrafish, and summarize mounting evidence of the role of early-life pain in shaping emotional traits later in life. We also call for further development of animal models to probe the impact of early-life pain exposure on behavioral traits, brain disorders and novel therapeutic treatments.

Background: Assisted reproductive technology (ART) has been associated with low birth weight of fresh embryo transfer (FRESH) derived and increased birth weight of frozen embryo transfer (FET)-derived newborns. Owing to that, we focused on imprinted insulin-like growth factor 2 (IGF2)/H19 locus known to be important for normal growth. This locus is regulated by H19 imprinting control region (ICR) with seven binding sites for the methylation-sensitive zinc finger regulatory protein (CTCF). A polymorphism rs10732516 G/A in the sixth binding site for CTCF, associates with a genotype-specific trend to the DNA methylation. Due to this association, 62 couples with singleton pregnancies derived from FRESH (44 IVF/18 ICSI), 24 couples from FET (15 IVF/9 ICSI), and 157 couples with spontaneously conceived pregnancies as controls were recruited in Finland and Estonia for genotype-specific examination. DNA methylation levels at the H19 ICR, H19 DMR, and long interspersed nuclear elements in placental tissue were explored by MassARRAY EpiTYPER (n = 122). Allele-specific changes in the methylation level of H19 ICR in placental tissue (n = 26) and white blood cells (WBC, n = 8) were examined by bisulfite sequencing. Newborns' (n = 243) anthropometrics was analyzed by using international growth standards.Results: A consistent trend of genotype-specific decreased methylation level was observed in paternal allele of rs10732516 paternal A/maternal G genotype, but not in paternal G/maternal A genotype, at H19 ICR in ART placentas. This hypomethylation was not detected in WBCs. Also genotype-specific differences in FRESH-derived newborns' birth weight and head circumference were observed (P = 0.04, P = 0.004, respectively): FRESH-derived newborns with G/G genotype were heavier (P = 0.04) and had larger head circumference (P = 0.002) compared to newborns with A/A genotype. Also, the placental weight and birth weight of controls, FRESH- and FET-derived newborns differed significantly in rs10732516 A/A genotype (P = 0.024, P = 0.006, respectively): the placentas and newborns of FET-derived pregnancies were heavier compared to FRESH-derived pregnancies (P = 0.02, P = 0.004, respectively).Conclusions: The observed DNA methylation changes together with the phenotypic findings suggest that rs10732516 polymorphism associates with the effects of ART in a parent-of-origin manner. Therefore, this polymorphism should be considered when the effects of environmental factors on embryonic development are studied.

OBJECTIVE: To compare the effects of immediate delivery an expectant management among women whose pregnancies were complicated by preterm prelabor rupture of membranes (PROM) in the late preterm period (from 34 0/7 weeks until 36 6/7 weeks of gestation). DATA SOURCES: PubMed, Scopus, ClinicalTrials.gov, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception until December 2016. METHODS OF STUDY SELECTION: We included all randomized controlled trials with individual participant data reporting on late preterm PROM with randomization to immediate delivery or expectant management. The primary outcome was a composite of adverse neonatal outcomes: probable or definitive neonatal sepsis, necrotizing enterocolitis, respiratory distress syndrome, stillbirth, or neonatal death. TABULATION, INTEGRATION AND RESULTS: Of eight eligible trials (total n=3,203 mothers), three (2,563 mothers, 2,572 neonates) had individual participant data available. The composite adverse neonatal outcome occurred in 9.6% of neonates in the immediate delivery group and 8.3% in the expectant management group (relative risk [RR] 1.20, 95% CI 0.94-1.55). Neonatal sepsis rates were 2.6% and 3.5%, respectively (RR 0.74, 95% CI 0.47-1.15). Neonates in the immediate delivery group were more likely to be diagnosed with respiratory distress syndrome (RR 1.47, 95% CI 1.10-1.97), and to be admitted to the neonatal intensive care unit or special care nursery (RR 1.17, 95% CI 1.11-1.23) and had longer admissions. Mothers randomized to immediate delivery were less likely to have an antepartum hemorrhage (RR 0.57, 95% CI 0.34-0.95) or chorioamnionitis (RR 0.21, 95% CI 0.13-0.35), but more likely to undergo cesarean delivery (RR 1.26, 95% CI 1.08-1.47). CONCLUSION: In women with late preterm PROM, immediate delivery and expectant management resulted in comparable rates of the composite of adverse neonatal outcomes. Effects on individual secondary maternal and neonatal outcomes were mixed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, 42016032972.

