Inflammatory Bowel Disease and Risk of Birth Defects in Offspring.

BACKGROUND AND AIMS: The relationship between inflammatory bowel disease in pregnancy and birth defects is not understood. We evaluated whether Crohn's disease and ulcerative colitis in pregnant women were associated with the risk of birth defects in the offspring. METHODS: We undertook a retrospective cohort study of 2 184 888 pregnancies in Quebec, Canada, between 1989 and 2016. We calculated risk ratios [RR] and 95% confidence intervals [CI] for the association between inflammatory bowel disease and the risk of birth defects, using generalised estimating equations adjusted for maternal characteristics. We assessed associations in the period before 2000, when immunosuppressive biologic therapy and folic acid food fortification were not yet available, compared with the period after 2000 when these interventions were more widespread. RESULTS: This study included 13 099 women with Crohn's disease and 7798 with ulcerative colitis. Crohn's disease was associated with 1.90 times [95% CI 1.10-3.28] the risk of abdominal wall defects [gastroschisis, omphalocoele, and diaphragmatic hernia] and ulcerative colitis was associated with 1.53 times [95% CI 1.02-2.30] the risk of central nervous system defects. The association of Crohn's disease with abdominal wall defects was stronger before 2000 [RR 3.62, 95% CI 1.71-7.67] than after 2000 [RR 1.23, 95% CI 0.55-2.75]. Ulcerative colitis was associated with central nervous system defects regardless of time period. CONCLUSIONS: These findings suggest that inflammatory bowel disease is associated with the risk of abdominal wall and central nervous system defects, and that introduction of immunobiologic medications is unlikely to be associated with added risk. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

WNT1-associated osteogenesis imperfecta with atrophic frontal lobes and arachnoid cysts.

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.

The use of ultrasonography to study teratogenicity in ruminants: evaluation of Ipomoea carnea in goats.

BACKGROUND: Ipomoea carnea (I. carnea) is a poisonous plant found in Brazil and other tropical countries that often poison livestock. The plant contains the alkaloids calystegines and mainly swainsonine, which inhibit cellular enzymes and cause systematic cell death. The objective of this study was to evaluate the perinatal effects of I. carnea in goats. METHODS: Forty-seven pregnant goats were randomly allocated into 5 treatment groups and given the following doses (g/kg BW) of I. carnea: 0 (IC0), 1.0 (IC1), 3.0 (IC3), 5.0 (IC5) and 7.5 (IC7). The treatment animals were given fresh I. carnea from day 27 of gestation to parturition. Weight gains and serum biochemistry were evaluated. Fetuses were evaluated using ultrasonographic measurements. RESULTS: Goats from the IC7 group showed clinical signs of poisoning. Ultrasound examination revealed that I. carnea feeding in all treatment groups reduced fetal movement compared to the controls. There was an increase in the total number of birth defects (retrognathia and arthrogyposis) in the IC7 and IC5 groups compared to the controls. CONCLUSION: The results show that I. carnea has teratogenic potential in goats. In addition, ultrasounds were useful in evaluating fetotoxicity and teratogenicity.

Surgical congenital central nervous system anomalies in a tropical teaching hospital.

BACKGROUND: Surgical congenital malformations of the central nervous system (CNS) are structural defects with potential for morbidity and mortality more so if intervention is delayed. AIM: To determine the frequency and pattern of surgical CNS anomalies in our region. METHODS: We carried out a hospital-based prospective observational study of all consecutive children who presented to our unit over a 2-year period. Brain computerised tomography and/or magnetic resonance imaging was performed on all patients suspected of having cranial CNS abnormalities. RESULTS: There were 94 children with surgical congenital anomalies of the CNS during the study period, with a male to female ratio of 1:1.1. There was no parental consanguinity in all the cases neither were there any history of preconception use of folic acid in all the mothers of the patients. Prenatal ultrasound was done after the first trimester in 91 cases (97%), but anomaly was noted in only 23 cases (25.3%). Eighty-six percent of the patients presented after the first month of life. Though there was a general delay in presentation, patients with neural tube defect tended to present much earlier compared to others (p = 0.005). Likewise, patients with spinal anomalies tend to be seen much earlier. CONCLUSIONS: Late presentation of CNS anomalies is still the norm in our region. The result makes a case for an aggressive approach to periconceptional folic acid supplementation for our women and policy to encourage fortification of a staple food with folic acid. A nationwide effort to fully clarify the epidemiology is needed so as to indicate where the community and governmental resources, including educational efforts should be directed.

Frequencies of congenital anomalies among newborns admitted in nursery of Ayub Teaching Hospital Abbottabad, Pakistan.

