Case-control study of prolactin and placental lactogen in SGA pregnancies.

Prolactin and placental lactogens increase during pregnancy and are involved with many aspects of maternal metabolic adaptation to pregnancy, likely to impact on fetal growth. The aim of this study was to determine whether maternal plasma prolactin or placental lactogen concentrations at 20 weeks of gestation were associated with later birth of small-for-gestational-age babies (SGA). In a nested case-control study, prolactin and placental lactogen in plasma samples obtained at 20 weeks of gestation were compared between 40 women who gave birth to SGA babies and 40 women with uncomplicated pregnancies and size appropriate-for-gestation-age (AGA) babies. Samples were collected as part of the 'screening of pregnancy endpoints' (SCOPE) prospective cohort study. SGA was defined as birthweight <10th customized birthweight centile (adjusted for maternal weight, height, ethnicity, parity, infant sex, and gestation age) in mothers who remained normotensive. No significant differences were observed in concentrations of prolactin or placental lactogen from women who gave birth to SGA babies compared with women with uncomplicated pregnancies. However, a sex-specific association was observed in SGA pregnancies, whereby lower maternal prolactin concentration at 20 weeks of gestation was observed in SGA pregnancies that were carrying a male fetus (132.0 ± 46.7 ng/mL vs 103.5 ± 38.3 ng/mL, mean ± s.d., P = 0.036 Student's t-test) compared to control pregnancies carrying a male fetus. Despite the implications of these lactogenic hormones in maternal metabolism, single measurements of either prolactin or placental lactogen at 20 weeks of gestation are unlikely to be useful biomarkers for SGA pregnancies. LAY SUMMARY: Early identification during pregnancy of small for gestational age (SGA) babies would enable interventions to lower risk of complications around birth (perinatal), but current detection rates of these at risk babies is low. Pregnancy hormones, prolactin and placental lactogen, are involved in metabolic changes that are required for the mother to support optimal growth and development of her offspring during pregnancy. The levels of these hormones may provide a measurable indicator (biomarker) to help identify these at risk pregnancies. Levels of these hormones were measured in samples from week 20 of gestation from women who went on to have SGA babies and control pregnancies where babies were born at a size appropriate for gestation age. Despite the implications of prolactin and placental lactogen in maternal metabolism, no significant differences were detected suggesting that single measures of either prolactin or placental lactogen at 20 weeks gestation are unlikely to be useful biomarker to help detect SGA pregnancies.

Prolactin receptor-mediated activation of pSTAT5 in the pregnant mouse brain.

Pregnancy represents a period of remarkable adaptive physiology throughout the body, with many of these important adaptations mediated by changes in gene transcription in the brain. A marked activation of the transcription factor signal transducer and activator of transcription 5 (STAT5) has been described in the brain during pregnancy and likely drives some of these changes. We aimed to investigate the physiological mechanism causing this increase in phosphorylated STAT5 (pSTAT5) during pregnancy. In various tissues, STAT5 is known to be activated by a number of different cytokines, including erythropoietin, growth hormone and prolactin. Because the lactogenic hormones that act through the prolactin receptor (PRLR), prolactin and its closely-related placental analogue placental lactogen, are significantly increased during pregnancy, we hypothesised that this receptor was primarily responsible for the pregnancy-induced increase in pSTAT5 in the brain. By examining temporal changes in plasma prolactin levels and the pattern of pSTAT5 immunoreactivity in the hypothalamus during early pregnancy, we found that the level of pSTAT5 was sensitive to circulating levels of endogenous prolactin. Using a transgenic model to conditionally delete PRLRs from forebrain neurones (Prlrlox/lox /CamK-Cre), we assessed the relative contribution of the PRLR to the up-regulation of pSTAT5 in the brain of pregnant mice. In the absence of PRLRs on most forebrain neurones, a significant reduction in pSTAT5 was observed throughout the hypothalamus and amygdala in late pregnancy, confirming that PRLR is key in mediating this response. The exception to this was the hypothalamic paraventricular nucleus, where only 17% of pSTAT5 immunoreactivity during pregnancy was in PRLR-expressing cells. Taken together, these data indicate that, although there are region-specific mechanisms involved, lactogenic activity through the PRLR is the primary signal activating STAT5 in the brain during pregnancy.

Conditional Deletion of the Prolactin Receptor Reveals Functional Subpopulations of Dopamine Neurons in the Arcuate Nucleus of the Hypothalamus.

