Patient Pain and Satisfaction With 10, 30, and 70 mL Transcervical Foley Balloons for Cervical Ripening During Induction of Labor.

Objective To assess patient pain and satisfaction and time to delivery following transcervical Foley catheter balloon inflation to 10, 30, or 70 mL with simultaneous administration of oxytocin. Methods We performed a randomized prospective study with 30 or 70 mL transcervical Foley balloon catheters in combination with oxytocin during labor induction at term. A 10 mL group was included as a sham control group. Time to delivery was measured, and a patient questionnaire was administered at the time the catheter was expelled to determine patient pain and satisfaction. Results In 120 enrolled patients, there was a non-significant trend toward reduced time to delivery in the large Foley balloon group (10 mL: 30:45 ± 38:53, 30 mL: 26:41 ± 20:53, and 70 mL 22:40 ± 15:35, hh:mm, P = 0.412). The pain score at the time the balloon was expelled was significantly higher in the 70 ml group compared to the 10 ml and 30 ml groups (P = 0.004 and P = 0.034, respectively). We found no other differences in patient satisfaction or pain scores at the time of placement of the Foley catheter for the three groups. Conclusion Small gains in time to delivery should be balanced against patient experiences, and expectations of pain during the ripening process should be addressed at the time of Foley insertion.

Uterine Dehiscence in the Early Third Trimester: A Report of Two Cases.

As the incidence of cesarean deliveries increases, so do its accompanying complications. Although the incidence of uterine dehiscence in the late second trimester to the early third trimester is rare, it may be a potentially catastrophic complication if uterine rupture occurs. Here, we present two cases of uterine dehiscence at 28 and 29 weeks, which were diagnosed on prenatal ultrasound and confirmed intraoperatively at the time of cesarean delivery. We recommend consideration of earlier screening for preoperative detection of uterine dehiscence to help prevent maternal and neonatal morbidity and mortality.

Interest in and Barriers to Telehealth Uptake in an Obstetric and Pediatric Medicaid Population.

Telehealth has been shown to be generally well accepted by patients and physicians with an increasing desire and utilization of this practice since the COVID-19 pandemic. However, studies looking specifically at the United States' low socioeconomic populations' interest in and barriers to accessing Telehealth care are limited. In this study, we performed a survey to determine the interest of pediatric and obstetric patients on and the reasons they may or may not choose Telehealth visits in a practice that serves solely California Medicaid (Medi-Cal) patients. A total of 636 patients completed the questionnaire, 383 (60%) from an obstetric practice and 253 (40%) from a pediatric practice. The majority expressed that they were not interested in Telehealth (N=407, 64%), and 228 (36%) stated interest. Interest in Telehealth was related to domains of cost, access, and attitude (P<0.005 for each) for the entire sample. The highest scores (preference toward Telehealth) were noted in the domain of enjoyment; this suggests that both pediatric and obstetric patients may decline Telehealth in favor of in-person meetings simply because they like meeting with their provider. Despite readily available technology/access for Telehealth visits in low socioeconomic patients, in-person healthcare may be preferred by this patient population. In the world of changing healthcare delivery and epidemics, in-person visits are an important option for disadvantaged patients.

Cinaciguat (BAY-582667) Modifies Cardiopulmonary and Systemic Circulation in Chronically Hypoxic and Pulmonary Hypertensive Neonatal Lambs in the Alto Andino.

Neonatal pulmonary hypertension (NPHT) is produced by sustained pulmonary vasoconstriction and increased vascular remodeling. Soluble guanylyl cyclase (sGC) participates in signaling pathways that induce vascular vasodilation and reduce vascular remodeling. However, when sGC is oxidized and/or loses its heme group, it does not respond to nitric oxide (NO), losing its vasodilating effects. sGC protein expression and function is reduced in hypertensive neonatal lambs. Currently, NPHT is treated with NO inhalation therapy; however, new treatments are needed for improved outcomes. We used Cinaciguat (BAY-582667), which activates oxidized and/or without heme group sGC in pulmonary hypertensive lambs studied at 3,600 m. Our study included 6 Cinaciguat-treated (35 ug kg-1 day-1 x 7 days) and 6 Control neonates. We measured acute and chronic basal cardiovascular variables in pulmonary and systemic circulation, cardiovascular variables during a superimposed episode of acute hypoxia, remodeling of pulmonary arteries and changes in the right ventricle weight, vasoactive functions in small pulmonary arteries, and expression of NO-sGC-cGMP signaling pathway proteins involved in vasodilation. We observed a decrease in pulmonary arterial pressure and vascular resistance during the acute treatment. In contrast, the pulmonary pressure did not change in the chronic study due to increased cardiac output, resulting in lower pulmonary vascular resistance in the last 2 days of chronic study. The latter may have had a role in decreasing right ventricular hypertrophy, although the direct effect of Cinaciguat on the heart should also be considered. During acute hypoxia, the pulmonary vascular resistance remained low compared to the Control lambs. We observed a higher lung artery density, accompanied by reduced smooth muscle and adventitia layers in the pulmonary arteries. Additionally, vasodilator function was increased, and vasoconstrictor function was decreased, with modifications in the expression of proteins linked to pulmonary vasodilation, consistent with low pulmonary vascular resistance. In summary, Cinaciguat, an activator of sGC, induces cardiopulmonary modifications in chronically hypoxic and pulmonary hypertensive newborn lambs. Therefore, Cinaciguat is a potential therapeutic tool for reducing pulmonary vascular remodeling and/or right ventricular hypertrophy in pulmonary arterial hypertension syndrome.