OBJECTIVE: To compare the effects of immediate delivery an expectant management among women whose pregnancies were complicated by preterm prelabor rupture of membranes (PROM) in the late preterm period (from 34 0/7 weeks until 36 6/7 weeks of gestation). DATA SOURCES: PubMed, Scopus, ClinicalTrials.gov, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception until December 2016. METHODS OF STUDY SELECTION: We included all randomized controlled trials with individual participant data reporting on late preterm PROM with randomization to immediate delivery or expectant management. The primary outcome was a composite of adverse neonatal outcomes: probable or definitive neonatal sepsis, necrotizing enterocolitis, respiratory distress syndrome, stillbirth, or neonatal death. TABULATION, INTEGRATION AND RESULTS: Of eight eligible trials (total n=3,203 mothers), three (2,563 mothers, 2,572 neonates) had individual participant data available. The composite adverse neonatal outcome occurred in 9.6% of neonates in the immediate delivery group and 8.3% in the expectant management group (relative risk [RR] 1.20, 95% CI 0.94-1.55). Neonatal sepsis rates were 2.6% and 3.5%, respectively (RR 0.74, 95% CI 0.47-1.15). Neonates in the immediate delivery group were more likely to be diagnosed with respiratory distress syndrome (RR 1.47, 95% CI 1.10-1.97), and to be admitted to the neonatal intensive care unit or special care nursery (RR 1.17, 95% CI 1.11-1.23) and had longer admissions. Mothers randomized to immediate delivery were less likely to have an antepartum hemorrhage (RR 0.57, 95% CI 0.34-0.95) or chorioamnionitis (RR 0.21, 95% CI 0.13-0.35), but more likely to undergo cesarean delivery (RR 1.26, 95% CI 1.08-1.47). CONCLUSION: In women with late preterm PROM, immediate delivery and expectant management resulted in comparable rates of the composite of adverse neonatal outcomes. Effects on individual secondary maternal and neonatal outcomes were mixed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, 42016032972.

IntroductionIbuprofen exposure results in acute transient renal dysfunction in preterm neonates, but we are unaware of data on long-term renal safety.MethodsIn a previously studied cohort of extreme low birth weight (ELBW, cysC) at the age of 11 years. This data set in 93 ELBW cases may also generate data on long-term drug safety on ibuprofen. In this post hoc analysis, we linked markers of renal function in young adolescence in ELBW cases with their perinatal (prenatal maternal, setting at birth, treatment modalities including drug prescription during neonatal stay, neonatal creatinine values, postdischarge growth) characteristics, including but not limited to ibuprofen exposure during neonatal stay.ResultsIbuprofen exposure was not associated with significant differences in renal length or eGFRcysC. Moreover, we were unable to identify any other risk factor (perinatal characteristics, postnatal creatinine trends, postdischarge growth) on renal outcome in this cohort.ConclusionsNeonatal exposure to ibuprofen did not affect renal function. Larger studies are needed to explore the confounders of variability in renal function in former ELBW cases. This matters since ELBW relates to risk for hypertension, cardiovascular events and renal disease in later life and identification of risk factors holds the promise of secondary prevention.Trial registration numberNCT02147457.

Background:\ud Data on psychiatric disorders in survivors born very preterm (VP; 2499 g and/or gestational age ≥37 weeks), and 3) structured measure of psychiatric diagnoses using DSM or ICD criteria. Diagnoses of interest were Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Anxiety Disorder, Mood Disorder, Disruptive Behaviour Disorder (DBD), Eating Disorder, and Psychotic Disorder. A systematic search for eligible studies was conducted (PROSPERO Registration Number 47555).\ud \ud Findings:\ud Data were obtained from 10 studies (1385 VP/VLBW participants, 1780 controls), using a range of instruments and approaches to assigning diagnoses. Those born VP/VLBW had ten times higher odds of meeting criteria for ASD (odds ratio [OR] 10·6, 95% confidence interval [CI] 2·50, 44·7), five times higher odds of meeting criteria for ADHD (OR 5·42, 95% CI 3·10, 9·46), twice the odds of meeting criteria for Anxiety Disorder (OR 1·91, 95% CI 1·36, 2·69), and 1·5 times the odds of meeting criteria for Mood Disorder (OR 1·51, 95% CI 1·08, 2·12) than controls. This pattern of findings was consistent within age (

The problem in this study is related to the fulfillment of the principle of justice in making birth certificates intended for children born outside of marriage which is carried out legally between the two parents. This article is normative juridical research with a statutory and conceptual approach. The results of this legal research show that the principle of justice for illegitimate children can be fulfilled by adjusting the provisions regarding the making and issuance of birth certificates for illegitimate children based on the provisions on the status of illegitimate children in the Indonesia Constitutional Court Decision Number: 46/PUU-VIII/2010. Its cause in contrast to the provisions of the Indonesia Marriage Law regarding the distributive status of children outside of marriage, justice for children in the provisions of the status of children outside of marriage in the Indonesia Constitutional Court Decision Number: 46/PUU-VIII/2010 is more commutative. Furthermore, the provisions regarding the status of children out of wedlock in the Constitutional Court Decision Number: 46/PUU-VIII/2010 are teleologically more able to provide benefits and fulfill the purpose of establishing the rule of law and in line with the principle of child protection, namely the best interests of the child. The decision of the Indonesia Constitutional Court Number: 46/PUU-VIII/2010 can be implemented by creating a civil relationship between the child out of wedlock and the biological father and the family of the father. In addition, the Indonesia Constitutional Court Decision Number: 46/PUU-VIII/2010 also has an impact on the administrative field, namely by being able to issue birth certificates for children out of wedlock by including the name of the biological father, so that it is not limited to only including the name of the biological mother.

