Long-term neurodevelopmental outcome after intrauterine transfusion for hemolytic disease of the fetus/newborn: the LOTUS study

ObjectiveTo determine the incidence and risk factors for neurodevelopmental impairment (NDI) in children with hemolytic disease of the fetus/newborn treated with intrauterine transfusion (IUT).Study DesignNeurodevelopmental outcome in children at least 2 years of age was assessed using standardized tests, including the Bayley Scales of Infant Development, the Wechsler Preschool and Primary Scale of Intelligence, and the Wechsler Intelligence Scale for Children, according to the children's age. Primary outcome was the incidence of neurodevelopmental impairment defined as at least one of the following: cerebral palsy, severe developmental delay, bilateral deafness, and/or blindness.ResultsA total of 291 children were evaluated at a median age of 8.2 years (range, 2–17 years). Cerebral palsy was detected in 6 (2.1%) children, severe developmental delay in 9 (3.1%) children, and bilateral deafness in 3 (1.0%) children. The overall incidence of neurodevelopmental impairment was 4.8% (14/291). In a multivariate regression analysis including only preoperative risk factors, severe hydrops was independently associated with neurodevelopmental impairment (odds ratio, 11.2; 95% confidence interval, 1.7–92.7).ConclusionIncidence of neurodevelopmental impairment in children treated with intrauterine transfusion for fetal alloimmune anemia is low (4.8%). Prevention of fetal hydrops, the strongest preoperative predictor for impaired neurodevelopment, by timely detection, referral and treatment may improve long-term outcome

Long-Term follow up after intra-Uterine transfusionS; the LOTUS study

<p>Abstract</p> <p>Background</p> <p>The Leiden University Medical Center (LUMC) is the Dutch national referral centre for pregnancies complicated by haemolytic disease of the fetus and newborn (HDFN) caused by maternal alloimmunization. Yearly, 20-25 affected fetuses with severe anaemia are transfused with intra-uterine blood transfusions (IUT). Mothers of whom their fetus has undergone IUT for HDFN are considered high responders with regard to red blood cell (RBC) antibody formation. Most study groups report high perinatal survival, resulting in a shift in attention towards short- and long-term outcome in surviving children.</p> <p>Methods/Design</p> <p>We set up a large long-term observational follow-up study (LOTUS study), in cooperation with the Sanquin Blood Supply Foundation and the LUMC departments of Obstetrics, Neonatology and ImmunoHematology & Bloodtransfusion.</p> <p>The first part of this study addresses several putative mechanisms associated with blood group alloimmunization in these mothers. The second part of this study determines the incidence of long-term neurodevelopment impairment (NDI) and associated risk factors in children treated with IUT. All women and their life offspring who have been treated with IUT for HDFN in the LUMC from 1987-2008 are invited to participate and after consent, blood or saliva samples are taken. RBC and HLA antigen profile and antibodies are determined by serologic or molecular techniques. Microchimerism populations are tested by real time polymerase chain reaction (RT PCR).</p> <p>All children are tested for their neurological, cognitive and psychosocial development using standardised tests and questionnaires. The primary outcome is neurodevelopmental impairment (NDI), a composite outcome defined as any of the following: cerebral palsy, cognitive or psychomotor development < 2 standard deviation, bilateral blindness and/or bilateral deafness.</p> <p>Discussion</p> <p>The LOTUS study includes the largest cohort of IUT patients ever studied and is the first to investigate post-IUT long-term effects in both mother and child. The results may lead to a change in transfusion policy, in particular future avoidance of certain incompatibilities. Additionally the LOTUS study will provide clinicians and parents better insights in the long-term neurodevelopmental outcome in children with HDFN treated with IUTs, and may improve the quality of antenatal counselling and long-term guidance.</p

