Neonatal Polycythemia and Hyperviscosity

Is maternal polycystic ovary syndrome (PCOS) associated with increased risks for a broad spectrum of psychiatric and mild neurodevelopmental disorders in offspring? Maternal PCOS and/or anovulatory infertility is independently, and jointly with maternal obesity, perinatal problems, cesarean delivery and gestational diabetes, associated with increased risks in offspring for almost all groups of psychiatric and mild neurodevelopmental disorders with onset in childhood or adolescence. Maternal PCOS was previously associated with autism spectrum disorder, attention-deficit/hyperactivity disorders and possibly developmental delay in offspring. Few studies have investigated the association between maternal PCOS and other psychiatric and neurodevelopmental disorders in offspring. This was a population-based cohort study in Finland including all live births between 1996 and 2014 (n = 1 105 997). After excluding births to mothers with symptoms similar to PCOS, a total of 1 097 753 births by 590 939 mothers remained. Children were followed up until 31 December 2018, i.e. up to the age of 22 years. National registries were used to link data of the included births and their mothers. Data from 24 682 (2.2%) children born to mothers with PCOS were compared with 1 073 071 (97.8%) children born to mothers without PCOS. Cox proportional hazards modeling was used to evaluate the hazard ratio (HR) and 95% CI for the risk of neuropsychiatric disorders in relation to maternal PCOS. Stratified analyses were performed to test the independent role of PCOS and the joint effects of PCOS with maternal obesity, perinatal problems, cesarean delivery, gestational diabetes and use of fertility treatment. The analysis was adjusted for maternal age, country of birth, marriage status at birth, smoking, parity, psychiatric disorders, prescription of psychotropic N05/N06 during pregnancy and systemic inflammatory diseases when applicable. A total of 105 409 (9.8%) children were diagnosed with a neurodevelopmental or psychiatric disorder. Firstly, maternal PCOS was associated with any psychiatric diagnosis (HR 1.32; 95% CI 1.27-1.38) in offspring. Particularly, the risk was increased for sleeping disorders (HR 1.46; 95% CI 1.27-1.67), attention-deficit/hyperactivity disorders and conduct disorders (HR 1.42; 95% CI 1.33-1.52), tic disorders (HR 1.42; 95% CI 1.21-1.68), intellectual disabilities (HR 1.41; 95% CI 1.24-1.60), autism spectrum disorder(HR 1.40; 95% CI 1.26-1.57), specific developmental disorders (HR 1.37; 95% CI 1.30-1.43), eating disorders (HR 1.36; 95% CI 1.15-1.61), anxiety disorders (HR 1.33; 95% CI 1.26-1.41), mood disorders (HR 1.27; 95% CI 1.18-1.35) and other behavioral and emotional disorders (ICD-10 F98, HR 1.49; 95% CI 1.39-1.59). In short, there was no significant difference between sexes. The results were robust when restricting the analyses to the first-born children or births to mothers without psychiatric diagnosis or purchase of psychotropic medication. Secondly, stratified analysis according to maternal BMI showed that the risk of any neuropsychiatric disorder was increased in offspring to normal-weight mothers with PCOS (HR 1.20; 95% CI 1.09-1.32), and markedly higher in those to severely obese mothers with PCOS (HR 2.11; 95% CI 1.76-2.53) compared to offspring to normal-weight mothers without PCOS. When excluding perinatal problems, mothers with PCOS were still associated with increased risks of any neuropsychiatric disorders in offspring (HR 1.28; 95% CI 1.22-1.34) compared to mothers without PCOS. However, an additional increase was observed for PCOS in combination with perinatal problems (HR 1.99; 95% CI 1.84-2.16). Likewise, excluding cases with maternal gestational diabetes (HR 1.30; 95% CI 1.25-1.36), cesarean delivery (HR 1.29; 95% CI 1.23-1.35) or fertility treatment (HR 1.31; 95% CI 1.25-1.36) did not eliminate the associations. The register-based prevalence of PCOS was lower than previously reported, suggesting that this study may capture the most severe cases. To combine anovulatory infertility with PCOS diagnosis as PCOS exposure might introduce diagnostic bias. It was not feasible to distinguish between subtypes of PCOS. Furthermore, familial factors might confound the association between maternal PCOS and neuropsychiatric disorders in offspring. Maternal BMI was available for birth cohort 2004-2014 only and there was no information on gestational weight gain. This study provides further evidence that maternal PCOS and/or anovulatory infertility, independently and jointly with maternal obesity, perinatal problems, gestational diabetes and cesarean delivery, implies a broad range of adverse effects on offspring neurodevelopment. These findings may potentially help in counseling and managing pregnancies. This study was supported by the joint research funding of Shandong University and Karolinska Institute (SDU-KI-2019-08 to X.C and C.L.), THL Finnish Institute for Health and Welfare: Drug and pregnancy project [M.G.], the Swedish Research Council [2014-10171 to C.L.], the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council [SLL20170292 to C.L.], the Swedish Brain Foundation [FO2018-0141 and FO2019-0201 to C.L.]. X.C. was supported by the China Scholarship Council during her training in Karolinska Institute. L.K. was supported by the China Scholarship Council for his PhD study in Karolinska Institute. The authors have no competing interests to disclose. N/A.