BACKGROUND: Congenital anomalies play a significant role in perinatal and neonatal morbidity and mortality. The frequency of these congenital anomalies varies in different populations. Objective of this study was to find out the frequencies of congenital anomalies admitted in nursery of Ayub Teaching Hospital, Abbottabad. METHODS: In this descriptive, cross-sectional study all patients admitted in NICU from October 2009 to January 2010 were included. The patients were examined for major and minor congenital anomalies. The observations were recorded in tabulated form. RESULTS: A total of 2,360 patients were admitted in NICU during the study period. One hundred patients were noted to have congenital anomalies. The most frequent anomalies involved the central nervous system (31%). Meningomyelocele was the commonest defect (71%, 22 out of 31 cases of CNS defects), among these males were more (77%, 17 out of 22 of meningomyelocele cases) than females (14 out of 31). These were followed by patients born with congenital heart defects (16%). Patients with urogenital anomalies (6%) were all male except for one who had ambiguous genitalia. CONCLUSIONS: Cases of meningomyelocele were the commonest presenting congenital anomaly. More stress should be laid on the role of peri-conceptional vitamin supplementation like folic acid for the primary prevention of congenital defects.

Ataxia with loss of Purkinje cells in a mouse model for Refsum disease.

Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal alpha-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigmentosa. To study the pathogenesis of Refsum disease, we generated and characterized a Phyh knockout mouse. We studied the pathological effects of phytanic acid accumulation in Phyh(-/-) mice fed a diet supplemented with phytol, the precursor of phytanic acid. Phytanic acid accumulation caused a reduction in body weight, hepatic steatosis, and testicular atrophy with loss of spermatogonia. Phenotype assessment using the SHIRPA protocol and subsequent automated gait analysis using the CatWalk system revealed unsteady gait with strongly reduced paw print area for both fore- and hindpaws and reduced base of support for the hindpaws. Histochemical analyses in the CNS showed astrocytosis and up-regulation of calcium-binding proteins. In addition, a loss of Purkinje cells in the cerebellum was observed. No demyelination was present in the CNS. Motor nerve conduction velocity measurements revealed a peripheral neuropathy. Our results show that, in the mouse, high phytanic acid levels cause a peripheral neuropathy and ataxia with loss of Purkinje cells. These findings provide important insights in the pathophysiology of Refsum disease.

The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons.

Phr1 is the single well-conserved murine ortholog of the invertebrate ubiquitin ligase genes highwire (in Drosophila) and rpm-1 (in Caenorhabditis elegans). The function and mechanism of action of highwire and rpm-1 are similar--both cell-autonomously regulate synaptogenesis by down-regulating the ortholog of the mitogen-activated protein kinase kinase kinase dual leucine zipper kinase (MAPKKK DLK). Here, using a targeted conditional mutant, we demonstrate that Phr1 also plays essential roles in mammalian neural development. As in invertebrates, Phr1 functions cell-autonomously to sculpt motor nerve terminals. In addition, Phr1 plays essential roles in the formation of major CNS axon tracts including those of the internal capsule, in part via cell-nonautonomous mechanisms, and these results reveal a choice point for cortical axons at the corticostriatal boundary. Furthermore, whereas the neurite morphology phenotypes of highwire and rpm-1 are suppressed by loss of DLK in flies and worms, Phr1-dependent CNS defects persist in Phr1, DLK double mutants. Thus, in the mammalian nervous system Phr1 is required for formation of major CNS axon tracts via a mechanism that is both cell-nonautonomous and independent of DLK.

Risk of recurrence in major central nervous system malformations between 1976 and 2005.

OBJECTIVE: The goal of the current publication is to review isolated central nervous system malformations (CSMs) using a database in excess of 75 000 cases, with special regard to the risk of recurrence of these malformations alone or in combination. METHODS: In the period between 1 January 1976 and 31 December 2005, among the 75 320 documented cases, consultations were requested due to earlier isolated CSMs in the patients' histories in 3030 cases (4.2%). Processing the data we only considered disorders of genetic origin, and that was why we excluded the cases due to intrauterine infection. Monogenically inherited malformations were also excluded from the analysis. The diagnosis of the malformations was based on the prenatal diagnosis of ultrasonography as well as the findings of the foetopathological examination. RESULTS: In 65% of the cases, the couples sought counselling because of malformation in a previous pregnancy. In these cases, the risk of recurrence was thought to be 5.2%, while in the case of two affected children this figure stood at 21.9%. Analysing the values for the risk of recurrence in 5-year periods, neural tube defects (NTDs) (particularly anencephaly and spina bifida) showed a detectable decrease, which could be attributed to a growing use of folic acid supplementation around the time of conception and during pregnancy. CONCLUSION: There is a clear decrease of risk of recurrence of NTDs, while in the case of the other CSMs in this study, there is no noteworthy chronological change in their risk of recurrence.