Prevalence of the number of pre-gestational diagnoses and trends in the United States in 2006 and 2016.

INTRODUCTION: There is a trend in reproductive-aged women to live with more chronic conditions, likely resulting in pregnancies complicated by one or more pre-gestational diagnoses. The objective of this study is to determine the prevalence of women with pre-gestational diagnoses and pregnancy-related complications, and assess the trends of pre-gestational diagnoses between two time-points, ten-years apart from 2006 to 2016. MATERIALS AND METHODS: We abstracted pregnant patients from the Healthcare Cost and Utilization Project's National Inpatient Sample by the Agency for Healthcare Research and Quality in 2006 and 2016. We classified diagnosis codes, ICD 9 for 2006 and ICD 10 for 2016, as pre-gestational diagnoses or as pregnancy-related complications. Descriptive statistics were presented as frequencies and proportions for categorical variables. Chi-square analysis was performed. All statistical analyses were two-sided and p-value < .05 was considered to be statistically significant. RESULTS: Between 2006 and 2016, the percentage of patients with at least one pre-gestational diagnoses increased from 35.3% in 2006 to 53.8% in 2016 (p < .0001) and the percentage of patients with at least one pregnancy-related complication increased from 62.6% to 69.1% (p < .0001). We found a trend of increasing pregnancy-related complications with an increasing number of pre-gestational diagnoses. The prevalence of asthma and obesity, either alone or in combination were found to rise over the ten-year time span. CONCLUSION: The percent of patients entering pregnancy with any pre-gestational diagnosis has increased, along with the number of pregnancy-related complications. Future research is needed to understand the effects of these diagnoses in combination and the possible impact on pregnancy outcomes.

Outpatient Cervical Ripening With Misoprostol in Low-Risk Pregnancies.

Objective To determine if outpatient cervical ripening with daily misoprostol can reduce admission to delivery time in women with low-risk pregnancies at 39 or more weeks of gestation. Study design This is a retrospective cohort study of a convenience sample of low-risk pregnancies that underwent elective outpatient cervical ripening compared to matched controls for parity (nulliparous vs. parous) and gestational age. Time from admission to delivery, induction agents, presence of tachysystole, mode of delivery, length of hospitalization, neonatal intensive care unit (NICU) admission, and low Apgar scores were compared. Results Fifty-six patients who underwent outpatient cervical ripening with daily dosing of misoprostol were compared to 56 patients matched for parity and gestational weeks who underwent inpatient cervical ripening/induction of labor with misoprostol. We found the time from admission to delivery in the outpatient cervical ripening cohort was significantly lesser than the inpatient cohort (17.5 ± 11.5 hours outpatient vs. 26.6 ± 15.6 hours inpatient, P=0.001). More patients (N=18, 32%) were able to deliver within 12 hours of admission in the outpatient induction group compared to the inpatient group (N=8, 11%, P=0.010). There were no differences in frequency of cesarean delivery, uterine tachysystole with or without fetal heart rate changes, NICU admission, low Apgar scores, or low umbilical artery pH values between the two groups. Conclusion Outpatient cervical ripening with misoprostol may be a feasible alternative to inpatient cervical ripening in low-risk pregnancies, may help improve patient experience, and reduce the operational burden that elective induction confers upon labor and delivery units.

Common Combinations of Pregestational Diagnosis and Pregnancy Complications.

