Maternal fetal loss history and increased acute leukemia subtype risk in subsequent offspring: a systematic review and meta-analysis.

PURPOSE: History of fetal loss including miscarriage and stillbirth has been inconsistently associated with childhood (0-14 years) leukemia in subsequent offspring. A quantitative synthesis of the inconclusive literature by leukemia subtype was therefore conducted. METHODS: Eligible studies (N = 32) were identified through the screening of over 3500 publications. Random-effects meta-analyses were conducted on the association of miscarriage/stillbirth history with overall (AL; 18,868 cases/35,685 controls), acute lymphoblastic (ALL; 16,150 cases/38,655 controls), and myeloid (AML; 3042 cases/32,997 controls) leukemia. Sensitivity and subgroup analyses by age and ALL subtype, as well as meta-regression were undertaken. RESULTS: Fetal loss history was associated with increased AL risk [Odds Ratio (OR) 1.10, 95% Confidence Intervals (CI) 1.04-1.18]. The positive association was seen for ALL (OR 1.12, 95%CI 1.05-1.19) and for AML (OR 1.13, 95%CI 0.91-1.41); for the latter the OR increased in sensitivity analyses. Notably, stillbirth history was significantly linked to ALL risk (OR 1.33, 95%CI 1.02-1.74), but not AML. By contrast, the association of ALL and AML with previous miscarriage reached marginal significance. The association of miscarriage history was strongest in infant ALL (OR 2.34, 95%CI 1.19-4.60). CONCLUSIONS: In this meta-analysis involving >50,000 children, we found noteworthy associations by indices of fetal loss, age at diagnosis, and leukemia type; namely, of stillbirth with ALL and miscarriage history with infant ALL. Elucidation of plausible underlying mechanisms may provide insight into leukemia pathogenesis and indicate monitoring interventions prior to and during pregnancy.

[Hospital readmission after postpartum discharge of term newborns in two maternity wards in Stockholm and Marseille]. / Morbidité néonatale précoce après sortie de maternité : étude comparative entre deux maternités à Stockholm et Marseille.

The consequences of early postpartum discharge (EPPD, within 2 days after birth) on newborn health remain debated. Early discharge has been associated with increased neonatal morbidity. However, neonatal re-hospitalization can be prevented by careful follow-up during the 1st week after birth. We compared the early neonatal hospitalization of term newborns over 2 years in two hospitals: Karolinska University Hospital in Stockholm (n=7300 births), which allowed early discharge from 6h after birth with specific neonatal follow-up, and Marseille University Hospital (AP-HM) (n=4385) where postpartum discharge was more conventional after 72 h. During the study period, the EPPD rate was 41% vs. 2% in Stockholm and Marseille, respectively (P<0.001). Hospital readmission was comparable (5.6‰ vs. 7‰, P=0.2). The leading cause associated with hospitalization was icterus in Stockholm (76% vs. 26%, P<0.001) and feeding difficulties in Marseille (17% vs. 48%, P<0.001). In conclusion, close neonatal follow-up during the 1st week of life associated with restricted maternal and neonatal eligibility criteria for EPPD are required to prevent early neonatal re-hospitalization.

Extremely preterm infants who are small for gestational age have a high risk of early hypophosphatemia and hypokalemia.

AIM: Electrolyte balances have not been sufficiently evaluated in extremely preterm infants after early parenteral nutrition. We investigated the risk of early hypophosphatemia and hypokalemia in extremely preterm infants born small for gestational age (SGA) who received nutrition as currently recommended. METHODS: This prospective, observational cohort study included all consecutive extremely preterm infants born at 24-27 weeks who received high amino acids and lipid perfusion from birth. We evaluated the electrolyte levels of SGA infants and infants born appropriate for gestational age (AGA) during the first five days of life. RESULTS: The 12 SGA infants had lower plasma potassium levels from Day One compared to the 36 AGA infants and were more likely to have hypokalemia (58% vs 17%, p = 0.001) and hypophosphatemia (40% vs 9%, p < 0.01) during the five-day observation period. After adjusting for perinatal factors, SGA remained significantly associated with hypophosphatemia (odds ratio 1.39, confidence intervals 1.07-1.81, p = 0.01). CONCLUSION: Extremely preterm infants born SGA who were managed with currently recommended early parenteral nutrition had a high risk of early hypokalemia and hypophosphatemia. Potassium and phosphorus intakes should be set at sufficient levels from birth onwards, especially in SGA infants.