UNLABELLED: Tuberoinfundibular dopamine (TIDA) neurons, known as neuroendocrine regulators of prolactin secretion from the pituitary gland, also release GABA within the hypothalamic arcuate nucleus. As these neurons express prolactin receptors (Prlr), prolactin may regulate GABA secretion from TIDA neurons, potentially mediating actions of prolactin on hypothalamic function. To investigate whether GABA is involved in feedback regulation of TIDA neurons, we examined the physiological consequences of conditional deletion of Prlr in GABAergic neurons. For comparison, we also examined mice in which Prlr were deleted from most forebrain neurons. Both neuron-specific and GABA-specific recombination of the Prlr gene occurred throughout the hypothalamus and in some extrahypothalamic regions, consistent with the known distribution of Prlr expression, indicative of knock-out of Prlr. This was confirmed by a significant loss of prolactin-induced phosphorylation of STAT5, a marker of prolactin action. Several populations of GABAergic neurons that were not previously known to be prolactin-sensitive, notably in the medial amygdala, were identified. Approximately 50% of dopamine neurons within the arcuate nucleus were labeled with a GABA-specific reporter, but Prlr deletion from these dopamine/GABA neurons had no effect on feedback regulation of prolactin secretion. In contrast, Prlr deletion from all dopamine neurons resulted in profound hyperprolactinemia. The absence of coexpression of tyrosine hydroxylase, a marker for dopamine production, in GABAergic nerve terminals in the median eminence suggested that rather than a functional redundancy within the TIDA population, the dopamine/GABA neurons in the arcuate nucleus represent a subpopulation with a functional role distinct from the regulation of prolactin secretion. SIGNIFICANCE STATEMENT: Using a novel conditional deletion of the prolactin receptor, we have identified functional subpopulations in hypothalamic dopamine neurons. Although commonly considered a uniform population of neuroendocrine neurons involved in the control of prolactin secretion, we have shown that approximately half of these neurons express GABA as well as dopamine, but these neurons are not necessary for the feedback regulation of prolactin secretion. The absence of tyrosine hydroxylase in GABAergic nerve terminals in the median eminence suggests that only the non-GABAergic dopamine neurons are involved in the control of pituitary prolactin secretion, and the GABAergic subpopulation may function as interneurons within the arcuate nucleus to regulate other aspects of hypothalamic function.

Basic life support knowledge, self-reported skills and fears in Danish high school students and effect of a single 45-min training session run by junior doctors; a prospective cohort study.

BACKGROUND: Early recognition and immediate bystander cardiopulmonary resuscitation are critical determinants of survival after out-of-hospital cardiac arrest (OHCA). Our aim was to evaluate current knowledge on basic life support (BLS) in Danish high school students and benefits of a single training session run by junior doctors. METHODS: Six-hundred-fifty-one students were included. They underwent one 45-minute BLS training session including theoretical aspects and hands-on training with mannequins. The students completed a baseline questionnaire before the training session and a follow-up questionnaire one week later. The questionnaire consisted of an eight item multiple-choice test on BLS knowledge, a four-level evaluation of self-assessed BLS skills and evaluation of fear based on a qualitative description and visual analog scale from 0 to 10 for being first responder. RESULTS: Sixty-three percent of the students (413/651) had participated in prior BLS training. Only 28% (179/651) knew how to correctly recognize normal breathing. The majority was afraid of exacerbating the condition or causing death by intervening as first responder. The response rate at follow-up was 61% (399/651). There was a significant improvement in correct answers on the multiple-choice test (p < .001). The proportion of students feeling well prepared to perform BLS increased from 30% to 90% (p < .001), and the level of fear of being first responder was decreased 6.8 ± 2.2 to 5.5 ± 2.4 (p < .001). CONCLUSION: Knowledge of key areas of BLS is poor among high school students. One hands-on training session run by junior doctors seems to be efficient to empower the students to be first responders to OHCA.

Data quality of the monoclonal gammopathy of undetermined significance diagnosis in a hospital registry.

OBJECTIVE: To estimate the positive predictive value (PPV) and completeness of the monoclonal gammopathy of undetermined significance (MGUS) diagnosis coding in a hospital registry within a population-based health-care setting. PATIENTS AND METHODS: Through the Danish National Patient Registry (DNPR), we identified 627 patients registered with MGUS in two Danish regions during the period January 2001-February 2011. We reviewed the medical records of all patients registered with MGUS at the Department of Hematology, Aalborg University Hospital, and a sample of patients registered at the other three hematological departments in the two regions. We estimated the PPV of the MGUS diagnosis based on this sample of 327 medical records. We also estimated the completeness of the DNPR by linking data from the DNPR and data from a previously validated MGUS cohort of 791 patients identified through the laboratory system covering North Jutland Region. RESULTS: The diagnosis of MGUS was confirmed in 231 patients and assessed as probable in an additional 38 patients, corresponding to a PPV of 82.3% (95% confidence interval [CI] 78.1%-86.4%). By contrast, 58 (17.7%) of the patients did not definitively meet the diagnostic criteria for MGUS. When we excluded patients registered with malignant monoclonal gammopathy recorded prior to or within the first year after registration of MGUS in the DNPR, the PPV increased to 88.3% (95% CI 84.5%-92.1%). The DNPR only registered a diagnosis of MGUS in 133 of the 791 MGUS patients identified through the laboratory system, corresponding to a completeness of 16.8% (95% CI 14.1%-19.6%). CONCLUSION: The PPV of the diagnosis coding for MGUS in the DNPR is high and can be further improved by simple data restriction. However, the low completeness raises concern that MGUS patients registered in the hospital system may be highly selected.

