Disruption of the immune system during embryonic brain development by environmental chemicals was proposed as a possible cause of neurodevelopmental disorders. We previously found adverse effects... Show moreDisruption of the immune system during embryonic brain development by environmental chemicals was proposed as a possible cause of neurodevelopmental disorders. We previously found adverse effects of di-n-octyltin dichloride (DOTC) on maternal and developing immune systems of rats in an extended one-generation reproductive toxicity study according to the OECD 443 test guideline. We hypothesize that the DOTC-induced changes in the immune system can affect neurodevelopment. Therefore, we used in-vivo MRI and PET imaging and genomics, in addition to behavioral testing and neuropathology as proposed in OECD test guideline 443, to investigate the effect of DOTC on structural and functional brain development. Male rats were exposed to DOTC (0, 3, 10, or 30 mg/kg of diet) from 2 weeks prior to mating of the F0-generation until sacrifice of F1-animals. The brains of rats, exposed to DOTC showed a transiently enlarged volume of specific brain regions (MRI), altered specific gravity, and transient hyper-metabolism ([18F]FDG PET). The alterations in brain development concurred with hyper-responsiveness in auditory startle response and slight hyperactivity in young adult animals. Genomics identified altered transcription of key regulators involved in neurodevelopment and neural function (e.g. Nrgrn, Shank3, Igf1r, Cck, Apba2, Foxp2); and regulators involved in cell size, cell proliferation, and organ development, especially immune system development and functioning (e.g. LOC679869, Itga11, Arhgap5, Cd47, Dlg1, Gas6, Cml5, Mef2c). The results suggest the involvement of immunotoxicity in the impairment of the nervous system by DOTC and support the hypothesis of a close connection between the immune and nervous systems in brain development. Show less
Snoep, M.C.; Aliasi, M.; Meeren, L.E. van der; Jongbloed, M.R.M.; DeRuiter, M.C.; Haak, M.C. 2021
Impaired placentation is an important contributing factor to intra-uterine growth restriction and pre-eclampsia in fetuses with congenital heart defects (CHD). These pregnancy complications occur... Show moreImpaired placentation is an important contributing factor to intra-uterine growth restriction and pre-eclampsia in fetuses with congenital heart defects (CHD). These pregnancy complications occur more frequently in pregnancies with fetal CHD. One of the most important factors influencing the life of children with CHD is neurodevelopmental delay, which seems to start already in utero. Delayed neurodevelopment in utero may be correlated or even (partly) explained by impaired placentation in CHD cases. This systematic review provides an overview of published literature on placental development in pregnancies with fetal CHD. A systematic search was performed and the Newcastle-Ottawa scale was used to access data quality. Primary outcomes were placenta size and weight, vascular and villous architecture, immunohistochemistry, angiogenic biomarkers and/or placental gene expression. A total of 1161 articles were reviewed and 21 studies were included. Studies including CHD with a genetic disorder or syndrome and/or multiple pregnancies were excluded. Lower placental weight and elevated rates of abnormal umbilical cord insertions were found in CHD. Cases with CHD more frequently showed microscopic placental abnormalities (i.e. abnormal villous maturation and increased maternal vascular malperfusion lesions), reduced levels of angiogenic biomarkers and increased levels of anti-angiogenic biomarkers in maternal serum and umbilical cord blood. Altered gene expression involved in placental development and fetal growth were found in maternal serum and CHD placentas. In conclusion, abnormal placentation is found in CHD. More extensive studies are needed to elucidate the contribution of impaired placentation to delayed neurodevelopment in CHD cases. Show less