Newborn Respiratory Disorders

Long-term risk of psychiatric disorders in childhood and adolescence following neonatal invasive group B Streptococcus disease-A Danish cohort study.

The conventional therapeutic approach in polycythemic newborn infants is to apply partial exchange transfusion (PET) when hematocrit value exceeds 70% or when the infant develops symptoms with the exception of plethora. In order to investigate the possibility of using platelet count as a simple criterion implying the PET requirement, we retrospectively reviewed polycythemic newborn infants with respect to the relationship between thrombocytopenia and severity of symptoms, and the association of platelet count and the PET performance. Thrombocytopenia has been defined as a platelet count < 150,000/microL. We studied 18 polycythemic infants with thrombocytopenia (group 1, 35%) and 34 without it (group 2, 65%). Perinatal asphyxia, gestational toxemia and intrauterine growth retardation, which are the three common causative factors leading to polycythemia, were not significantly different in the two groups. No correlation existed between platelet counts and hematocrit values within each group, but there was a very significant difference between the two groups in terms of severity of clinical findings (P < 0001); no difference in terms of moderate findings and moderately significant difference with respect to mild symptoms and asymptomatic situation (P < 0.05). Partial exchange transfusion was performed in all patients in group 1, while only 12 infants in group 2 (32%) received transfusion and the difference was statistically significant (P < 0.05). A significant rise in platelet counts has been achieved only in group 1, while hematocrit values decreased significantly in both groups following PET. This study emphasizes the relationship between thrombocytopenia and the severity of clinical findings and PET performance rate in polycythaemic newborn infants, implying that thrombocytopenia is a possible marker of hyperviscosity, the results of which warrant further investigation.

Cerebral blood flow velocity in infants with polycythemia and hyperviscosity: Effects of partial exchange transfusion with Plasmanate

Autoimmune Liver Disease in Three Children with Sickle Cell Disease

Evidence on the beneficial effects of microorganisms in human milk is emerging. Obesity and gestational diabetes mellitus appear to be related to alterations in the maternal gut microbiota and human milk composition. However, knowledge about the influence of maternal obesity and gestational diabetes mellitus on the human milk microbiota remains limited. To summarize and systematically assess the evidence on the influence of obesity and gestational diabetes mellitus on the diversity and/or composition of the human milk microbiota. A systematic review following PRISMA guidelines was conducted. Searches were performed in the MEDLINE, Cochrane Database of Systematic Reviews, Web of Science, and EMBASE, as well as in ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. The ROBINS-E tool was used to assess the risk of bias. Out of 1,473 studies identified and 24 protocol records, eight studies were selected for final analysis. Exposure to gestational diabetes mellitus and maternal obesity were associated with changes in the human milk microbiota's diversity and/or composition. Lactating women exposed to obesity had a higher prevalence of Staphylococcus and a lower prevalence of Bifidobacterium in their milk. Those exposed to gestational diabetes mellitus had a higher prevalence of Staphylococcus, Gemella, and Prevotella. Findings regarding bacterial phyla prevalence were inconclusive. Based on the findings presented in this systematic review, it is not yet possible to draw definitive conclusions regarding the true influence of maternal obesity and/or gestational diabetes mellitus on the diversity or composition of the human milk microbiota.