This prospective cohort study evaluated whether the cognitive development, neurological condition, anthropometrics and blood pressure of 4-year-old IVF twins differed from those of 4-year-old IVF singletons; 103 IVF singletons and 48 IVF twins born after conventional IVF treatment were included. Primary outcome was total intelligence quotient (IQ). Secondary outcomes were minor neurological dysfunction, anthropometrics and blood pressure. Unadjusted analyses found that the total IQ score of twins was lower than that of singletons, with a mean difference of -5.4 (-9.7 to -1.0). Weight (singletons: 18.6 [18.1 to 19.1] kg; twins: 16.9 [16.0 to 17.9] kg) and height (singletons: 108.8 [107.9 to 109.8] cm; twins: 105.9 [104.0 to 107.7] cm) of twins were lower than those of singletons (mean values [95% CI]). All differences disappeared after adjusting for mediators and confounders. Neurological outcome, systolic and diastolic blood pressure of twins and singletons were similar. Four-year-old IVF twins had a lower total IQ (-5.4 points], lower bodyweight (-1.7 kg) and were shorter (-2.9 cm) than 4-year-old IVF singletons. After adjustment, the adverse twin effect disappeared, implying that increased risk for impaired health and development in twins also holds true for IVF twins, and is not altered by IVF. (C) 2017 Reproductive Healthcare Ltd. Published by Elsevierd. All rights reserved.

STUDY QUESTION: Are the in vitro procedure, ovarian hyperstimulation or a combination of these two associated with blood pressure (BP) of 9-year-old IVF children born to subfertile couples?SUMMARY ANSWER: Our study demonstrates that ovarian hyperstimulation and the in vitro procedure are not associated with BP values in 9-year-old children born to subfertile couples.WHAT IS KNOWN ALREADY: Possible long-term effects of IVF on child health and development have been studied relatively little. This is surprising, as it is known that environmental conditions may influence embryonic and foetal development which may result in health related problems in later life. Some studies suggested that IVF is associated with higher BP at pre-school age. Yet, it is unclear whether this may be also true for older children and if so, which component of IVF, i.e. the ovarian hyperstimulation, the embryo culture or a combination of these, attributes to this potentially less favourable BP.STUDY DESIGN, SIZE, DURATION: The Groningen Assisted Reproductive Technology cohort-study is a prospective assessor-blinded study of children followed from before birth onwards. In total, 170 children were assessed at the age of 9 years. The attrition rate up until the 9-year-old assessment was 21%.PARTICIPANTS/MATERIALS, SETTING, METHODS: We evaluated cardiovascular health, focusing on BP (in mmHg and the internationally recognized percentiles of the US National High BP Education Program), heart rate and anthropometrics of 57 children born following controlled ovarian hyperstimulation-IVF/ICSI (COH-IVF/ICSI); 47 children born after modified natural cycle-IVF/ICSI (MNC-IVF/ICSI); and 66 children who were conceived naturally by subfertile couples (Sub-NC). Cardiovascular parameters were measured multiple times on one day. In addition, anthropometric data, including BMI and skinfold thickness, were collected. MAIN RESULTS AND THE ROLE OF CHANCE: Systolic BP in mmHg did not differ between the COH-IVF/ICSI (mean 106.9, SD 6.7), MNC-IVF/ICSI (mean 104.8, SD 5.9) and Sub-NC (mean 106.3, SD 5.3) groups. In addition, systolic BP percentiles did not differ between the groups: COH-IVF/ICSI (mean 62.4, SD 20.2); MNC-IVF/ICSI (mean 56.3, SD 19.3); and Sub-NC (mean 62.3, SD17.8). Also, after adjustment for confounders BP in the three groups was similar. Heart rate and anthropometric values in the three groups did not differ. For instance, BMI values in the COH-IVF/ICSI-children were 16.3 (median value, range 13.0-24.7), in MNC-IVF/ ICSI-children 16.1 (range 12.7-22.5) and in Sub-NC children 16.3 (range 12.7-24.0).LIMITATIONS, REASONS FOR CAUTION: The size of our study groups does not allow for pertinent conclusions on the effect of ovarian hyperstimulation and the in vitro procedure. The lack of a fertile control group may be regarded as another limitation.WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that ovarian hyperstimulation and in vitro procedures are not associated with cardiovascular health in 9-year-old. Yet, BP percentiles of the three groups were higher than the expected 50th percentile. This might indicate that children of subfertile couples have a higher BP than naturally conceived children.STUDY FUNDING/COMPETING INTEREST(S): The study was financially supported by the University Medical Center Groningen (UMCG), the two graduate schools of the UMCG, BCN, SHARE and the Cornelia Stichting. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare.

Reading and math skills of preterm born (birth weight 1500 g or gestational age:532 weeks) children and full term (FT) children were compared during the first weeks of grade 1. The participants were 194 preterm born and 175 FT children born between 2001 and 2006. There were more precocious readers among FT than among preterm students, but even the latter performed close to the national norm. FT and preterm group differences among non-readers were minor with only rapid naming showing a robust difference. Math performance showed a stable difference in favor of FT students and the difference was sustained in the full-scale IQcontrol. Major brain pathology increased the likelihood of poor scholastic skills, but lower birth weight relative to gestational age did not. Somewhat surprisingly, maternal education was not associated with school readiness skills. (C) 2017 Elsevier Inc. All rights reserved.

