Controversies in antenatal corticosteroid treatment.

Antenatal corticosteroids are now established as one of the cornerstones of therapy in the prevention of neonatal morbidity and mortality prior to preterm birth. Although this practice is widely accepted, a significant number of controversies exist. This review explores the knowledge gaps regarding the use of antenatal corticosteroids in the preterm, late preterm and term populations. Furthermore, the role of antenatal corticosteroids in special populations, such as diabetes, multiple pregnancies and periviable gestations, where high-quality data from randomized controlled trials are lacking, is also considered.

Brimonidine Toxicity Secondary to Topical Use for an Ulcerated Hemangioma.

Combigan (Allergan, Irvine, CA) is an ophthalmic solution that combines 0.2% brimonidine, a selective α-2 adrenergic agonist, with 0.5% timolol, a nonselective ß-adrenergic antagonist. It is approved for the reduction of intraocular pressure in patients with glaucoma or ocular hypertension. There have been recent reports of successful treatment of superficial infantile hemangiomas (IHs) using Combigan topically. We report the case of a 2-month-old girl who developed life-threatening brimonidine toxicity requiring intubation and mechanical ventilation secondary to central nervous system depression and apnea after topical application to an ulcerated IH.

Relation between time interval from antenatal corticosteroids administration to delivery and neonatal outcome in twins.

AIM: The aim of this study was to evaluate the perinatal outcome in twins, who were administered one complete course of antenatal corticosteroids (ACS) depending on the time interval from corticosteroids to delivery. METHODS: We carried out a retrospective analysis of medical data of women with twins who received a course of ACS and delivered before 34 weeks within or beyond 7 days after ACS were given. Among 652 twin deliveries between 2006 and 2014, 106 met the criteria (50 patients delivered <7 days and 56 ≥ 7 days after ACS administration). RESULTS: There were no differences in the mean gestational age at labor, mean birthweight, perinatal mortality or newborns' general condition between women who delivered <7 and ≥7 days after corticosteroids. Newborns in the ≥7 days group suffered from respiratory disorders significantly more often (74.1% vs 54.5%, P = 0.003) and were hospitalized longer (42.6 ± 19.1 vs 33.4 ± 21.7 days, P < 0.001). Significantly more infants in the <7 days group were administered antibiotics (55.6% vs 25%, P = 0.001). In the multiple logistic regression analysis, the only factors significantly influencing the incidence of respiratory complications in twins were delivery following ACS therapy within 7 days (adjusted odds ratio, 0.16; 95% confidence interval, 0.02-0.90) and female sex (adjusted odds ratio, 0.71; 95% confidence interval 0.40-0.90). CONCLUSION: There is a relation between neonatal outcomes in twins and time interval between ACS administration and birth. Therefore, a single ACS course should be administered with caution in order to allow for the completion of the treatment without exceeding an interval of 7 days to delivery. © 2016 Japan Society of Obstetrics and Gynecology.

Postnatal development and LPS responsiveness of pulmonary adenosine receptor expression and of adenosine-metabolizing enzymes in mice.

BACKGROUND: Adenosine levels are regulated by ecto-5'-nucleotidase/CD73 and adenosine deaminase (ADA). Adenosine regulates endothelial permeability and anti-inflammatory responses via adenosine receptors. Here, the adenosine receptors and purine-converting enzymes were studied during postnatal development and inflammation. METHODS: Newborn, 1-, 10-, 14-d-old and adult C57BL/6 mice were challenged intraperitoneally (i.p.) with lipopolysaccharide (LPS) for 6 h. The inflammatory response was evaluated by histochemistry. Expression levels of adenosine receptors (A1, A2A, A2B, and A3), CD73, and ADA were measured by quantitative reverse transcription polymerase chain reaction. A1 was studied by immunohistochemistry, and enzyme activities were analyzed by thin-layer chromatography. RESULTS: LPS caused respiratory distress in newborns within 24 h. LPS induced neutrophils at the basal stage and alveolar congestion. Low activity and expression of CD73 increased after birth. Expression of ADA after LPS increased 16-fold in adults and 2-fold in newborns (P < 0.05). A1 expression was high in newborns and increased after LPS (P < 0.05). A1 was localized to endothelial membranes. A2A decreased after LPS in newborns and increased in adults (P < 0.05). The expression of A3 increased in newborns and adults after LPS. CONCLUSION: Low pulmonary CD73 expression, LPS-induced suppression of A2A, LPS-induced increase of A1 expression, and severe respiratory distress were distinguishing responses in the newborns from those in the adults.

Maternal antidepressant use and adverse outcomes: a cohort study of 228,876 pregnancies.