Cardiorespiratory development in extremely preterm infants: vulnerability to infection and persistence of events beyond term-equivalent age.

OBJECTIVE: Apnoea, bradycardia and hypoxemia occur frequently in extremely preterm infants, yet there is little longitudinal data describing cardiorespiratory development in these infants. This prospective study characterized early age-dependent changes in cardiorespiratory function and determined how activity is affected by factors such as underlying disease, postnatal insults and therapeutic interventions. PATIENTS AND METHODS: Thirty-three infants born between 23 and 28 weeks gestational age (GA) were monitored weekly from birth to beyond term-equivalent age (i.e. 25-45 weeks postconceptional age, PCA). Baseline cardiorespiratory activity as well as apnoea/hypopnoea, bradycardia and hypoxemia events were examined using impedance pneumography, electrocardiography (ECG) and pulse oximetry, respectively. RESULTS: Three hundred thirty-eight cardiorespiratory recordings lasting 3236 h were analysed. While the respiratory rate (RR) did not change during the early postnatal period, heart rate (HR) decreased and O2 saturation improved. There were 5973 total cardiorespiratory events, and their incidence decreased with advancing age. However, they still occurred frequently at term-equivalent age and after hospital discharge (mean PCA at discharge=38.3+/-0.5 weeks). Moreover, infection significantly increased apnoea/hypopnoea and hypoxemia incidence. CONCLUSION: The persistence of cardiorespiratory events beyond term-equivalent age as well as the marked impact of infection on cardiorespiratory function indicate that close surveillance after hospitalization is of crucial importance in extremely preterm infants.

Neurotransmitters and neuromodulators during early human development.

BACKGROUND: Neurotransmitters such as monoamines appear in the embryo before the neurones are differentiated. They may have other functions than neurotransmission during embryogenesis such as differentiation and neuronal growth. For example, serotonin may act as a morphogen. A number of neuropeptides are expressed during ontogenesis, but their function has been difficult to establish. Maybe some of them remain as evolutionary residues. Fast-switching neurotransmitters like the excitatory amino acids and the more ionotropic receptors dominate in the human brain, but appear probably later during evolution as well as during ontogeny. METHODS: The distribution of catecholamines during development has been analysed with a fluorescence method, while most of the other neurotransmitters have been mapped with immunohistochemical methods. The classical method to determine the physiological role of a neurotransmitter or modulator is to study the physiological effect of its antagonist, blocking the endogenous activity. By transgenic technique, the genes encoding for enzymes involved in the synthesis of neurotransmitters can be knocked-out. MAJOR FINDINGS: Pharmacological blocking of endogenous activity has, for example, demonstrated that adenosine suppresses fetal respiration. Knocking out the dopamine beta-hydroxylase gene results in fetal death, suggesting that noradrenaline is essential for survival. Some neurotransmitters change their effect during embryogenesis, e.g. GABA which is excitatory in the embryo, but inhibitory after birth due to a switch from a high to low chloride content in the nerve cells. It is possible that this is of importance for the wiring of neuronal network in early life. NMDA receptors dominate in the foetus, while kainate and AMPA receptors appear later. At birth, there is a surge of neurotransmitters such as catecholamines, which may be of importance for the neonatal adaptation. CONCLUSIONS: Neurotransmitters and modulators are not only important for the neural trafficking in the embryo, but also for the development of the neuronal circuits. Prenatal or neonatal stress (hypoxia), as well as various drugs, may disturb the wiring and cause long-term behavioural effects (fetal and neonatal programming).

Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor.

Caffeine is believed to act by blocking adenosine A(1) and A(2A) receptors (A(1)R, A(2A)R), indicating that some A(1) receptors are tonically activated. We generated mice with a targeted disruption of the second coding exon of the A(1)R (A(1)R(-/-)). These animals bred and gained weight normally and had a normal heart rate, blood pressure, and body temperature. In most behavioral tests they were similar to A(1)R(+/+) mice, but A(1)R(-/-) mice showed signs of increased anxiety. Electrophysiological recordings from hippocampal slices revealed that both adenosine-mediated inhibition and theophylline-mediated augmentation of excitatory glutamatergic neurotransmission were abolished in A(1)R(-/-) mice. In A(1)R(+/-) mice the potency of adenosine was halved, as was the number of A(1)R. In A(1)R(-/-) mice, the analgesic effect of intrathecal adenosine was lost, and thermal hyperalgesia was observed, but the analgesic effect of morphine was intact. The decrease in neuronal activity upon hypoxia was reduced both in hippocampal slices and in brainstem, and functional recovery after hypoxia was attenuated. Thus A(1)Rs do not play an essential role during development, and although they significantly influence synaptic activity, they play a nonessential role in normal physiology. However, under pathophysiological conditions, including noxious stimulation and oxygen deficiency, they are important.