Diffusion MRI (dMRI) studies using the tensor model have identified abnormal white matter development associated with perinatal risk factors in preterm infants studied at term equivalent age (TEA). However, this model is an oversimplification of the underlying neuroanatomy. Fixel-based analysis (FBA) is a novel quantitative framework, which identifies microstructural and macrostructural changes in individual fibre populations within voxels containing crossing fibres. The aim of this study was to apply FBA to investigate the relationship between fixel-based measures of apparent fibre density (FD), fibre bundle cross-section (FC), and fibre density and cross-section (FDC) and perinatal risk factors in preterm infants at TEA. We studied 50 infants (28 male) born at 24.0-32.9 (median 30.4) weeks gestational age (GA) and imaged at 38.6-47.1 (median 42.1) weeks postmenstrual age (PMA). dMRI data were acquired in non-collinear directions with b-value 2500 s/mm2 on a 3 Tesla system sited on the neonatal intensive care unit. FBA was performed to assess the relationship between FD, FC, FDC and PMA at scan, GA at birth, days on mechanical ventilation, days on total parenteral nutrition (TPN), birthweight z-score, and sex. FBA reveals fibre population-specific alterations in FD, FC and FDC associated with clinical risk factors. FD was positively correlated with GA at birth and was negatively correlated with number of days requiring ventilation. FC was positively correlated with GA at birth, birthweight z-scores and was higher in males. FC was negatively correlated with number of days on ventilation and days on TPN. FDC was positively correlated with GA at birth and birthweight z-scores, negatively correlated with days on ventilation and days on TPN and higher in males. We demonstrate that these relationships are fibre-specific even within regions of crossing fibres. These results show that aberrant white matter development involves both microstructural changes and macrostructural alterations. ispartof: NEUROIMAGE-CLINICAL vol:23 ispartof: location:Netherlands status: published

Though clinical trials for medical applications of dimethyl sulfoxide (DMSO) reported toxicity in the 1960s, later, the FDA classified DMSO in the safest solvent category. DMSO became widely used in many biomedical fields and biological effects were overlooked. Meanwhile, biomedical science has evolved towards sensitive high-throughput techniques and new research areas, including epigenomics and microRNAs. Considering its wide use, especially for cryopreservation and in vitro assays, we evaluated biological effect of DMSO using these technological innovations. We exposed 3D cardiac and hepatic microtissues to medium with or without 0.1% DMSO and analyzed the transcriptome, proteome and DNA methylation profiles. In both tissue types, transcriptome analysis detected >2000 differentially expressed genes affecting similar biological processes, thereby indicating consistent cross-organ actions of DMSO. Furthermore, microRNA analysis revealed large-scale deregulations of cardiac microRNAs and smaller, though still massive, effects in hepatic microtissues. Genome-wide methylation patterns also revealed tissue-specificity. While hepatic microtissues demonstrated non-significant changes, findings from cardiac microtissues suggested disruption of DNA methylation mechanisms leading to genome-wide changes. The extreme changes in microRNAs and alterations in the epigenetic landscape indicate that DMSO is not inert. Its use should be reconsidered, especially for cryopreservation of embryos and oocytes, since it may impact embryonic development.

Whether infant regulatory behavior problems already in the first month of life indicate an increased risk of childhood neurobehavioral problems, and whether maternal depression in the postpartum and early childhood underpins these associations remain unclear. Altogether, 2049–2364 mothers from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Neonatal Perception Inventory on regulatory behavior problems at the infant’s age of 15.6 days (SD 3.2, range 1–30), the Infant Behavior Questionnaire-Revised on temperament at 6.5 months (SD 0.9, range 4.2–12.4), and the Ages and Stages Questionnaire-3 on developmental milestones and the Child Behavior Checklist on behavioral problems at 3.5 years (SD 0.7, range 1.9–6.0). Maternal depressive symptoms were measured by the Center for Epidemiological Studies Depression Scale (infancy follow-ups) and Beck Depression Inventory-II (childhood follow-up). Father-rated infant temperament and paternal depressive symptoms were also available (n = 1474). Higher levels of infant regulatory behavior problems predicted higher levels of mother- and father-rated negative affectivity temperament (0.13 SD units per SD unit, 95% confidence interval 0.09–0.17; and 0.09, 0.04–0.14, respectively), lower levels of mother-rated orienting/regulation temperament (− 0.09, − 0.13 to − 0.05) and problem-solving skills (− 0.12, − 0.21 to − 0.04), and higher levels of Externalizing (0.07, 0.03–0.11) and Total behavioral problems (0.07, 0.03–0.11). Regulatory behaviors partially mediated the effect of maternal depressive symptoms. Regulatory behavior problems already during the first month of life predict neurobehavioral outcomes, and partially mediate the effect of maternal depressive symptoms. Our study may inform design of interventions aimed at timely prevention in children at risk. Electronic supplementary material The online version of this article (10.1007/s00787-018-1243-8) contains supplementary material, which is available to authorized users.