Maternal diabetes during pregnancy has been associated with long-term health outcomes in offspring, but studies on specific neuropsychiatric outcomes remain limited. We aimed to evaluate the association between maternal diabetes and neuropsychiatric disorders. This binational cohort study included 2 722 687 mother-child pairs from South Korea and 181 134 mother-child pairs from Japan, from 2010 to 2017, followed until December 31, 2023. Maternal diabetes was categorized as pregestational or gestational using ICD-10 codes. Offspring outcomes included severe neuropsychiatric disorder, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models in a stabilized inverse probability of treatment weighted cohort and sibling-comparison cohort. Sibling-comparison analyses were conducted and validated in an independent Japanese cohort. Among 2 722 687 mother-child pairs (mean follow-up, 10.3 years) in the full cohort, 783 265 offspring (26.7%) were exposed to maternal diabetes (756 193 gestational; 20 815 pregestational). Pregestational diabetes was associated with increased risks of any neuropsychiatric disorder (aHR, 1.29 [95% CI, 1.22-1.36]), severe neuropsychiatric disorder (1.33 [1.16-1.53]), ADHD (1.24 [1.16-1.31]), ASD (1.39 [1.25-1.55]), and intellectual disability (1.57 [1.40-1.77]). Associations remained consistent across maternal and perinatal subgroups. Gestational diabetes showed only modest associations (aHR, 1.05 [95% CI, 1.00-1.08]) and was nonsignificant in sibling analyses in both Korea (1.01 [0.98-1.05]) and Japan (0.90 [0.76-1.06]). Pregestational diabetes was associated with increased neuropsychiatric risk in offspring, whereas gestational diabetes showed no meaningful association in sibling analyses, and adequate management before and during pregnancy remains important.

Born Large for Gestational Age: Bigger Is Not Always Better

Nearly 2% of all pregnancies nowadays are complicated by maternal pregestational or gestational diabetes. Long before diabetic fetopathy was acknowledged, macrosomia was dreaded by obstetricians because of the trauma risk and the need for mutilating operations. Diabetic fetopathy was described and maternal glucosuria quantified by Henrich Bennewitz in 1824. However, most authors ignored his findings and well into the 20th century, series of ‘giant babies’ were published without even mentioning diabetes mellitus. When insulin became available in 1923, maternal but not fetal mortality decreased. In 1952, Priscilla White classified six forms of maternal diabetes during pregnancy and reported an overall intrauterine, intrapartum, and neonatal death rate of 45%. But not all those infants died from macrosomia-associated traumatism and birth asphyxia: the main finding in the deceased infants was pulmonary hyaline membranes, demonstrated by Louis Gluck in 1973 to result from retarded surfactant maturation in diabetic fetuses.

Maternal obesity and gestational diabetes mellitus (GDM) are associated with insulin resistance and health risks for mother and offspring. Obesity is also characterized by low-grade inflammation, which in turn, impacts insulin sensitivity. The placenta secretes inflammatory cytokines and hormones that influence maternal glucose and insulin handling. However, little is known about the effect of maternal obesity, GDM and their interaction, on placental morphology, hormones and inflammatory cytokines. In a South African cohort of non-obese and obese pregnant women with and without GDM, this study examined placental morphology using stereology, placental hormone and cytokine expression using real-time PCR, western blotting and immunohistochemistry, and circulating TNFα and IL-6 concentrations using ELISA. Placental expression of endocrine and growth factor genes was not altered by obesity or GDM. However, LEPTIN gene expression was diminished, syncytiotrophoblast TNFα immunostaining elevated and stromal and fetal vessel IL-6 staining reduced in the placenta of obese women in a manner that was partly influenced by GDM status. Placental TNFα protein abundance and maternal circulating TNFα concentrations were reduced in GDM. Both maternal obesity and, to a lesser extent, GDM were accompanied by specific changes in placental morphometry. Maternal blood pressure and weight gain and infant ponderal index were also modified by obesity and/or GDM. Thus, obesity and GDM have specific impacts on placental morphology and endocrine and inflammatory states that may relate to pregnancy outcomes. These findings may contribute to developing placenta-targeted treatments that improve mother and offspring outcomes, which is particularly relevant given increasing rates of obesity and GDM worldwide. KEY POINTS: Rates of maternal obesity and gestational diabetes (GDM) are increasing worldwide, including in low-middle income countries (LMIC). Despite this, much of the work in the field is conducted in higher-income countries. In a well-characterised cohort of South African women, this study shows that obesity and GDM have specific impacts on placental structure, hormone production and inflammatory profile. Moreover, such placental changes were associated with pregnancy and neonatal outcomes in women who were obese and/or with GDM. The identification of specific changes in the placenta may help in the design of diagnostic and therapeutic approaches to improve pregnancy and neonatal outcomes with particular significant benefit in LMICs.

