High lithium concentration at delivery is a potential risk factor for adverse outcomes in breastfed infants: a retrospective cohort study.

BACKGROUND: Neonatal effects of late intrauterine and early postpartum exposure to lithium through mother's own milk are scarcely studied. It is unclear whether described symptoms in breastfed neonates are caused by placental lithium transfer or postnatal exposure to lithium through breastfeeding. We aimed to investigate lithium clearance and neonatal morbidity in breastfed infants with high versus low serum lithium concentrations at birth. METHODS: This retrospective study focused on breastfed infants to women treated with lithium during and after pregnancy, born between 2006 and 2021 in Stockholm, Sweden. Information on serum lithium concentrations and adverse neonatal outcomes was obtained from medical records. Neonatal symptoms and lithium clearance were compared between a high exposure group (HEG, lithium concentrations ≥ 0.6 meq/l) and a low exposure group (LEG, < 0.6 meq/l). RESULTS: A total of 25 infant-mother dyads were included. Median lithium serum concentration at birth was 0.90 meq/l in the HEG as compared with 0.40 meq/l in the LEG (p < 0.05). The difference was still significant at follow-up (0.20 meq/l vs 0.06 meq/l, p < 0.05), despite reduction in maternal dose. The rate of neonatal symptoms was 85.7% in HEG and 41.2% in LEG (p = 0.08) at birth and 28.6% vs 11.8% at follow-up (p = 0.55). Furthermore, 28.6% of infants in HEG were admitted to neonatal care, vs 5.9% in LEG (p = 0.19). Two infants in the HEG had therapeutic lithium levels at follow-up. All infants with symptoms at follow-up were either in the HEG or exposed to additional psychotropic medication. CONCLUSIONS: Neonatal symptoms are common after late intrauterine lithium exposure, however transient, treatable and mostly mild. In this study, a high lithium concentration at birth was a risk factor for an increased lithium level at follow-up. Polypharmacy may constitute an additional risk factor. This study suggests that the late intrauterine exposure to lithium might add to the adverse effects in lithium-exposed, breastfed infants. Consequently we recommend breastfed infants with therapeutic lithium concentrations at birth to be followed up promptly to avoid lithium toxicity.

Umbilical cord clamping in the early phases of the COVID-19 era - a systematic review and meta-analysis of reported practice and recommendations in guidelines.

OBJECTIVES: At the beginning of the COVID-19 pandemic, delayed umbilical cord clamping (CC) at birth may have been commonly discouraged despite a lack of convincing evidence of mother-to-neonate SARS-CoV-2 transmission. We aimed to systematically review guidelines, and reports of practice and to analyze associations between timing of CC and mother-to-neonate SARS-CoV-2 transmission during the early phases of the pandemic. METHODS: Major databases were searched from December 1, 2019, to July 20, 2021. INCLUSION: studies and guidelines describing CC practice in women with SARS-CoV-2 infection during pregnancy until 2 postnatal days, giving birth to live-born neonates. EXCLUSION: no extractable data. Two reviewers independently screened studies for eligibility and assessed study quality. Pooled prevalence rates were calculated. RESULTS: Forty-eight studies (1476 neonates) and 40 guidelines were included. Delayed CC was recommended in 70.0% of the guidelines. Nevertheless, delayed CC was reported less often than early CC: 262/1476 (17.8%) vs 511/1476 (34.6%). Neonatal SARS-CoV-2 positivity rates were similar following delayed (1.2%) and early CC (1.3%). Most SARS-CoV-2 transmissions (93.3%) occurred in utero. CONCLUSION: Delayed CC did not seem to increase mother-to-neonate SARS-CoV-2 transmission. Due to its benefits, it should be encouraged even in births where the mother has a SARS-CoV-2 infection. SYSTEMATIC REVIEW REGISTRATION: Prospero CRD42020199500.

Stabilisation and resuscitation with intact cord circulation is feasible using a wide variety of approaches; a scoping review.

AIM: This scoping review identified studies on approaches to intact cord resuscitation and/or stabilisation (ICR/S) for neonates delivered by Caesarean section (C-section). METHODS: A systematic literature search was carried out using the PubMed, Web of Science, Scopus, Cochrane and CINAHL databases to identify papers published in English from inception to 14 November 2022. RESULTS: We assessed 2613 studies and included 18 from 10 countries, covering 1-125 C-sections: the United States, the United Kingdom, Australia, India, Italy, China, France, The Netherlands, New Zealand and Taiwan. The papers were published from 2014 to 2023, and the majority were randomised controlled trials and observational studies. Different platforms, equipment and staff positions in relation to the operating table were described. Options for resuscitation and stabilisation included different bedding and trolley approaches, and maintaining aseptic conditions was mainly addressed by the neonatal team scrubbing in. Hypothermia was prevented by using warm surfaces, polythene bags and radiant heaters. Equipment was kept easily accessible by mounting it on a trolley or a separate mobile pole. CONCLUSION: We could not reach definitive conclusions on the optimal method for performing ICR/S during a C-section, due to study variations. However, a number of equipment and management options appeared to be feasible approaches.