OBJECTIVE: The purpose of this study was to describe antidepressant medication use patterns during pregnancy and pregnancy outcomes. STUDY DESIGN: We evaluated a cohort of 228,876 singleton pregnancies that were covered by Tennessee Medicaid, 1995-2007. RESULTS: Of 23,280 pregnant women with antidepressant prescriptions before pregnancy, 75% of them filled none in the second or third trimesters of pregnancy, and 10.7% of them used antidepressants throughout pregnancy. Filling 1, 2, and ≥3 antidepressant prescriptions during the second trimester was associated with shortened gestational age by 1.7 (95% confidence interval [CI], 1.2-2.3), 3.7 (95% CI, 2.8-4.6), and 4.9 (95% CI, 3.9-5.8) days, when controlled for measured confounders. Third-trimester selective serotonin reuptake inhibitor use was associated with infant convulsions; adjusted odds ratios were 1.4 (95% CI, 0.7-2.8); 2.8 (95% CI, 1.9-5.5); and 4.9 (95% CI, 2.6-9.5) for filling 1, 2, and ≥3 prescriptions, respectively. CONCLUSION: Most women discontinue antidepressant medications before or during the first trimester of pregnancy. Second-trimester antidepressant use is associated with preterm birth, and third-trimester selective serotonin reuptake inhibitor use is associated with infant convulsions.

The Relationship between Antenatal Corticosteroid Administration-to-Delivery Intervals and Neonatal Respiratory Distress Syndrome and Respiratory Support.

Background: Administration of antenatal corticosteroids (ACSs) is an effective strategy for managing preterm infants, which improves neonatal respiratory distress syndrome (NRDS) and attenuates the risk of neonatal mortality. However, many preterm infants are not exposed to a complete course of ACS administration, and the effects of different ACS-to-delivery intervals on NRDS and respiratory support remain unclear. Therefore, this study explored the relationship between ACS-to-birth intervals and NRDS and respiratory support in preterm infants. Methods: In this retrospective cohort study, the preterm infants born between 240/7 and 316/7 wks of gestation were recruited from January 2015 to July 2021. All participants were categorised based on the time interval from the first ACS dose to delivery: <24 h, 1-2 d, 2-7 d, and >7 d. Multivariable logistic regression analysis examined the relationships between the ACS-to-birth interval and primary or secondary outcome while adjusting for potential confounders. Results: Of the 706 eligible neonates, 264, 83, 292, and 67 received ACS-to-delivery intervals of <24 h, 1-2 d, 2-7 d, and >7 d, respectively. After adjusting these confounding factors, the multivariable logistic analysis showed a significantly increased risk of NRDS (aOR: 1.8, 95% CI: 1.2-2.7), neonatal mortality (aOR: 2.8, 95% CI: 1.1-6.8), the need for surfactant use (aOR: 2.7, 95% CI: 1.7-4.4), endotracheal intubation in the delivery room (aOR: 1.9, 95% CI: 1.0-3.7), and mechanical ventilation (aOR: 1.9, 95% CI: 1.1-3.4) in the ACS-to-delivery interval of <24 h group when compared with the ACS-to-birth interval of 2-7 d group. Conclusions: Neonatal outcomes such as NRDS, neonatal mortality, the need for surfactant use, intubation in the delivery room, and the risk of mechanical ventilation are higher when the neonates are exposed to an ACS interval for less than 24 h before delivery.

Implementation of less-invasive surfactant administration in a Canadian neonatal intensive care unit.

BACKGROUND: Less-invasive surfactant administration (LISA) is a recent technique used extensively in Europe but rarely used in North America. The aim of this study was to describe our experience following LISA implementation using poractant in a Canadian neonatal intensive care (NICU). METHODS: A retrospective analysis was conducted from June 2017 to April 2021 of LISA procedures in preterm infants. Data were collected on patient characteristics, outcomes following LISA, laryngoscopy, and adverse events. The primary outcome was the rate of successful LISA procedures. SETTING: Level IIIa academic NICU. RESULTS: LISA was successful in 93 of 101 infants (92%). Median gestational age was 30.9 weeks (interquartile range [IQR]: 29.4-33.0). All infants received atropine and fentanyl premedication. Eight LISA procedures were unsuccessful: five because of thoracic rigidity and three because of inability to expose the vocal cords. In the 93 successful procedures, a second dose of surfactant was needed for 15 of 93 infants (16.1%), either by repeated LISA (7/15; 7.5%) or by endotracheal intubation (8/15; 8.6%). In 63.4% of successful procedures, one laryngoscopy attempt was made. The median duration of laryngoscopy attempts was 60 s (IQR: 52-110). Two types of catheters were used: the multi-access catheter (MAC) or the Angiocath in 67% and 33% of procedures, respectively. One infant had bradycardia and 30.6% had profound desaturation of <75%. CONCLUSION: LISA with poractant alfa was implemented in a Canadian NICU with a high degree of procedural success. Fentanyl may lead to more adverse events with a risk of interrupting LISA and may not be the ideal agent for this procedure. These results may encourage wider dissemination of LISA in North America.