The folate metabolic enzyme ALDH1L1 is restricted to the midline of the early CNS, suggesting a role in human neural tube defects.

Folate supplementation prevents up to 70% of human neural tube defects (NTDs), although the precise cellular and metabolic sites of action remain undefined. One possibility is that folate modulates the function of metabolic enzymes expressed in cellular populations involved in neural tube closure. Here we show that the folate metabolic enzyme ALDH1L1 is cell-specifically expressed in PAX3-negative radial glia at the midline of the neural tube during early murine embryogenesis. Midline restriction is not a general property of this branch of folate metabolism, as MTHFD1 displays broad and apparently ubiquitous expression throughout the neural tube. Consistent with previous work showing antiproliferative effects in vitro, ALDH1L1 upregulation during central nervous system (CNS) development correlates with reduced proliferation and most midline ALDH1L1(+) cells are quiescent. These data provide the first evidence for localized differences in folate metabolism within the early neural tube and suggest that folate might modulate proliferation via effects on midline Aldh1l1(+) cells. To begin addressing its role in neurulation, we analyzed a microdeletion mouse strain lacking Aldh1l1 and observed neither increased failure of neural tube closure nor detectable proliferation defects. Although these results indicate that loss-of-function Aldh1l1 mutations do not impair these processes in mice, the specific midline expression of ALDH1L1 and its ability to dominantly suppress proliferation in a folate responsive manner may suggest that mutations contributing to disease are gain-of-function, rather than loss-of-function. Moreover, a role for loss-of-function mutations in human NTDs remains possible, as Mthfr null mice do not develop NTDs even though MTHFR mutations increase human NTD risk.

Neural tube defects and folate: case far from closed.

Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents approximately 50-75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.

Anophthalmia, cleft lip/palate, facial anomalies, and CNS anomalies and hypothalamic disorder in a newborn: a midline developmental field defect.

We describe an infant with a unique pattern of midline defects, including anophthalmia, cleft lip and palate, macrocephaly, cutis aplasia, and micrognathia. CNS anomalies including massive hydrocephalus with destruction of most recognizable structures were observed. The infant also developed panhypopituitarism, diabetes insipidus, and a seizure disorder. We postulate that this patient could represent a more complex form of the Delleman syndrome or a new morphogenetic syndrome secondary to ventral induction with extension to the developmental fields of the first and second branchial arches.

[Cytological examination of the amniotic fluid in normal pregnancy and in cases of fetal central nervous system abnormalities]. / Badania cytologiczne plynu owodniowego w ciazy fizjologicznej oraz w przypadkach wad centralnego ukladu nerwowego u plodu.

Cytological and biochemical investigations were carried out on 60 samples of amniotic fluid obtained from 30 pregnant women with risk for development of fetal central nervous abnormality (FCNA) and 30 pregnant women in whom prenatal diagnosis was indicated for other reasons (control group). Cytological evaluation was done in an interference-polarization Nomarski microscope evaluating the cells in direct preparation and after staining with neutral red. Parallelly with cytological evaluation alpha-1-fetoprotein (AFP) and acetylcholinesterase (AChE) were determined in amniotic fluid. In three cases with open neural tube anomaly characteristic cells with strongly puckered and vacuolized cytoplasmic membranes were found. In these cases the levels of AFP and AChE exceeded the normal range. In two cases of closed abnormalities of the central nervous system diagnosed by ultrasonography no abnormalities were note by cytological and biochemical methods. The study confirmed the usefulness of the cytological examination of amniotic fluid, as a method supplementing biochemical and ultrasonographic investigations as part of prenatal diagnosis.

[Results of comprehensive care of infants with congenital and acquired defects of the central nervous system]. / Výsledky komplexní péce o kojence s vrozenými a získanými poskozeními centrálního nervového systému.

The paper is the result of five years paediatric, neurological and neurosurgical care of 102 infants with inborn and acquired damage of the central nervous system. Early diagnosis, a suitably indicated neurosurgical operation, comprehensive paediatric and neurosurgical care ensure along with rehabilitation and psychic stimulation, optimum therapeutic results. So far only few reports on results of long-term studies of thus treated child patients were published. The paper is an example of interdisciplinary cooperation.

Sauna and congenital defects.

To test a recent hypothesis on the causal relationship between sauna-induced hyperthermia and congenital defects, 100 consecutive cases of defects of the central nervous system and 202 cases of orofacial clefts were singled out from the Finnish Registry of Malformations. The mothers and their time-area-matched referents were interviewed for their sauna habits. Almost every pregnant mother (98.5%) had visited the sauna regularly, and yet, the incidence of the CNS defects in Finland is among the lowest ever reported. No differences in the sauna habits were observed between the case and referent mothers. It is concluded that the relatively mild, temporal hyperthermia caused by the sauna should not be considered hazardous for the developing embryo.