Bilirubin Levels in Neonates ≥35 Weeks of Gestation Receiving Delayed Cord Clamping for an Extended Time-An Observational Study.

OBJECTIVE: To describe bilirubin levels in neonates ≥350/7 gestational weeks, receiving delayed cord clamping (CC), in relation to the updated Bhutani nomogram. STUDY DESIGN: This was a retrospective, observational study based on data from medical records and local data sheets. Singleton neonates, born vaginally at a gestational age ≥350/7, and with a registered time to CC and at least one registered bilirubin, were included. We excluded neonates with positive direct antiglobulin test or hemolytic disorders. Adjusted analyses were performed using ANOVA and linear or logistic regression. RESULTS: We analyzed 558 neonates, mean gestational age (SD) 39.9 (1.3) weeks. CC was performed at a median (IQR) time of 6 (5-8) minutes. The dataset contained 1330 bilirubin measurements. Median (IQR) age at bilirubin measurement was 37 (22-54) hours. Bilirubin percentiles in neonates with CC time ≥2 minutes were similar, or lower, compared with the Bhutani nomogram between 12 and 72 hours, but with greater 95th percentile at later hours of age. Phototherapy was initiated in 13 (2.3 %) of the neonates. We found no association between time to CC and hyperbilirubinemia (ß = -0.05, P = .07). Need for phototherapy was marginally greater in neonates with shorter time to CC. CONCLUSIONS: Bilirubin levels were not correlated to time to CC. Our findings indicate that CC beyond 2 minutes can be performed without additional monitoring for jaundice.

Lithium use during breastfeeding was safe in healthy full-term infants under strict monitoring.

AIM: Previous studies on breastfeeding during lithium therapy have shown conflicting results. The aim of this study was to evaluate the safety when practising thorough follow-up of the infants. METHOD: This retrospective study focused on women with lithium medication, and their breastfed infants born between 2006 and 2021 in Stockholm, Sweden. Information about infant serum lithium concentrations and clinical status was collected from medical records. RESULTS: In total, 30 infants exposed to lithium through breastmilk, 21 girls and 9 boys, were included. The median age at follow-up was 40 days (range 8-364 days). The median lithium serum concentration was 0.10 mmol/L in the second week of life (range <0.05-0.7 mmol/L), 0.08 in week 2-4 (range <0.05-1.2), 0.06 in the second month of life (range <0.05-0.2) and 0.07 after 2 months of age (range <0.05-0.2). Unexpectedly high lithium concentrations were found in two infants in the first month of life. Apart from poor weight gain, no adverse effects were found. CONCLUSION: Serum lithium concentrations in breastfed infants were stabilised at barely measurable levels after the first weeks of life. Before that, concentrations higher than the mothers were found. Lithium treatment during breastfeeding can be considered safe under strict follow-up.

Cord clamping beyond 3 minutes: Neonatal short-term outcomes and maternal postpartum hemorrhage.

BACKGROUND: Delaying cord clamping (CC) for 3-5 minutes reduces iron deficiency and improves neurodevelopment. Data on the effects of CC beyond 3 minutes in relation to short-term neonatal outcomes and maternal risk of postpartum hemorrhage are scarce. METHODS: This was a prospective observational study performed in two delivery departments. Pregnant women with vaginal deliveries were included. Time to CC, estimated postpartum blood loss, and perinatal data were recorded. Spearman's correlation analysis and comparisons between newborns clamped before and after 3 minutes were performed. RESULTS: In total, 904 dyads were included. The mean gestational age ± standard deviation was 40.1 ± 1.2 weeks. CC was performed at a median time of 6 minutes (range 0-23.5). Apgar scores at 5 and 10 minutes were positively correlated with time to CC (correlation coefficient .140, P < .001 and .161, < .001). There was no correlation between CC time and bilirubin level (correlation coefficient .021, P = .54). The median postpartum blood loss was 300 mL (70-2550 mL), with a negative correlation between CC time and postpartum blood loss (-0.115, P = .001). The postpartum blood loss was larger in the group clamped at ≤3 minutes (median [interquartile range] 400 mL [300-600] vs 300 mL [250-450], [P = .003]]. CONCLUSIONS: Umbilical CC times beyond 3 minutes in vaginal deliveries were not associated with negative short-term outcomes in newborns and were associated with a smaller maternal postpartum blood loss. Although CC time as long as 6 minutes could be considered as safe, further research is needed to decide the optimal timing.