Lipocalin-2 silencing suppresses inflammation and oxidative stress of acute respiratory distress syndrome by ferroptosis via inhibition of MAPK/ERK pathway in neonatal mice.

Neonatal acute respiratory distress syndrome (ARDS) has high morbidity and mortality rates worldwide, but there is a lack of pharmacologic treatment and clinical targeted therapies. In this study, we aimed to explore the effects of Lipocalin-2 (LCN2) on ferroptosis-mediated inflammation and oxidative stress in neonatal ARDS and the potential mechanism. In this study, we established an in vivo ARDS mouse model and an in vitro ARDS cell model by LPS (Lipopolysaccharide) stimulation. Lung tissue injury was evaluated by wet/dry ratios and histopathological examination. LCN2 expression was detected by qRT-PCR and Western blot. Inflammatory factors, oxidative stress and apoptosis were also detected. Ferroptosis was identified by detection of Fe2+ level and ferroptosis-associated protein expressions. Mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinase (ERK) pathway signaling was examined by Western blot analysis. The data revealed that LCN2 expression was significantly upregulated in neonatal mice with ARDS. Interference with LCN2 protected LPS-induced lung in neonatal mouse by reducing the radio of wet/dry and alleviating pathological damages. In addition, LCN2 silencing repressed LPS-induced inflammation, oxidative stress in vivo and in vitro, as well as apoptosis. Meanwhile, decreased level of Fe2+ and transferrin while increased levels of ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) were observed. The expression MAPK/ERK pathway was inhibited by depletion of LCN2. The present results suggest that LCN2 knockdown protected LPS-induced ARDS model via inhibition of ferroptosis-related inflammation and oxidative stress by inhibiting the MAPK/ERK pathway, thereby presenting a novel target for the treatment of ARDS.

Magnesium sulphate for pre-eclampsia: care of the neonate.

Whilst the care of women requiring magnesium sulphate for pre-eclampsia and eclampsia is well documented, there is considerably less guidance on the identification and treatment of magnesium toxicity in women and neonates within midwifery literature, particularly in relation to neonatal care. Given the potential risk of magnesium toxicity in the neonate and the ensuing problems that may occur, it is essential that all midwives are knowledgeable about the care and observations required for the fetus and neonate. This paper provides a background to the neonatal anatomy and physiology, recognition of neonatal magnesium toxicity and implications for midwifery practice.

Comparison of respiratory distress syndrome amongst preterm twins (28-34 Weeks) born within and after two weeks of completion of single antenatal corticosteroid course: A bidirectional cohort study.

BACKGROUND: The literature on neonatal outcomes in preterm twins delivered before 34 weeks but within and after 14 days of a single initial steroid course is limited. MATERIAL AND METHODS: This bidirectional (226 prospective and 42 retrospectives) cohort study was performed at a tertiary care teaching hospital in South India. We compared the respiratory distress syndrome and neonatal death amongst preterm twins from 28 to 34 weeks born < 14 days (Group A, n=268) and after 14 days (Group B, n=268) of completion of a single course of antenatal steroids. We used multivariable regression analysis (log-binomial model) to adjust for confounding variables. We generated a propensity-matched score with probit regression to analyse outcomes (respiratory distress and neonatal deaths). RESULTS: The two groups had significant differences in the distribution of birthweight, gestation period and mode of delivery. On adjusted analysis, the period of gestation below 33 weeks and weight below 1.5 kg had the maximum influence on respiratory and other morbidities, and weight less than 1 kg on neonatal death. [adjusted relative risk (ARR) 26.06, (95%CI=2.37-285.5), p=0.008]. On propensity scoring after matching all these variables, we found an [ARR of 2.0 (95% CI: 1.03-3.88), P=0.017] for neonatal death after 14 days of steroid injection. The ARR for respiratory distress syndrome was 1.13 in those born after 14 days of steroids, though it did not reach statistical significance. CONCLUSION: On propensity scoring, the steroid-delivery interval more than 14 days was associated with a significantly increased risk (ARR of 2) of neonatal death.

Profuse oral secretions after propafenone administration in neonates.