Objective: To evaluate cardiac autonomic function in adults born preterm. Study design: We studied the association between prematurity and cardiac autonomic function using heart rate variability measurements in 600 adults (mean age of 23.3 years) from a geographically based cohort in Northern Finland. There were 117 young adults born early preterm (

Item does not contain fulltext STUDY QUESTION: Does embryo culture medium influence pregnancy and perinatal outcome in IVF? SUMMARY ANSWER: Embryo culture media used in IVF affect treatment efficacy and the birthweight of newborns. WHAT IS KNOWN ALREADY: A wide variety of culture media for human preimplantation embryos in IVF/ICSI treatments currently exists. It is unknown which medium is best in terms of clinical outcomes. Furthermore, it has been suggested that the culture medium used for the in vitro culture of embryos affects birthweight, but this has never been demonstrated by large randomized trials. STUDY DESIGN, SIZE, DURATION: We conducted a multicenter, double-blind RCT comparing the use of HTF and G5 embryo culture media in IVF. Between July 2010 and May 2012, 836 couples (419 in the HTF group and 417 in the G5 group) were included. The allocated medium (1:1 allocation) was used in all treatment cycles a couple received within 1 year after randomization, including possible transfers with frozen-thawed embryos. The primary outcome was live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples that were scheduled for an IVF or an ICSI treatment at one of the six participating centers in the Netherlands or their affiliated clinics. MAIN RESULTS AND THE ROLE OF CHANCE: The live birth rate was higher, albeit nonsignificantly, in couples assigned to G5 than in couples assigned to HTF (44.1% (184/417) versus 37.9% (159/419); RR: 1.2; 95% confidence interval (CI): 0.99-1.37; P = 0.08). Number of utilizable embryos per cycle (2.8 +/- 2.3 versus 2.3 +/- 1.8; P < 0.001), implantation rate after fresh embryo transfer (20.2 versus 15.3%; P < 0.001) and clinical pregnancy rate (47.7 versus 40.1%; RR: 1.2; 95% CI: 1.02-1.39; P = 0.03) were significantly higher for couples assigned to G5 compared with those assigned to HTF. Of the 383 live born children in this trial, birthweight data from 380 children (300 singletons (G5: 163, HTF: 137) and 80 twin children (G5: 38, HTF: 42)) were retrieved. Birthweight was significantly lower in the G5 group compared with the HTF group, with a mean difference of 158 g (95% CI: 42-275 g; P = 0.008). More singletons were born preterm in the G5 group (8.6% (14/163) versus 2.2% (3/137), but singleton birthweight adjusted for gestational age and gender (z-score) was also lower in the G5 than in the HTF group (-0.13 +/- 0.08 versus 0.17 +/- 0.08; P = 0.008). LIMITATIONS, REASONS FOR CAUTION: This study was powered to detect a 10% difference in live births while a smaller difference could still be clinically relevant. The effect of other culture media on perinatal outcome remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: Embryo culture media used in IVF affect not only treatment efficacy but also perinatal outcome. This suggests that the millions of human embryos that are cultured in vitro each year are sensitive to their environment. These findings should lead to increased awareness, mechanistic studies and legislative adaptations to protect IVF offspring during the first few days of their existence. STUDY FUNDING/COMPETING INTERESTS: This project was partly funded by The NutsOhra foundation (Grant 1203-061) and March of Dimes (Grant 6-FY13-153). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NTR1979 (Netherlands Trial Registry). TRIAL REGISTRATION DATE: 1 September 2009. DATE OF FIRST PATIENT'S ENROLMENT: 18 July 2010.

Very preterm birth, before the gestational age (GA) of 32 weeks, increases the risk of obstructed airflow in adulthood. We examined whether all preterm births (GA

Background. Around 30% of pregnancies conclude in a gestational loss. Most women who suffer a gestational loss become pregnant again. However, mothers who have experienced this situation live the new pregnancy with fear and anxiety. Objective. To perform an update of the main works done in the study of post-traumatic stress and related symptoms during pregnancy after a gestational loss. Method. The Medline database was consulted. Articles published from 2007 to date were selected. Key words related to the topic of study were used. Results. The studies reviewed showed five entities that deserve attention during a pregnancy achieved after a gestational loss: post-traumatic stress, depression, anxiety, relationship, and relationship with the future child. There is a relationship between the presence of post-traumatic stress and the risk of developing depression and anxiety. Discussion and conclusion. Women who experience perinatal loss, regardless of the type of loss and the gestational age in which it occurs, are at risk of continuing grief, symptoms of depression, anxiety, and post-traumatic stress in later pregnancy. The gestational age and the time elapsed between the perinatal loss and the next pregnancy seem to be the most influential factors in the development of post-traumatic stress sindrome, and symptoms of dysfunctional grief, anxiety, and depression.

Objectives To determine the long-term effects of moderately-late preterm (MLP) birth on respiratory and allergic symptoms, lung function, and exercise capacity in adolescence. Study design Outcome variables in this prospective cohort were prevalence of symptoms determined by International Study of Asthma and Allergies in Childhood questionnaires, lung function, and exercise measures. Results Response rate was 47% and did not vary importantly by background characteristics. In total, 71 children (aged 13-14 years) participated in the measurements, 37 born MLP and 34 born full term. Both groups were comparable in height, weight, and exercise activities but differed in gestational age (MLP 34 ± 1 weeks, full term 39 ± 0.9 weeks) and birth weight (MLP 2442 ± 539 g, full term 3693 ± 393 g). Adolescents born MLP reported more (dry) cough (MLP 25% vs those born full term 3%, P = .016) and hay fever (MLP 34% vs those born full term 9%, P = .015). Adolescents born MLP did not report more wheeze, dyspnea, asthma, and eczema. Most lung function measurements were within the normal range for both groups, except peak expiratory flow (MLP 86% of predicted vs those born full term 93%, P = .05) and maximum expiratory flow when 75% of the forced vital capacity has been exhaled (MLP 86% predicted vs those born full term 96% predicted, P = .06), which were at the lower limit of normal. We observed no differences between the groups in exercise parameters. Conclusion Moderately late preterm birth has little effect on respiratory health in adolescence. Adolescents born MLP report few symptoms, have only slightly more lung function abnormalities than those born full term, and do not differ in the maximal exercise test and in physical activity level. Trial registration ISRCTN 80622320.