Objective: To compare effects of immediate delivery vs expectant monitoring on neurodevelopmental and behavioral outcomes at 5 years of age in offspring of women with mild late preterm hypertensive... Show moreObjective: To compare effects of immediate delivery vs expectant monitoring on neurodevelopmental and behavioral outcomes at 5 years of age in offspring of women with mild late preterm hypertensive disorders.Study design: We studied children born during the HYPITAT-11 trial, in which 704 women with a hypertensive disorder between 34 and 37 weeks of gestation were randomized to immediate delivery or expectant monitoring. Participating women were asked to complete the Ages and Stages Questionnaire (ASQ) for developmental outcome and the Child Behavior Checklist (CBCL) for behavioral problems when their child was 5 years old. Outcomes were dichotomized and analyzed by logistic regression analysis. We also assessed factors influencing development and behavior at both 2 and 5 years after a hypertensive pregnancy.Results: Five years after the original study 322(46%) women were contacted for follow-up, of whom 148 (46%) responded. In the delivery group 22%(n = 14/65) of the children had an abnormal ASQ score compared to 21% (n = 13/62) in the expectant monitoring group (p = 0.9). Abnormal CBCL-scores were found in 19% (n = 14/72) of the children in the delivery group versus in 27% (n = 20/75) in the expectant monitoring group (p = 0.3). The main predictor of development and behavior at 2 and 5 years was fetal growth restriction (for abnormal development OR 2.1, CI 1.0-4.4; for behavior problems OR 2.2, CI 1.1-5.5). Higher maternal education decreased abnormal behavior outcomes (OR 0.5, CI 0.2-0.9) and a similar tendency was observed for developmental problems (OR 0.6, CI 0.3 - 1.1).Conclusion: We did not find different developmental and behavior outcomes at 5 years of age between a management policy of immediate delivery and expectant management in preterm hypertensive disorders. The increased risk of developmental delay at 2 years of age after immediate delivery, we found in the 2 year follow up study, did not persist at 5 years of age. (C) 2019 Elsevier B.V. All rights reserved. Show less
Winkelhorst, D.; Kamphuis, M.M.; Steggerda, S.J.; Rijken, M.; Oepkes, D.; Lopriore, E.; Klink, J.M.M. van 2019
Objectives: To evaluate the perinatal and long-term neurodevelopmental outcome in a cohort of children with intracranial haemorrhage (ICH) due to fetal and neonatal alloimmune thrombocytopenia ... Show moreObjectives: To evaluate the perinatal and long-term neurodevelopmental outcome in a cohort of children with intracranial haemorrhage (ICH) due to fetal and neonatal alloimmune thrombocytopenia (FNAIT) and to clearly outline the burden of this disease. Subjects and Methods: We performed an observational cohort study and included all consecutive cases of ICH caused by FNAIT from 1993 to 2015 at Leiden University Medical Centre. Neurological, motor, and cognitive development were assessed at a minimum age of 1 year. The primary outcome was adverse outcome, defined as perinatal death or severe neurodevelopmental impairment (NDI). Severe NDI was defined as any of the following: cerebral palsy (Gross Motor Function Classification System [GMFCS] level >= II), bilateral deafness, blindness, or severe motor and/or cognitive developmental delay (<-2 SD). Results: In total, 21 cases of ICH due to FNAIT were included in the study. The perinatal mortality rate was 10/21 (48%). Long-term outcome was assessed in 10 children (n = 1 lost to follow-up). Severe and moderate NDI were diagnosed in 6/10 (60%) and 1/10 (10%) of the surviving children. The overall adverse outcome, including perinatal mortality or severe NDI, was 16/20 (80%). Conclusions: The risk of perinatal death or severe NDI in children with ICH due to FNAIT is high. Only screening and effective preventive treatment can avoid this burden. (C) 2018 The Author(s) Published by S. Karger AG, Basel Show less
An increasing number of fetal diseases are being detected prior to birth due to major improvements in prenatal ultrasound examinations and the wide implementation of screening programs. For various... Show moreAn increasing number of fetal diseases are being detected prior to birth due to major improvements in prenatal ultrasound examinations and the wide implementation of screening programs. For various diseases, fetal therapy may be a life-saving option or an alternative to postnatal treatment, to prevent permanent organ damage. A major breakthrough in fetal therapy was the introduction of intrauterine blood transfusion for severe fetal anemia in the early 1960s. Since then, fetal therapy has gradually evolved resulting in a dramatic increase in overall survival in several fetal diseases. In the Netherlands, fetal surgical interventions are