Maternal and infant outcomes associated with lithium use in pregnancy

Background Concerns about teratogenicity and offspring complications limit use of lithium in pregnancy. We aimed to investigate the association between in-utero lithium exposure and risk of pregnancy complications, delivery outcomes, neonatal morbidity and congenital malformations. Methods Meta-analysis of primary data analyzed using a shared protocol. Six study sites participated: Denmark, Canada, Netherlands, Sweden, UK, and US, totaling 727 lithium-exposed pregnancies compared to 21,397 reference pregnancies in mothers with a mood disorder, but unexposed to lithium. Main outcome measures included: (1) pregnancy complications, (2) delivery outcomes, (3) neonatal readmission to hospital within 28 days of birth, and (4) congenital malformations (major malformations and cardiac malformations). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were generated using logistic regression models. Site-specific prevalence rates and ORs were pooled using random-effects meta-analytic models. Findings Lithium exposure was not associated with any of the pre-defined pregnancy complications or delivery outcomes. There was an increased risk for neonatal readmission in lithium exposed (27·5%) versus reference group (14·3%) (Pooled aOR1·62; 95% CI: 1·12–2·33). Lithium exposure during first trimester was associated with increased risk of major malformations (7·4% versus 4·3%; pooled aOR 1·71, 95% CI: 1·07–2·72). Similarly, more lithium exposed children had major cardiac malformations, albeit not stasticially significant (2·1% versus 1·6%; pooled aOR 1·54, 95% CI: 0·64–3·70). Limitations in our study include: Serum lithium 5 levels were not available, hence no analyses related to dose-response effects could be performed, and residual confounding from e.g. substance abuse cannot be ruled out. Interpretation Treatment decisions must weigh the potential for increased risks, considering both effct sizes and the precision of the estimates, in particular associated with first-trimester lithium use against its effectiveness at reducing relapse

Lithium exposure during pregnancy increases fetal growth

Background: Lithium is an effective treatment in pregnancy and postpartum for the prevention of relapse in bipolar disorder, but there is a lack of knowledge about the potential adverse impact on fetal development. Aims: To investigate the impact of lithium exposure on early fetal growth. Methods: In this retrospective observational cohort study, we included all singleton pregnancies of women using lithium and referred for advanced fetal ultrasound scanning between 1994 and 2018 to the University Medical Centers in Leiden and Rotterdam, the Netherlands (n=119). The Generation R study, a population-based cohort, served as a non-exposed control population from the same geographic region (n=8184). Fetal head circumference, abdominal circumference, femur length, and transcerebellar diameter were measured by ultrasound at 18–22 weeks of gestation. Results: Lithium use during pregnancy was associated with an average increase in head circumference of 1.77 mm (95% confidence interval: 0.53, 3.01), in abdominal circumference of 5.54 mm (95% confidence interval: 3.95, 7.12) and in femur length of 0.59 mm (95% confidence interval: 0.22, 0.96) at 18–22 weeks gestation. Furthermore, lithium use during pregnancy was associated with an average increase in birth weight of 142.43 grams (95% confidence interval: 58.01, 226.89), whereas it was associated with an average decrease of 1.41 weeks in gestational duration (95% confidence interval: −1.78, −1.05). Conclusions: Lithium use during pregnancy was associated with increased fetal growth parameters at 18–22 weeks gestational age and increased birth weight. Furthe

Dose response relationship between lithium serum levels during pregnancy and birth outcomes

Introduction: Lithium use during pregnancy reduces the risk of mood episodes in the perinatal period for women with bipolar disorder. Some previous studies found deleterious effects of intrauterine lithium exposure on birth outcomes, yet little is known about a dose response relationship. The current study investigated the influence of maternal lithium serum levels on birth outcomes. Methods: This retrospective observational cohort study included women with a bipolar spectrum disorder who were referred to a specialized psychiatric and obstetric outpatient clinic from 2003 to 2019 and used lithium during the entire pregnancy. For 101 pregnancies at least one lithium level during pregnancy was available. A weighted average lithium level was calculated for the entire pregnancy, as well as for each trimester. Detailed information on maternal, obstetric and neonatal outcomes were retrieved from the medical records. Linear and logistic regression models were used to investigate the association between weighted average lithium level and pregnancy duration, birth weight percentiles, preterm birth and large for gestational age births (LGA). In subsequent exploratory analyses, we studied the role of thyroid-stimulating hormone (TSH) and thyroxine (T4) as a mediator in the found associations. Results: The weighted average lithium serum level during pregnancy was negatively associated with pregnancy duration and positively with preterm birth, but not with birth weight percentile or LGA. In exploratory analyses, TSH and T4 did not mediate the association between average lithium serum level and pregnancy duration. Conclusion: The results of this cohort study during pregnancy indicate a dose response relationship between maternal lithium serum levels and pregnancy duration.</p

Successful treatment of fetal hemolytic disease due to glucose phosphate isomerase deficiency (GPI) using repeated intrauterine transfusions : a case report