Continuous fetal monitoring during partial exchange transfusion in a patient with sickle cell disease crisis

IntroductionNeonatal hypoglycaemia is a common neonatal problem and there is active debate surrounding screening, associated factors and long term consequences. There is controversy surrounding the outcome of transient neonatal hypoglycaemia...

Context:Maternal obesity and gestational diabetes mellitus (GDM) can both contribute to adverse neonatal outcomes. The extent to which this may be mediated by differences in placental metabolism and nutrient transport remains to be determined.Objective:Our objective was to examine whether raised maternal body mass index (BMI) and/or GDM contributed to a resetting of the expression of genes within the placenta that are involved in energy sensing, oxidative stress, inflammation, and metabolic pathways.Methods:Pregnant women from Spain were recruited as part of the “Study of Maternal Nutrition and Genetics on the Foetal Adiposity Programming” survey at the first antenatal visit (12–20 weeks of gestation) and stratified according to prepregnancy BMI and the incidence of GDM. At delivery, placenta and cord blood were sampled and newborn anthropometry measured.Results:Obese women with GDM had higher estimated fetal weight at 34 gestational weeks and a greater risk of preterm deliveries and cesarean section. Birth weight was unaffected by BMI or GDM; however, women who were obese with normal glucose tolerance had increased placental weight and higher plasma glucose and leptin at term. Gene expression for markers of placental energy sensing and oxidative stress, were primarily affected by maternal obesity as mTOR was reduced, whereas SIRT-1 and UCP2 were both upregulated. In placenta from obese women with GDM, gene expression for AMPK was also reduced, whereas the downstream regulator of mTOR, p70S6KB1 was raised.Conclusions:Placental gene expression is sensitive to both maternal obesity and GDM which both impact on energy sensing and could modulate the effect of either raised maternal BMI or GDM on birth weight.

The aim of this study was to compare biomarkers of cardiac dysfunction in cord blood in women with uncomplicated pregnancies and pregnancies complicated by maternal pre-gestational and gestational diabetes and to correlate these findings with fetal echocardiography parameters of cardiac function. Fetal echocardiographic assessment was performed longitudinally on 78 fetuses in the normal cohort and 32 in the diabetic cohort by measuring tricuspid annular plane systolic excursion, mitral annular plane systolic excursion, myocardial performance index, interventricular septum (IVS) thickness and left fractional shortening between July 2015 and December 2017. Cord blood samples were obtained at birth and levels of troponin I (TnI), B-type natriuretic peptide (BNP) and the amnio terminal segment of its prohormone measured. Women with diabetes had significantly higher median body mass index and mean z-scores for BNP. Significant associations were observed between maternal diabetes and obesity and cord-blood BNP z-scores. The effect of diabetes on TnI levels were similar, with mean values higher in women with gestational diabetes compared to normal pregnancies; however, this difference did not reach statistical significance. These biomarker findings correlated with an increased IVS thickness in the diabetic group. No difference was demonstrated in the other cardiac function parameters measured. Biochemical markers of cardiac dysfunction are elevated in infants of diabetic and obese mothers and correlated with increased IVS thickness.