Simplified bedside assessment of pulmonary gas exchange in very preterm infants at 36 weeks' postmenstrual age.

INTRODUCTION: We aimed to develop and validate a prediction table for a simplified measure of rightward shift of the fetal oxyhaemoglobin saturation (SpO2) versus inspired oxygen pressure (PIO2) curve as an objective marker of lung disease severity in very preterm infants, independent of unit altitude or oxygen prescribing policies. METHODS: Very preterm infants (n=219) had an oxygen reduction test at median (IQR) test age of 354 (345-360) weeks' postmenstrual age (PMA). Shift was derived from at least three paired SpO2 versus PIO2 measurements using a computer algorithm, using the fetal oxyhaemoglobin dissociation curve as the reference. Linear regression of resultant shift values enabled construction of a table to predict shift using a single paired SpO2 versus PIO2 measurement, validated subsequently in a separate infant cohort using Bland-Altman analysis. Receiver operating curve analysis provided threshold values equating to a clinical diagnosis of mild bronchopulmonary dysplasia (BPD) or moderate to severe BPD. RESULTS: The median (IQR) age of 63 infants in the validation cohort was 360 (356-362) weeks' PMA. Mean difference (95% CI) between predicted and measured shift was 2.1 (-0.8% to 4.9%) with wide limits of agreement (-20.7% to 24.8%). Predicted shift >10.1 kPa identified mild BPD with 71% sensitivity and 88% specificity while values>13.0 kPa identified moderate to severe BPD with 81% sensitivity and 100% specificity. DISCUSSION: Shift predicted from a single paired SpO2 versus PIO2 measurement using our validated table enables objective bedside screening of lung disease severity in very preterm infant cohorts at 36 weeks' PMA.

A Case of Severe Infant-to-Placenta Hemorrhage in Association with Prolonged Delayed Cord Clamping.

BACKGROUND Delayed cord clamping is a well-established and evidence-based clinical practice which has improved the outcomes of many infants. Because of the positive effects of delayed cord clamping, non-evidence-based practices, including delaying cord clamping for up to 1 h until complete non-severance of the placenta, are becoming more widespread. CASE REPORT A full-term infant, born vigorous and well at a hospital, was hypotonic and poorly perfused at 50 min of age. Lab tests at 2 h of age showed metabolic acidosis with a pH of 6.95 and base excess of -18. The hemoglobin level decreased from 226 g/L in the umbilical cord at birth to 108 g/L in the infant at 12 h of age. Infection, cardiac malformation, and internal hemorrhage were ruled out. Review of the perinatal history revealed the cord was deliberately not clamped until the infant was about 50 min old and the placenta was placed below the level of the child during this time. The infant was considered to have lost a large volume of blood into the placenta, causing a hypovolemic shock. CONCLUSIONS Different medical societies recommend delayed cord clamping from at least 30 sec up to 3 min, and there is no evidence of additional benefits after the placenta has been delivered and cord pulsations have ceased. This case report shows that extremely late cord clamping can be acutely dangerous to the infant. It is important to discourage from this practice, and if parents reject cord clamping, the positioning of the placenta may be important.

Physical Activity in 6.5-Year-Old Children Born Extremely Preterm.

Physical activity (PA) can prevent cardiovascular diseases. Because of increased risks of impairments affecting motor activity, PA in children born preterm may differ from that in children born at term. In this prospective cohort study, we compared objectively measured PA in 71 children born extremely preterm (<27 weeks gestational age), to their 87 peers born at term, at 6.5 years of age. PA measured with accelerometer on the non-dominant wrist for 7 consecutive days was compared between index and control children and analyzed for associations to prenatal growth, major neonatal brain injury, bronchopulmonary dysplasia and neonatal septicemia, using ANOVA. Boys born extremely preterm spent on average 22 min less time per day in moderate to vigorous physical activity (MVPA) than control boys (95% CI: -8, -37). There was no difference in girls. Amongst children born extremely preterm, major neonatal brain injury was associated with 56 min less time in MVPA per day (95%CI: -88, -26). Subgroups of children born extremely preterm exhibit lower levels of physical activity which may be a contributory factor in the development of cardiovascular diseases as adults.

Physiology and Predictors of Impaired Gas Exchange in Infants with Bronchopulmonary Dysplasia.