concentrated in one center, the LUMC, a tertiary medical center which serves as the national referral center for fetal therapy. Although an increasing number of children are being born alive after fetal therapy, reliable data on the long-term neurodevelopmental outcome remain scarce. Follow-up studies are of paramount importance to increase our knowledge on the quality of long-term survival and to identify potential risk factors for adverse outcome. In this thesis, studies on the long-term neurodevelopmental outcome after fetal therapy for various fetal diseases are presented including intrauterine transfusion for fetal anemia, fetoscopic laser surgery for twin-twin transfusion syndrome and selective reduction in complicated monochorionic pregnancies. Show less
With the availability of prenatal diagnostics in the last century, the fetus became a patient. Obstetricians looked togheter with neonatologist and pediatric surgeons, who in the past needed to... Show moreWith the availability of prenatal diagnostics in the last century, the fetus became a patient. Obstetricians looked togheter with neonatologist and pediatric surgeons, who in the past needed to treat sick neonates, for an earlier moment of treatment. An example of such a shift towards an earlier moment of treatment is the treatment of fetal tachycardia. Allready in utero medication can be given to the fetus transplacentally or direct fetally. In order to convert the tachycardia into a sinus rhythm. Another example is the anemic fetus who can be given an intrauterine blood transfusion to treat the anemia. A further example is the monochorionic twin with twin to twin transfusion syndrome. It is possible to coagulate the pathologic bloodvessel connections which cause the syndrome. Fetal death can be prevented by performing this procedure. A condition for the introduction of new techniques in medicine is that they are tested on efficacy and safety. That’s why new diagnostic and therapeutic procedures demand proper follow-up. Unwanted side effects, such as clubfeet after early amniocentesis, can be detected through careful and thorough follow-up before new techniques are applied on larger scale. Because follow-up research is needed after introduction of new techniques and because prognosis of the future child is very important for the expectant parents, we conducted the following studies. Chapter one comprehends the introduction of the thesis with a brief history of prenatal medicine. The introduction of new intrauterine treatment options increased possibilities. Not only can we timely diagnose abnormalities that cannot be treated (eg Down syndrome) but we can also diagnose diseases timely and treat abnormalities. Abnormalities that otherwise would lead to intrauterine fetal death (eg hydrops fetalis). Even performing intrauterine procedures that will increase a better start in life and therefore better starting point for postnatal treatment (eg prune belly syndrome). The importance of follow-up at infancy is on the one hand for the evaluation of new techniques, and on the other hand to inform parents adequately in case the fetus has an abnormality. Information on prognosis is important in making difficult decisions on either terminating the pregnancy, start intrauterine treatment or expectant management. Chapter two describes the annual results from all centers for invasive prenatal diagnosis in the Netherlands over the period 1991-2000, with particular emphasis on indications, abnormal results, type of invasive procedures, and terminations of pregnancy. The percentage of invasive prenatal diagnosis increased from 5% of births in 1991 to 6% in 1996 and subsequently remained level. During the study period, the number of pregnant women aged 36 and older increased by 70%, but the number of procedures because of maternal age remained stable. The percentage abnormal test results was 4.7 and increased from 3.6 in 1991 to 5.4 in 2000. The detection rate for abnormal results varied from 2% for maternal age to 28% for abnormalities detected by ultrasound examination. Important trends were the relative decrease of cordocentesis (-82%) and chorionic villi biopsy (-18%) in favour of amniocentesis. There was a significant decrease in the percentage of pregnant women aged 36 or older who underwent invasive prenatal diagnosis without previous screening. Chapter three represents de results of a (semi) randomized controlled study that compared the effects