Item does not contain fulltext STUDY QUESTION: Do in vitro fertilization (IVF) multiples generate higher hospital costs than IVF singletons, from birth up to age 5? SUMMARY ANSWER: Hospital costs from birth up to age 5 were significantly higher among IVF/ICSI multiple children compared with IVF/ICSI singletons; however, when excluding the costs incurred during the birth admission period, hospital costs of multiples and singletons were comparable. WHAT IS KNOWN ALREADY: Concern has risen over the long-term outcome of children born after IVF. The increased incidence of multiple births in IVF as a result of double-embryo transfer predisposes children to a poorer neonatal outcome such as preterm birth and low birthweight. As a consequence, IVF multiples require more medical care. Costs and consequences of poorer neonatal outcomes in multiples may also exist later in life. STUDY DESIGN, SIZE, DURATION: All 5497 children born from IVF in 2003-2005, whose parents received IVF or ICSI treatment in one of five participating Dutch IVF centers, served as a basis for a retrospective cohort study. Based on gestational age, birthweight, Apgar and congenital malformation, children were assigned to one of three risk strata (low-, moderate- or high-risk). PARTICIPANTS/MATERIALS, SETTING, METHODS: To enhance the efficiency of the data collection, 816 multiples and 584 singletons were selected for 5-year follow-up based on stratified (risk) sampling. Parental informed consent was received of 322 multiples and 293 singletons. Individual-level hospital resource use data (hospitalization, outpatient visits and medical procedures) were retrieved from hospital information systems and patient charts for 302 multiples and 278 singletons. MAIN RESULTS AND THE ROLE OF CHANCE: The risk of hospitalization (OR 4.9, 95% CI 3.3-7.0), outpatient visits (OR 2.6, 95% CI 1.8-3.6) and medical procedures (OR 1.7, 95% CI 1.2-2.2) was higher for multiples compared with singletons. The average hospital costs amounted to euro10 018 and euro2093 during the birth admission period (P < 0.001), euro1131 and euro696 after the birth admission period to the first birthday (not significant (n.s.)) and euro1084 and euro938 from the second to the fifth life year (n.s.) for multiples and singletons, respectively. Hospital costs from birth up to age 5 were 3.3-fold higher for multiples compared with singletons (P < 0.001). Among multiples and singletons, respectively, 90.8 and 76.2% of the total hospital costs were caused by hospital admission days and 8.9 and 25.2% of the total hospital costs during the first 5 years of life occurred after the first year of life. LIMITATIONS, REASONS FOR CAUTION: Resource use and costs outside the hospital were not included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the increased use of healthcare resources by IVF/ICSI multiples compared with IVF/ICSI singletons. Single-embryo transfer may result in substantial savings, particularly in the birth admission period. These savings need to be compared with the extra costs of additional embryo transfers needed to achieve a successful pregnancy. Besides costs, health outcomes of children born after single-embryo transfer should be compared with those born after double-embryo transfer. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a research grant (grant number 80-82310-98-09094) from the Netherlands Organization for Health Research and Development (ZonMw). There are no conflicts of interest in connection with this article. TRIAL REGISTRATION NUMBER: Not applicable.

Premature birth has been associated with poor neurodevelopmental outcomes. However, the relation between such outcomes and brain growth in the neonatal period has not yet been fully elucidated. This study investigates longitudinal brain development between birth and term-equivalent age (TEA) by quantitative imaging in a cohort of premature infants born between 26 and 36 weeks gestational age (GA), to provide insight into the relation of brain growth with later neurodevelopmental outcomes., Longitudinal T2-weighted magnetic resonance images (MRI) of 84 prematurely born infants acquired shortly after birth and TEA were automatically segmented into cortical gray matter (CGM), unmyelinated white matter (UWM), subcortical gray matter (SGM), cerebellum (CB) and cerebrospinal fluid (CSF). General linear models and correlation analysis were used to study the relation between brain volumes and their growth, and perinatal variables. To investigate the ability of the brain volumes to predict children's neurodevelopmental outcome at 18-24 months and at 5 years of age, a linear discriminant analysis classifier was tested and several general linear models were fitted and compared by statistical tests., From birth to TEA, relative volumes of CGM, CB and CSF with respect to total intracranial volume increased, while relative volumes of UWM and SGM decreased. The fastest growing tissues between birth and TEA were found to be the CB and the CGM. Lower GA at birth was associated with lower growth rates of CGM, CB and total tissue. Among perinatal factors, persistent ductus arteriosus was associated with lower SGM, CB and IC growth rates, while sepsis was associated with lower CSF and intracranial volume growth rates., Model comparisons showed that brain tissue volumes at birth and at TEA contributed to the prediction of motor outcomes at 18-24 months, while volumes at TEA and volume growth rates contributed to the prediction of cognitive scores at 5 years of age. The family socio-economic status (SES) was not correlated with brain volumes at birth or at TEA, but was strongly associated with the cognitive outcomes at 18-24 months and 5 years of age., This study provides information about brain growth between birth and TEA in premature children with no focal brain lesions, and investigates their association with subsequent neurodevelopmental outcome. Parental SES was found to be a major determinant of neurodevelopmental outcome, unrelated to brain growth. However, further research is necessary in order to fully explain the variability of neurodevelopmental outcomes in this population.