Effects of neuroactive substances on the morphine-induced respiratory depression; an in vitro study.

Effects of different neuroactive substances on morphine-induced respiratory depression were studied in medullary respiration-related structures using in vitro brainstem-spinal cord preparation from 1 to 4-day-old rats. Application of morphine (10 microM) reduced respiratory rhythm (fR) as measured by C4 ventral root activity. The depressant effects of morphine were reversed by acetylcholine (10 microM), substance P (50 nM), thyrotropin releasing hormone (TRH) (100 nM) and forskolin (10 microM). The adenosine receptor antagonist, theophylline (100 microM), the dopamine receptors antagonist, haloperidol (10 microM), the cyclooxygenase inhibitor, indomethacin (10 microM) and the phospholipase A(2) inhibitor, quinacrine (10 microM) had no effect on morphine-induced respiratory depression.

Maternal caffeine intake has minor effects on adenosine receptor ontogeny in the rat brain.

Maternal caffeine intake has been suggested to influence the offspring. We have studied the effects of maternal caffeine intake on adenosine and GABA receptors, targets for caffeine, during development of the rat brain. Caffeine (0.3 g/L) was added to the drinking water of rat dams during pregnancy and early postnatal life. Adenosine A1 and A2A and GABAA receptor development was studied using receptor autoradiography and in situ hybridization. Pups were examined on embryonic d 14 (E14), E18, E21, 2 h after birth (P2h), P24h, postnatal d 3 (P3), P7, P14, and P21. Adenosine A, receptor mRNA was detected at E14 and receptors at E18. A1 mRNA levels increased from the level reached at E18 between P3 and P14 (maximally a doubling), whereas A, receptors, studied by [3H]-1,3-dipropyl-8-cyclopentyl xanthine binding, increased later and to a much larger extent (about 10-fold) postnatally. Caffeine treatment had no significant effect on adenosine A1 receptors or on A1 receptor mRNA. A2A mRNA had reached adult levels by E18, whereas receptor levels were low or undetectable before birth and increased dramatically until P14. Caffeine did not influence A2A receptors or A2A receptor mRNA at any stage during development. [3H]-flunitrazepam binding, representing GABAA receptors, showed large regional variations during ontogeny, but there were no clear differences between the caffeine-exposed and the nonexposed pups. Thus, exposure to a low dose of caffeine during gestation and postnatal life had only minor effects on development of adenosine A, and A2A receptors and GABAA receptors in the rat brain.

Adenosinergic modulation of respiratory neurones in the neonatal rat brainstem in vitro.

1. The mechanism underlying adenosinergic modulation of respiration was examined in vitro by applying the whole-cell patch-clamp technique to different types of respiration-related neurones located in the rostral ventrolateral medulla of neonatal rats (0-4 days old). 2. The adenosine A1-receptor agonist (R)-N6-(2-phenylisopropyl)-adenosine (R-PIA, 10 microM; n = 31) increased the burst distance of rhythmic C4 inspiratory discharges and decreased the duration of inspiratory discharges (control: 8.00 +/- 2.49 s and 918 +/- 273 ms; R-PIA: 12.10 +/- 5.60 s and 726 +/- 215 ms). 3. Expiratory neurones demonstrated a reversible decrease in input resistance (Rin), a depression of action potential discharges and a hyperpolarization of the membrane potential (Vm) during application of R-PIA (1-10 microM). Similar responses of Rin and Vm to R-PIA were evident after synaptic activity had been blocked by 0.5 microM tetrodotoxin (TTX). 4. Some of the biphasic expiratory (biphasic E) neurones, but none of the inspiratory neurones, demonstrated changes in Rin or Vm during R-PIA application. With TTX present, R-PIA did not alter Vm or Rin in biphasic expiratory or inspiratory neurones. 5. Furthermore, R-PIA decreased the spontaneous postsynaptic activities of all neurones examined. The effects of R-PIA on respiratory activity, Rin and Vm could be reversed by the A1-receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX; 200 nM). 6. Our data suggest that the modulation of respiratory output induced by adenosinergic agents can be explained by (1) a general decrease in synaptic transmission between medullary respiration-related neurones mediated by presynaptic A1-receptors, and (2) an inactivation, via membrane hyperpolarization, of medullary expiratory neurones mediated by postsynaptic A1-receptors. Furthermore, our data demonstrate that inactivation of expiratory neurones does not abolish the respiratory rhythmic activity, but only modulates respiratory rhythm in vitro.