Propafenone, an antiarrhythmic drug that is effective for treating supraventricular tachycardias, can induce well-known proarrhythmic and systemic adverse effects. We describe a previously unreported adverse effect in 3 newborns: oral propafenone-induced profuse oral secretions and respiratory distress of sufficient severity to necessitate discontinuation of propafenone.

The effects of a preterm labor episode prior to 34 weeks are evident in late preterm outcomes, despite the administration of betamethasone.

OBJECTIVE: We sought to assess whether betamethasone (BETA) <34 weeks reduces adverse outcomes in late preterm infants. STUDY DESIGN: We performed a retrospective cohort study of patients with spontaneous birth 34-36 6/7 weeks. We determined whether patients were exposed to preterm labor (PTL) <34 weeks and BETA and calculated the incidence of adverse respiratory and composite outcomes and neonatal intensive care unit admission. We used chi(2) analyses to determine associations between PTL+BETA and adverse outcomes, and Poisson regression to model cumulative incidence and control for confounders. RESULTS: We enrolled 700 mother-infant pairs. The 36-week PTL+BETA infants were at increased risk of respiratory outcome (incident risk ratio [IRR], 2.73; 95% confidence interval [CI], 1.37-5.45), neonatal intensive care unit admission (IRR, 2.01; 95% CI, 1.14-3.56), and composite outcome (IRR, 1.70; 95% CI, 1.08-2.68) compared to those without PTL+BETA. Chorioamnionitis was independently associated with all adverse outcomes. CONCLUSION: We hypothesize that early PTL is a surrogate for intrauterine inflammation and is responsible for the observed adverse outcomes in those with PTL+BETA.

A register study of the impact of stopping third trimester selective serotonin reuptake inhibitor exposure on neonatal health.

OBJECTIVE: To determine whether risk for adverse neonatal outcomes are reduced by stopping SSRI use before the end of pregnancy. METHOD: Using population health data, maternal health and prenatal SSRI prescriptions were linked to neonatal birth records (N = 119,547) (1998-2001). Neonates SSRI-exposed in the last 14 days (L14) of gestation were compared with infants who had gestational exposure, but not during the last 14 days (NL14). Propensity score matching was used to control for potential confounders (total exposure, maternal health characteristics). RESULTS: Increased risk for neonatal respiratory distress was present where L14 exposure occurred compared with risk where exposure stopped before L14. However, controlling for potential maternal and neonatal confounders, differences disappeared. CONCLUSION: Controlling for maternal illness severity, reducing exposure to SSRI's at the end of pregnancy had no significant clinical effect on improving neonatal health. These findings raise the possibility that some adverse neonatal outcomes may not be an acute pharmacological condition such as toxicity or withdrawal.

Complications of Antenatal Corticosteroids in Infants Born by Early Term Scheduled Cesarean Section.

OBJECTIVE: To compare neonatal hypoglycemia and respiratory morbidity rates in pregnancies complicated by diabetes following early term scheduled cesarean section (ETSCS) with and without maternal corticosteroid administration. RESEARCH DESIGN AND METHODS: In a retrospective cohort study, women with any form of diabetes in pregnancy undergoing ETSCS were included. Primary outcomes were admission rates to the neonatal intensive care unit (NICU) for respiratory distress syndrome (RDS)/transient tachypnea of the newborn (TTN) and/or neonatal hypoglycemia. RESULTS: NICU admission rates for neonatal hypoglycemia were significantly higher (24.2% vs. 4.4%, P = 0.003) and RDS/TTN rates were nonsignificantly higher (15.2% vs. 7.2%, P = 0.209) following corticosteroid administration. CONCLUSIONS: Corticosteroids were not beneficial among women with any form of diabetes in pregnancy undergoing ETSCS and, indeed, may be harmful. In our hospital, we have ceased the use of corticosteroids for women under these circumstances.

Neonatal transient respiratory depression after maternal urapidil infusion for hypertension.

Urapidil is a potent antihypertensive drug that has been in clinical use for more than 20 years. It has been proven to be an effective and well-tolerated antihypertensive drug during pregnancy, but clinical experiences with urapidil have been described in only a limited number of studies. There have also been only limited observations on the (side-)effects of urapidil on the neonate. We describe here a case of postnatal transient respiratory depression following maternal administration of urapidil. We suggest that the fetal and neonatal effects of more recently implemented antihypertensive drugs, such as urapidil, should be included in a prospective evaluation of antihypertensive treatment of women during pregnancy. Infants of mothers who received urapidil should be carefully watched in the immediate postnatal phase as urapidil may still exert some significant effects on the neonate.