Aim To determine the association between sucking in infants born preterm and developmental outcomes at 5 years. Method Thirty-four infants were included (mean gestational age 30wks 4d, mean birthweight 1407g). The Neonatal Oral-Motor Assessment Scale was used longitudinally from 37 to 50 weeks postmenstrual age. At 5 years, we assessed motor skills, intelligence, language, verbal memory, and behavioural problems. Linear regression analyses were performed to test whether aspects of sucking behaviour predicted these developmental outcomes. Where linear regression was not appropriate, Spearman's correlation coefficients were calculated between sucking and developmental outcomes. Results Sucking was associated with total motor skills (B [unstandardized correlation coefficient for normally distributed data]=22.66, 95% confidence interval [CI] 6.61 to 38.71), balance (Spearman's ρ=0.64, p

Background Low-birth-weight infants (LBW) are at an increased risk of iron deficiency that has been associated with impaired neurodevelopment. We hypothesized that iron supplementation of LBW infants improves cognitive scores and reduces behavioral problems until school age. Methods We randomized 285 marginally LBW (2,000-2,500 g) infants to receive 0, 1, or 2 mg/kg/day of iron supplements from 6 weeks to 6 months of age. At 7 years of age, 205 participants were assessed regarding cognition using Wechsler Intelligence Scale for Children (WISC-IV) and behavior using the parental questionnaires Child Behavior Checklist (CBCL) and Five to Fifteen (FTF). Results There were no significant differences between the intervention groups in WISC-IV or FTF. However, the CBCL scores for externalizing problems were significantly different, in favor of supplemented children (P=0.045). When combining the supplemented groups, they had significantly lower scores for externalizing behavior compared with placebo (median (interquartile range): 44 [34;51] vs. 48.5 [41;56] P=0.013), and their risk ratio (95% confidence interval) for a total behavioral score above the cutoff for clinical problems was 0.31 (0.09-1.0), P=0.054. Conclusion Lower scores of externalizing behavior in supplemented children support our previous findings at 3 years, and suggest that iron supplementation may have long-lasting effects on behavioral functions.

Children born extremely preterm may have difficulties in response inhibition, but the neural basis of such problems is unknown. We recorded magnetoencephalography (MEG) during a somatosensory Go/NoGo task in six-year-old children born extremely preterm (EPT; n = 22) and in children born full term (FT; n = 21). The children received tactile stimuli randomly to their left little (target) and index (non-target) finger and were instructed to squeeze a soft toy with the opposite hand every time they felt a stimulus on the little finger. Behaviorally, the EPT children performed worse than the FT children, both in responding to the target finger stimulation and in refraining from responding to the non-target finger stimulation. In MEG, after the non-target finger stimulation (i.e., during the response inhibition), the sensorimotor alpha and beta oscillation levels in the contralateral-to-squeeze hemisphere were elevated in the FT children when compared with a condition with corresponding stimulation but no task (instead the children were listening to a story and not attending to the fingers). This NoGo task effect was absent in the EPT children. Further, in the sensorimotor cortex contralateral to the tactile stimulation, the post-stimulus suppression was less pronounced in the EPT than FT children. We suggest that the missing NoGo task effect and lower suppression of sensorimotor oscillations are markers of deficient functioning of the sensorimotor networks in the EPT children.

Does ovarian hyperstimulation, the in vitro procedure, or a combination of these two negatively influence blood pressure (BP) and anthropometrics of 4-year-old children born following IVF? Higher systolic blood pressure (SBP) percentiles were found in 4-year-old children born following conventional IVF with ovarian hyperstimulation compared with children born following IVF without ovarian hyperstimulation. Increasing evidence suggests that IVF, which has an increased incidence of preterm birth and low birthweight, is associated with higher BP and altered body fat distribution in offspring but the underlying mechanisms are largely unknown. We performed a prospective, assessor-blinded follow-up study in which 194 children were assessed. The attrition rate up until the 4-year-old assessment was 10%. We measured BP and anthropometrics of 4-year-old singletons born following conventional IVF with controlled ovarian hyperstimulation (COH-IVF, n = 63), or born following modified natural cycle IV (MNC-IVF, n = 52), or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Both IVF and ICSI were performed. Primary outcome measures were the SBP percentiles and diastolic BP (DBP) percentiles. Anthropometric measures included triceps and subscapular skinfold thickness. Several multivariable regression analyses were applied in order to correct for subsets of confounders. The value 'B' is the unstandardized regression coefficient. SBP percentiles were significantly lower in the MNC-IVF group (mean 59, SD 24) than in the COH-IVF (mean 68, SD 22) and Sub-NC groups (mean 70, SD 16). The difference in SBP between COH-IVF and MNC-IVF remained significant after correction for current, early life and parental characteristics (B: 14.09; 95% confidence interval (CI): 5.39-22.79), whereas the difference between MNC-IVF and Sub-NC did not. DBP percentiles did not differ between groups. After correction for early life factors, subscapular skinfold thickness was thicker in the COH-IVF group than in the Sub-NC group (B: 0.28; 95% CI: 0.03-0.53). Larger study groups are necessary to draw firm conclusions. An effect of gender or ICSI could not be properly investigated as stratifying would further reduce the sample size. We corrected for the known differences between MNC-IVF and COH-IVF but it is possible that the groups differ in additional, more subtle parental characteristics. In addition, we measured BP on 1 day only, had no control group of children born to fertile couples (precluding investigating effects of the underlying subfertility) and included singletons only. As COH-IVF is associated with multiple births we may have underestimated cardiometabolic problems after COH-IVF. Finally, multivariable regression analysis does not provide clear insight in the causal mechanisms and we have performed further explorative analyses. Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome but this is the first study suggesting that ovarian hyperstimulation, as used in IVF treatments, could be a causative mechanism. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo that result in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to assess further the role of ovarian hyperstimulation in poorer cardiometabolic outcome and investigate the underlying mechanisms. The findings emphasize the importance of cardiometabolic monitoring of the growing number of children born following IVF. The authors have no conflicts of interest to declare. The study was supported by the University Medical Center Groningen, the Cornelia Foundation and the school for Behavioral- and Cognitive Neurosciences. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report