Age- and temperature-dependent effects of opioids on medulla oblongata respiratory activity: an in vitro study in newborn rat.

Influences of post-natal age (P0-P4) and temperature (22.5 degrees-31.5 degrees C) on the action(s) of opioids on respiratory activities from neonatal rat brainstem-spinal cord preparations were examined in this study. A temperature-dependent mu-opioid receptor effect on respiration was found. In addition, the effect of morphine increased with postnatal age (P0-P4). Hence, age and temperature must be taken into account when performing studies on medullary respiration-related structures using the neonatal rat brainstem-spinal cord preparation.

Adenosine modulates inspiratory neurons and the respiratory pattern in the brainstem of neonatal rats.

The role of adenosine in the modulation of respiration-related neurons was examined using an in vitro brainstem-spinal cord preparation from neonatal rats (0-4 d old). Respiratory activity was recorded from the C4 or C5 ventral roots by suction electrodes and from inspiratory related neurons (I neurons) in the rostral ventrolateral medulla by microelectrodes. The following substances were added to the preparation superfusate, and their effect was evaluated: the adenosine A1 receptor agonist N6-(2-phenylisopropyl)adenosine, R(-)isomer (R-PIA), the adenosine uptake blocker dipyridamole, the adenosine receptor antagonist theophylline, and the specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). R-PIA and dipyridamole decreased the activity of I neurons and the C4 respiratory burst rate. Furthermore, these compounds induced a significantly more irregular respiratory rate in three-quarters of preparations from the youngest animals (<48 h old) compared with that of controls. Theophylline or DPCPX reversed the effects of both R-PIA and dipyridamole on respiratory rate, regularity of respiratory rate, inspiratory time, amplitude, and intra-burst frequency of I neurons. Thus, adenosine depresses both the I neurons in the rostral ventrolateral medulla and the respiratory motor output. This depression of I neurons and respiratory rate can be abolished by theophylline primarily through a blockade of medullary adenosine A1 receptors. An age-dependent correlation of the effects of R-PIA and dipyridamole, with a more pronounced decrease in respiratory activity in preparations from younger animals, indicates that adenosinergic modulation of medullary respiration-related neurons changes during the first days of postnatal life.

Actions of opioids on respiratory activity via activation of brainstem mu-, delta- and kappa-receptors; an in vitro study.

Opioid-induced respiratory depression is well documented. However, exact sites of action and mechanisms for opioid-induced effects on respiration have not yet been elucidated. The present study was carried out on isolated brainstem-spinal cord preparations from newborn rats in order to explore the opioid activity on brainstem mu-, delta- and kappa-receptors. The brainstem-spinal cord was isolated from 0- to 4-day-old Sprague-Dawley rats. The preparation was perfused with artificial cerebrospinal fluid (28.5 degrees C) equilibrated with 95% O2 and 5% CO2 at a pH of 7.4. Neuronal respiratory activity was recorded from the ventrolateral part of the medulla oblongata and efferent impulses from C4 or C5 ventral roots. Effects of the mu-receptor agonist DAGO, the delta-receptor agonist DPDPE and the kappa-receptor agonist U50,488 on respiratory frequency (fR), inspiratory time (Ti) and peak integrated C4 amplitude (Int[C4]) were measured. In addition, the effect of pre-treatment with the mu1 receptor antagonist naloxanazine (35 mg/kg, subcutaneous injection) was evaluated. DAGO reduced fR and Ti in a concentration-dependent manner and caused a reduction of Int(C4) at high concentrations (10 microM). The mu1 receptor antagonist naloxanazine shifted the fR concentration-response curve for DAGO to the right (P < 0.05). DPDPE had no effect on respiratory activities whereas U50,488, like DAGO, reduced fR and Int(C4) in a concentration-dependent manner. It was concluded that mu-opioid receptors, including the mu1 were involved in fR reduction whereas kappa-opioid receptors were involved in reduction of both fR and respiratory amplitude. Delta-opioid receptors do not seem to participate in respiratory modulation at this age.