Exposure to female pheromones during pregnancy causes postpartum anxiety in mice.

The postpartum period is associated with an increased incidence of pathological anxiety, exerting a substantial burden on both the mother and the baby. We have shown that pharmacological suppression of prolactin in early pregnancy decreases maternal neurogenesis to cause postpartum anxiety. The present data demonstrate that physiological suppression of prolactin secretion through exposure to unfamiliar female pheromones throughout pregnancy prevented the normal postpartum attenuation of anxiety in mice, resulting in high anxiety relative to postpartum controls. Female pheromone-exposed mice also showed severely impaired maternal behavior in an anxiogenic situation. Mice exposed to female pheromones had decreased serum prolactin levels in early pregnancy, resulting in an ablation of the normal increase of neurogenesis on day 7 of pregnancy. These data demonstrate that low serum prolactin levels in early pregnancy, whether induced pharmacologically or as a physiological consequence of exposure to unfamiliar female pheromones, result in failure to show the normal adaptive decrease in anxiety after birth. This provides new insight into possible mechanisms that might underlie postpartum anxiety in women.

Prolactin-induced mitogenesis in the subventricular zone of the maternal brain during early pregnancy is essential for normal postpartum behavioral responses in the mother.

High prolactin during pregnancy, which is essential for normal postpartum maternal behavior, increases neurogenesis in the subventricular zone of the lateral ventricle (SVZ) of the maternal brain. Because SVZ mitogenesis generates new olfactory neurons and may contribute to perception of novel odorants, we hypothesized that the prolactin-induced increase in SVZ mitogenesis during pregnancy might be important for normal maternal interactions with pups. To investigate this hypothesis, prolactin secretion was suppressed for 3 d early in pregnancy in mice, using a carefully timed dose of bromocriptine. The bromocriptine-induced reduction in prolactin prevented the normal increase in generation of neural progenitors in the SVZ of the maternal brain. Another group of bromocriptine-treated animals were allowed to continue their pregnancy until term, and then maternal behaviors were evaluated postpartum. Low prolactin during early pregnancy, and the consequent suppression of mitogenesis in the SVZ of the maternal brain, was subsequently followed by increased postpartum anxiety and markedly impaired maternal behavior. In another group of pregnant females, injections of the mitotic inhibitor methylazoxymethanol to specifically suppress neurogenesis in the mother during early pregnancy without affecting prolactin secretion also caused postpartum anxiety and impaired maternal behavior. These data demonstrate that prolactin-induced increase in generation of neural progenitors in the SVZ of the maternal brain during early pregnancy is required for normal expression of postpartum maternal behaviors.

Male pheromones initiate prolactin-induced neurogenesis and advance maternal behavior in female mice.

Prolactin is required for rapid onset of maternal behavior after parturition, inducing adaptive changes in the maternal brain including enhanced neurogenesis in the subventricular zone during pregnancy. The resultant increase in olfactory interneurons may be required for altered processing of olfactory cues during the establishment of maternal behavior. Pheromones act through olfactory pathways to exert powerful effects on behavior in rodents and also affect prolactin secretion. Hence, this study aimed to investigate the effect of male pheromones on neurogenesis and maternal behavior in female mice. Virgin female mice were housed individually or in split-cages where they had pheromonal but not physical contact with a male. Maternal behavior was assessed in a foster pup retrieval paradigm. Some mice were injected with bromodeoxyuridine, and the labeled cells visualized using immunohistochemistry. The data show that exposure to male pheromones, for a duration equivalent to a murine pregnancy, advanced maternal behavior in both virgin and postpartum female mice. The pheromone action was dependent on prolactin and ovarian steroids, and was associated with increased cell proliferation in the subventricular zone and subsequent increases in new neurons in the olfactory bulb. Moreover, the effect of pheromones on both cell proliferation and maternal behavior could be induced solely through administration of exogenous prolactin to mimic the pheromone-induced changes in prolactin secretion. The data suggest that male pheromones induce a prolactin-mediated increase in neurogenesis in female mice, resulting in advanced maternal behavior.