Rationale: A sensitive outcome measure for infants with bronchopulmonary dysplasia would facilitate clinical benchmarking and enhance epidemiologic understanding, evaluation of clinical interventions, and outcome prediction.Objectives: Noninvasive assessment of pulmonary gas exchange in preterm infants with and without bronchopulmonary dysplasia to grade disease severity and to identify determinants of impaired gas exchange.Methods: This is a prospective observational study in very preterm infants. Inspired oxygen partial pressure (PiO2) was decreased stepwise to achieve oxygen saturation as measured by pulse oximetry (SpO2) that decreased from 95% to 86%. Right shift, V⋅a/Q⋅, and right-left shunt were derived from the resulting SpO2 versus PiO2 curve and compared with current disease severity classification. Potential determinants of shift, V⋅a/Q⋅, and shunt were identified using principal components analysis and multiple linear regression.Measurements and Main Results: A total of 219 infants with median (interquartile range) gestation of 28 weeks and 0 days (26 weeks and 0 days to 29 weeks and 0 days) had a valid study at 35 weeks and 4 days (34 weeks and 1 day to 39 weeks and 3 days) of postmenstrual age. Shift increased and V⋅a/Q⋅ decreased as severity of bronchopulmonary dysplasia increased. Infants with moderate-severe disease also had increased shunt. Extent of impaired gas exchange overlapped between severity groups. Infants requiring mechanical support but no supplemental oxygen at 36 weeks' postmenstrual age had similar values of shift, V⋅a/Q⋅, and shunt to preterm infants without bronchopulmonary dysplasia. Lower gestation and increased duration of invasive ventilation independently predicted increased shift, decreased V⋅a/Q⋅, and increased shunt. Shift was the most sensitive and specific index of the severity of bronchopulmonary dysplasia.Conclusions: Most infants with bronchopulmonary dysplasia have impaired oxygenation quantified by a simple, sensitive bedside test. Shift of the SpO2/PiO2 curve may be useful for prediction and measurement of preterm infant respiratory outcomes.

Low Exercise Capacity Increases the Risk of Low Cognitive Function in Healthy Young Men Born Preterm: A Population-Based Cohort Study.

BACKGROUND: Preterm birth is a risk factor for decreased exercise capacity and impaired cognitive functions in later life. The objective of this study was to disentangle the associations between preterm birth, physical fitness and cognitive performance in young adulthood. METHODS: This population-based cohort study included 218,802 young men born in Sweden 1973-1983. Data on birth characteristics was obtained from the Medical Birth Register and linked to exercise capacity assessed by ergometer cycling and cognitive tests performed at conscription for military service in 1993-2001. Cognitive performance was assessed using stanine (STAndard NINE) scores. The results were adjusted for socioeconomic factors. RESULTS: Exercise capacity was positively associated with cognitive performance across all gestational ages. The sub-group of men who were born extremely preterm (gestational age <28 weeks) and had low exercise capacity exhibited the lowest odds ratio (OR = 0.26, 95%CI:0.09-0.82) of having a cognitive function above the mean stanine score (2.9) for men born at term with normal birth weight. Men born extremely preterm with a high exercise capacity had similar or even higher ORs for cognitive function (OR = 0.59; 95% CI:0.35-0.99) than men born at term with low Wmax (OR = 0.57; 95% CI:0.55-0.59). CONCLUSIONS: Physical fitness is associated with higher cognitive function at all gestational ages, also in young men born extremely preterm. Targeting early physical exercise may be a possible intervention to enhance cognitive performance and educational achievements in populations at risk, such as childhood and adult survivors of preterm birth.

Long-term impact of preterm birth on exercise capacity in healthy young men: a national population-based cohort study.

BACKGROUND: Increasing numbers of survivors of preterm birth are growing into adulthood today. Long-term health-effects of prematurity are still poorly understood, but include increased risk for diabetes, obesity and cardiovascular diseases in adult life. To test if reduced physical fitness may be a link in the causal chain of preterm birth and diseases in later life, the association of preterm birth and adult exercise capacity was investigated. The hypothesis was that preterm birth contributes independently of other risk factors to lower physical fitness in adulthood. METHODS AND FINDINGS: Population-based national cohort study of all males conscripting for military service in 1993-2001 and born in Sweden 1973-1983, n = 218,820. Data were retrieved from the Swedish Conscript Register, the Medical Birth Register and the Population and Housing Census 1990. Primary outcome was the results from maximal exercise test (Wmax in Watt) performed at conscription. Association to perinatal and socioeconomic risk factors, other co-variates and confounders were analysed. General linear modelling showed that preterm birth predicted low Wmax in a dose-response related pattern, with 25 Watt reduction in Wmax for the lowest gestational ages, those born ≤27 weeks. Low birth weight for gestational age also independently predicted low Wmax compared to normal and high birth weight (32 Watt reduction for those with a birth weight Standard Deviation Score <2). Low parental education was significantly associated with reduced Wmax (range 17 Watt), as well as both low and high current BMI, with severe obesity resulting in a 16 Watt deficit compared to Wmax top performance. CONCLUSION: Being born preterm as well as being born small for gestational age predicts low exercise capacity in otherwise healthy young men. The effect size of being born preterm equal or exceed that of other known risk factors for unfitness in adults, such as low parental education and overweight.