Hemolytic anemia due to GPI deficiency can be severe and life threatening during fetal life. When parents decline invasive testing, ultrasound monitoring of fetuses at risk is feasible. Intrauterine transfusion can be effective for the treatment of severe fetal anemia due to GPI deficiency

Brain development after intrauterine exposure to lithium: A magnetic resonance imaging study in school-age children

Objective: Lithium is often continued during pregnancy to reduce the risk of perinatal mood episodes for women with bipolar disorder. However, little is known about the effect of intrauterine lithium exposure on brain development. The aim of this study was to investigate brain structure in children after intrauterine exposure to lithium. Methods: Participants were offspring, aged 8–14 years, of women with a diagnosis of bipolar spectrum disorder. In total, 63 children participated in the study: 30 with and 33 without intrauterine exposure to lithium. Global brain volume outcomes and white matter integrity were assessed using structural MRI and diffusion tensor imaging, respectively. Primary outcomes were total brain, cortical and subcortical gray matter, cortical white matter, lateral ventricles, cerebellum, hippocampus and amygdala volumes, cortical thickness, cortical surface area and global fractional anisotropy, and mean diffusivity. To assess how our data compared to the general population, global brain volumes were compared to data from the Generation R study (N = 3243). Results: In our primary analyses, we found no statistically significant associations between intrauterine exposure to lithium and structural brain measures. There was a non-significant trend toward reduced subcortical gray matter volume. Compared to the general population, lithium-exposed children showed reduced subcortical gray and cortical white matter volumes. Conclusion: We found no differences in brain structure between lithium-exposed and non-lithium-exposed children aged 8–14 years following correction for multiple testing. While a rare population to study, future and likely multi-site studies with larger datasets are required to validate and extend these initial findings

Neurodevelopment in school-aged children after intrauterine exposure to antipsychotics

Objective: Antipsychotics are increasingly prescribed in pregnancy, yet little is known about potential long-term developmental effects on children. In this study, we investigated the effect of prenatal antipsychotic exposure on neurodevelopmental functioning in school-aged children. Methods: We performed a cross-sectional neurodevelopmental assessment of 91 children aged 6–14 years whose mothers had severe mental illness and were either exposed or unexposed to antipsychotic medication during pregnancy. Neurodevelopmental outcomes were assessed using validated neurodevelopmental assessment instruments to examine the child's IQ and global cognitive functioning, and the presence of any psychiatric disorders and/or learning problems in the child was assessed by parental report. Results: No statistically significant associations were found between antipsychotic exposure during pregnancy and either adverse neurodevelopmental outcomes (IQ, neuropsychological function), likelihood of psychiatric diagnosis, or learning problems based on parental report. Analyses were likely limited in power to detect subtler differences in neurodevelopmental functioning because of small sample size and heterogeneity of the sample. Conclusions: In this exploratory cohort study, intrauterine exposure to antipsychotics was not associated with any adverse effect on IQ or neurodevelopmental functioning in a cohort of school-aged children (6–14 years)

Brain development after intrauterine exposure to lithium: A magnetic resonance imaging study in school-age children

Objective: Lithium is often continued during pregnancy to reduce the risk of perinatal mood episodes for women with bipolar disorder. However, little is known about the effect of intrauterine lithium exposure on brain development. The aim of this study was to investigate brain structure in children after intrauterine exposure to lithium. Methods: Participants were offspring, aged 8?14 years, of women with a diagnosis of bipolar spectrum disorder. In total, 63 children participated in the study: 30 with and 33 without intrauterine exposure to lithium. Global brain volume outcomes and white matter integrity were assessed using structural MRI and diffusion tensor imaging, respectively. Primary outcomes were total brain, cortical and subcortical gray matter, cortical white matter, lateral ventricles, cerebellum, hippocampus and amygdala volumes, cortical thickness, cortical surface area and global fractional anisotropy, and mean diffusivity. To assess how our data compared to the general population, global brain volumes were compared to data from the Generation R study (N?=?3243). Results: In our primary analyses, we found no statistically significant associations between intrauterine exposure to lithium and structural brain measures. There was a non-significant trend toward reduced subcortical gray matter volume. Compared to the general population, lithium-exposed children showed reduced subcortical gray and cortical white matter volumes. Conclusion: We found no differences in brain structure between lithium-exposed and non-lithium-exposed children aged 8?14 years following correction for multiple testing. While a rare population to study, future and likely multi-site studies with larger datasets are required to validate and extend these initial findings