Epidemiological studies suggest a higher prevalence of congenital malformations in children conceived through assisted reproductive technologies. There are a few studies that address CHD specifically and most have examined data from registries. We examined the relationship between CHD and assisted conception using data collected in a specialist paediatric cardiac service in the United Kingdom.Between April, 2010 and July, 2011, the parents of children attending paediatric cardiology clinics at the Royal Brompton Hospital, London, were invited to complete a questionnaire that enquired about the nature of their child’s conception, the route for their original referral, and a number of potential confounding exposures. “Cases” were defined as children diagnosed with one or more carefully defined CHDs and “controls” as those with normal hearts.Of 894 new attendees with complete data, half of them were cases (n=410, 45.9%). The overall prevalence of assisted conception was 5.4% (n=44). Logistic regression analysis demonstrated a non-significant increase in the crude odds for the use of assisted reproduction (odds ratio 1.21, 95% confidence interval 0.66–2.22) in this group. After adjustment for gestation, parity, year of birth, and maternal age, the odds ratio reduced (odds ratio 0.95, 95% confidence interval 0.48–1.88). Increased rates of assisted conception were observed in a number of CHD subgroups, although no significant differences were found.These findings do not suggest an overall association between CHD and assisted reproduction in this population.

Objective: To compare the effect of maternal age on assisted reproductive technology (ART) and spontaneous conception (SC) pregnancies regarding maternal and neonatal complications. Design: Nordic retrospective population-based cohort study. Data from national ART registries were cross-linked with national medical birth registries. Setting: Not applicable. Patient(s): A total of 300,085 singleton deliveries: 39,919 after ART and 260,166 after SC. Intervention(s): None. Main Outcome Measure(s): Hypertensive disorders in pregnancy (HDP), placenta previa, cesarean delivery, preterm birth (PTB; = 28 weeks). Adjusted odds ratios (AORs) were calculated. Associations between maternal age and outcomes were analyzed. Result(s): The risk of placenta previa (AOR 4.11-6.05), cesarean delivery (AOR 1.18-1.50), PTB (AOR 1.23-2.19), and LBW (AOR 1.44-2.35) was significantly higher in ART than in SC pregnancies for most maternal ages. In both ART and SC pregnancies, the risk of HDP, placenta previa, cesarean delivery, PTB, LBW, and SGA changed significantly with age. The AORs for adverse neonatal outcomes at advanced maternal age (>35 years) showed a greater increase in SC than in ART. The change in risk with age did not differ between ART and SC for maternal outcomes at advanced maternal age. Conclusion(s): Having singleton conceptions after ART results in higher maternal and neonatal outcome risks overall, but the impact of age seems to be more pronounced in couples conceiving spontaneously. (C) 2016 by American Society for Reproductive Medicine.

Aim The aim of the study was to assess the influence of decreasing gestational age on the risk of developmental delay in various domains at age 4 years among children born at a wide range of gestational ages. Method In a community-based cohort, the parents of 1439 preterm-born children (24 0/7 to 35 6/7wks) and 544 term-born children (38 0/7 to 41 6/7wks) born in 2002 and 2003 completed the Ages and Stages Questionnaire (ASQ) when their child was 3 years 7 months to 4 years 1 month old. The prevalence rates of abnormal scores on the ASQ-total problems scale were compared in preterm and term-born children and the resulting odds ratios for gestational age groups were calculated and adjusted for social and biological covariates. Results The prevalence rates of abnormal scores on the ASQ-total problems scale increased with decreasing gestational age: from 4.2% among term-born children to 37.5% among children born at 2425 weeks gestation (p Interpretation The risk of developmental delay increases exponentially with decreasing gestational age below 36 weeks gestation on all developmental domains of the ASQ. Adjustment for covariates did not alter the pattern of exponential increase in developmental risk with decreasing gestational age. We speculate that both direct perinatal cerebral injuries and tropic and maturational brain disturbances are involved.