of transabdominal chorionic villus sampling and early amniocentesis on fetal mortality and child morbidity. Women requesting early prenatal diagnosis for advanced maternal age were allocated to early amniocentesis or transabdominal chorionic villus sampling either by randomization or, if they declined randomization, by their own choice. Of the 212 women who entered the study, 117 were randomized, 70 chose early amniocentesis and 25 chose transabdominal chorionic villus sampling. Overall, 130 women underwent early amniocentesis and 74 underwent transabdominal chorionic villus sampling at a median gestation of 12 weeks. Mosaic karyotypes were found in 5.4% of the early amniocenteses and in none of the chorionic villus samples. All unintended fetal losses occurred after early amniocentesis with a frequency of 6.2%. Talipes equinovarus was only observed after early amniocentesis with a frequency of 3.1%. The results of this study are in the Cochrane Database. In the nineties the early amniocentesis was abandonded because of the results of 3 controlled studies, including our study, that showed an increased risk of miscarriages and higher incidence of clubfeet. The conclusion of this chapter is that chorionic villus sampling remains the method of choice if prenatal diagnosis is needed in the first trimester of pregnancy. In chapter four the outcome of pregnancies with prenatally diagnosed central nervous system (CNS) malformations are described. Maternal and neonatal records of prenatally diagnosed CNS malformations were retrospectively reviewed over a 6-year period (1993–1998). Information on current development of surviving children was obtained by contacting the care-giving pediatric neurologist. During the study period 124 fetuses were diagnosed with a CNS malformation. Data on pregnancy and delivery were available for 118 pregnancies. Additional malformations were present in 47% of fetuses. A total of 46% of pregnancies were terminated, and 15% ended in spontaneous intrauterine death. A total of 39% of pregnancies resulted in live birth, and 25% of the infants were still alive at the age of 3 months. One child was lost to follow-up, one infant died at the age of 4 months, and two children died at the age of 3 years. Psychomotor development of the remaining 25 children was normal for 5, slightly disabled for 7, moderately disabled for 5 and severely disabled for 8. The conclusion of this chapter is that due to the high rate of termination of pregnancy and to the frequent association with other anomalies, the survival rate of pregnancies in which a CNS defect had been diagnosed prenatally was only 25%. More than 50% of surviving children were moderately or severely disabled. Chapter five decribes the neurodevelopmental assessment in children born with an umbilical artery pH < 7 in the period 1991-1992. During the study period, 1614 umbilical artery pH measurements were performed. Thirty (1.9%) were < 7. Of all infants born with an umbilical artery pH < 7 obstetric, neonatal, and pediatric records were reviewed. From this group 23 infants were admitted to the neonatal intensive care unit, and 8 of them required intubation. Twenty-eight children survived the neonatal period. At an age of 1 to 3 years, children were visited at home for semi-structured questioning of the mother and a Denver Developmental Screening Test of the child.Three children experienced an episode of mild hypertonia. One child had a mild motor developmental delay. The conclusion of this study is that babies born with an umbilical artery pH < 7 are at great risk to experience considerable short-term morbidity. Those who leave the neonatal intensive care unit without major problems have good outcomes, and pessimism in counselling their parents is unwarranted. Chapter six describes the long-term neurodevelopmental outcome in 33 children after twin-to-twin transfusion syndrome (TTTS). Maternal and neonatal medical records of all TTTS-cases admitted to our center between 1990 and 1998 were reviewed. Neurological and mental development at school age was assessed during a home visit in all TTTS-survivors. A total of 33 pregnancies with TTTS were identified. Four couples opted for termination of pregnancy. All other pregnancies were managed conservatively, 18 (62%) with serial amnioreductions and 11 (38%) without intrauterine interventions. Mean gestational age at delivery was 28 (range: 20-37) weeks. Perinatal mortality was 