Neonatal outcome following pregnancy exposure to antidepressants: a prospective controlled cohort study.

OBJECTIVE: To determine the incidence of early adverse effects associated with antidepressant drug use during pregnancy. DESIGN: Prospective, controlled cohort study. SETTING: A Drug and Health Information Centre in Milan, Italy. POPULATION: A total of 200 neonates exposed to antidepressants in utero and 1200 controls. METHODS: Women who took antidepressants during pregnancy and delivered liveborn children between 1995 and 2003 were selected. Each case was matched for maternal age and gravidity to six randomly selected controls (not exposed to teratogenic drugs or drugs known to cause neonatal side effects). Odds ratio was estimated for attributable risks. MAIN OUTCOME MEASURES: Neonatal adverse events and Special Care Unit admission rate, assessed through an interview with the mothers. RESULTS: Of the 200 neonates exposed to antidepressants in utero, 14 had adverse events and 3 required Special Care Unit admission. Jaundice (n = 5), agitation (n = 3) and respiratory distress (n = 2) were the most common symptoms. In the control group, 50 newborns had side effects and no statistically significant differences in the prevalence rate compared to the exposed group were found, even after stratification for drugs and pregnancy period of exposure. Only the prematurity rate was significantly higher in exposed compared to non-exposed newborns (OR = 2.31; 95% CI 1.14-4.63). CONCLUSIONS: These results do not support an association between antidepressant exposure and unsafe fetal and neonatal outcomes in newborns. However, a collaborative international multicentre epidemiological monitoring of the use of psychotropic drugs during pregnancy is needed in order to guarantee pregnant women and their children safe and effective treatments, both at brief and long time from exposure.

[Insulin treatment of gestational diabetes and respiratory outcome in late-preterm and term babies]. / Diabète gestationnel traité par insuline et risque de détresse respiratoire sévère chez le nouveau-né de plus de 34 semaines d'aménorrhée.

While the incidence of diabetes mellitus (DM) during pregnancy has been steadily increasing in recent years, the link between gestational DM and respiratory outcome in neonates has not been firmly established. To address this gap in understanding, we asked whether DM status and its treatment during pregnancy influence risk of neonatal respiratory distress. We conducted retrospective analysis of a large cohort to determine the relationship between maternal DM status (non-DM, insulin-treated DM [DTI], and non-insulin-treated DM [DTR]) and respiratory distress in term and near-term singletons, born at Robert-Debré Hospital over a 7-year period. Of 18,095 singletons delivered at 34 weeks of gestation or later, 412 (2.3%) were admitted to the NICU for respiratory distress within the first hours of life. The incidence of NICU admissions due to respiratory distress was 2.2% in the non-DM group, 2.1% in the DTR group, and 5.7% in the DTI group. Insulin treatment of DM, together with several other perinatal factors, was associated with an increased risk for severe respiratory distress. In a multivariate model, we found that DTI, but not DTR, was a risk factor independent of gestational age and cesarean section, with an IRR of 1.44 (95% CI, 1.00-2.08). The data indicate that newborns of mothers with DM treated with diet are not at risk for severe respiratory distress. Conversely, newborns of mothers with DM treated with insulin are associated with elevated risk for severe respiratory disease and should therefore be closely monitored.

In vivo lipid-derived free radical formation by NADPH oxidase in acute lung injury induced by lipopolysaccharide: a model for ARDS.

Intratracheal instillation of lipopolysaccharide (LPS) activates alveolar macrophages and infiltration of neutrophils, causing lung injury/acute respiratory distress syndrome. Free radicals are a special focus as the final causative molecules in the pathogenesis of lung injury caused by LPS. Although in vitro investigation has demonstrated radical generation after exposure of cells to LPS, in vivo evidence is lacking. Using electron spin resonance (ESR) and the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN), we investigated in vivo free radical production by rats treated with intratracheal instillation of LPS. ESR spectroscopy of lipid extract from lungs exposed to LPS for 6 h gave a spectrum consistent with that of a POBN/carbon-centered radical adduct (aN=14.94+/-0.07 G and abetaH=2.42+/-0.06 G) tentatively assigned as a product of lipid peroxidation. To further investigate the mechanism of LPS-initiated free radical generation, rats were pretreated with the phagocytic toxicant GdCl3, which significantly decreased the production of radical adducts with a corresponding decrease in neutrophil infiltration. NADPH oxidase knockout mice completely blocked phagocyte-mediated, ESR-detectable radical production in this model of acute lung injury. Rats treated intratracheally with LPS generate lipid-derived free radicals via activation of NADPH oxidase.