50% (29/58). Birth weight of donor twins was less than recipient twins. Systolic blood pressure at birth was lower in donors than in recipients and donors required more frequently inotropic support postnatally than recipients. The incidence of hypertension at birth was higher in recipients than in donors. Abnormal cranial ultrasonographic findings were reported in 41% (12/29) of the neonates. All long-term survivors (n = 29) were assessed during a home visit. Mean gestational age at birth of the surviving twins was 31 (range: 25-37) weeks. Mean age at follow-up was 6 (range: 4-11) years. The incidence of cerebral palsy was 21% (6/29). Five out of six children with cerebral palsy had an abnormal mental development. The incidence of cerebral palsy in the group of survivors treated with serial amnioreduction was 26% (5/19). Four children were born after intrauterine fetal death of their co-twin: two of them had cerebral palsy. The conclusion therefore is: the incidence of adverse neurodevelopmental outcome in TTTS-survivors is high, especially after intrauterine fetal death of a co-twin. In chapter seven the long-term neurodevelopmental status of children treated with intrauterine red blood cell and platelet transfusion (IUT) for fetal hydrops caused by parvovirus B19 infection is described. Maternal and neonatal records of all intrauterine transfusions for congenital parvovirus B19 infection in our center between 1997 - 2005 were reviewed. A total of 25 IUT sessions were performed in 24 hydropic fetuses. Sixteen survivors aged 6 months to 8 years were included in the follow-up study. All children underwent a general pediatric, a neurological examination and a neurodevelopment examination (developmental index by Bayley Scales of Infant Development or Snijders-Oomen test). Eleven children (68%) were normal and 5 children (32%) demonstrated a delayed psychomotor development with a suboptimal neurological examination (mild delay n=3, severe delay n=2). Neurodevelopmental status did not correlate with pre-IUT hemoglobin, platelet, or blood pH values. Growth and general health status were normal in all. Two children had minor congenital defects. Neurodevelopmental status was abnormal in 5 out of 16 survivors and was not related with the severity of fetal anemia and acidemia. We hypothesize that fetal parvovirus B19 infection may induce central nervous system damage. Chapter eight describes the results of a retrospective cohort study of children with fetal arrhythmia. In the Leiden University Medical Center, 44 fetuses were diagnosed with fetal cardiac arrhythmia between January 1990 and December 2005. Twenty-eight with supravenricular tachycardia (SVT), 7 with atrial flutter (AF) and 9 with atrioventricular block (AVB). The incidence of cardiac anomalies was 18%. Hydrops was seen in 42-50%. Direct or transplacental fetal antiarrhythmic medication was given in 76% of cases. In the SVT group, 19 children needed medication postpartum. In 16/19 infants, the arrhythmia ceased within the first year of life. In the SVT and AF group mortality was 6%. In 21% of these cases Wolff Parkinson White (WPW) syndrome was diagnosed. Mental scores were normal in all survivors. Of the seven cases of AVB included in the follow-up there is no survivor. The other two cases were lost for long-term follow-up, but their medical records noted pacemaker therapy in one and severe mental retardation in the other. In conclusion, mortality in SVT and AF patients in our study was 6% but mental scores were normal in all survivors. Twenty-one per cent of survivors had WPW syndrome. Prognosis in AVB patients was poor. Chapter nine comprehends the general discussion. We look into the demands of follow-up after prenatal diagnosis and therapy. How does loss to follow-up influence outcome? What is the best age to test for follow-up? Which test to use. After prenatal therapy, follow-up should always be performed as a standard procedure. Follow-up needs to comprehend the review of the medical records, specific testing and standard neurologic and developmental tests. An example of a good test, and age of testing is to perform a Bayley Scale of Infant Development test at the age of 2 with neurologic testing (e.g. Touwen). At the age of 5-6 years a further examination can be performed. Follow-up at a later age looks less sensible because postnatal factors influence outcome and prenatal techniques are developing continuously. Show less