Objective Single pregestational diagnoses have been demonstrated to be associated with pregnancy-related complications. But, the effect of multiple diagnoses is understudied. The objective of this study is to determine the most common combinations of pregestational diagnoses and to determine if specific combinations increase the risk of pregnancy-related complications. Study design We performed a cross-sectional study of the 2016 Healthcare Cost and Utilization Project's National Inpatient Sample (HCUP NIS) database. Inclusion criteria were: Diagnosis-related groups assumed to be associated with delivery, and three or fewer International Classification of Diseases, Tenth Revision (ICD-10), clinical modification codes with a prevalence greater than or equal to 0.5%, or clinically important risk factors in Bateman's co-morbidity index. Chi-squared analysis of combinations of pregestational diagnoses was performed to assess the relative risk of pregnancy-related complications. Results The 2016 database included 255,233 delivered pregnancies. The most common combinations of pregestational diagnoses involved advanced maternal age, prior cesarean delivery, obesity, and tobacco use. Most combinations did not demonstrate an increased risk for complications greater than the risk with a single diagnosis. In those with statistically significant risk, all were 3-fold or less except we noted a 4.4-fold higher risk (95% CI: 3.16-6.15) of preeclampsia in obese patients of advanced maternal age compared to patients who were only of advanced maternal age. Conclusion Our results revealed that common combinations of pregestational diagnoses, in general, do not increase the risk for common pregnancy-related complications greater than the risk with a single diagnosis. This is reassuring, given that women entering pregnancy with multiple co-morbidities are becoming more common.

Efficacy of Long-Term Treatment with Once-Daily Baricitinib 2 mg in Patients with Active Rheumatoid Arthritis: Post Hoc Analysis of Two 24-Week, Phase III, Randomized, Controlled Studies and One Long-Term Extension Study.

INTRODUCTION: To evaluate long-term efficacy of once-daily baricitinib 2 mg in patients with active rheumatoid arthritis who had an inadequate response (IR) to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) or biologic DMARDs (bDMARD). METHODS: Data from patients treated with baricitinib 2 mg daily in two 24-week, phase III studies, RA-BUILD (csDMARD-IR; NCT01721057) and RA-BEACON (bDMARD-IR; NCT01721044), and one long-term extension study (RA-BEYOND; NCT01885078), were analyzed (120 weeks). The main outcomes were achievement of low-disease activity (LDA; Simple Disease Activity Index [SDAI] ≤ 11), clinical remission (SDAI ≤ 3.3), Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5 and improvement from baseline of ≥ 0.22, and safety. Analysis populations included (1) all patients and (2) never-rescued patients. Completer and non-responder imputation (NRI) analyses were conducted on each population. RESULTS: In RA-BUILD, 684 were randomized (229 to baricitinib 2 mg, 180 of whom completed RA-BUILD and entered RA-BEYOND). In RA-BEACON, 527 were randomized (174 to baricitinib 2 mg, 117 of whom completed RA-BEACON and entered RA-BEYOND). In RA-BUILD-BEYOND, 85.1% (63/74, completer) and 27.5% (63/229, NRI) of csDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 40.5% (30/74, completer) and 13.1% (30/229, NRI) were in SDAI remission; 62.2% (46/74, completer) and 20.1% (46/229, NRI) had HAQ-DI ≤ 0.5 and 81.1% (60/74, completer); and 26.2% (60/229, NRI) achieved ≥ 0.22 change from baseline at week 120. In RA-BEACON-BEYOND, 86.5% (32/37, completer) and 18.4% (32/174, NRI) of bDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 24.3% (9/37, completer) and 5.2% (9/174, NRI) were in SDAI remission; 50.0% (19/38, completer) and 10.9% (19/174, NRI) had HAQ-DI ≤ 0.5; and 73.7% (28/38, completer) and 16.1% (28/174, NRI) achieved ≥ 0.22 change from baseline at week 120. Rates of adverse events of special interest were consistent with previous reports. CONCLUSIONS: Long-term treatment with baricitinib 2 mg demonstrated efficacy for up to 120 weeks and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01721057, NCT01721044, and NCT01885078.

Colorectal Cancer Diagnosed During Pregnancy With Delayed Treatment.

Colorectal cancer during pregnancy is rare. Because of a pattern of delay in childbearing and because colorectal cancer is now diagnosed more often in young adults, the incidence is expected to rise. Diagnosis during pregnancy is challenging as many of the symptoms mimic common pregnancy symptoms. Colonoscopy is the gold standard for diagnosis, but pregnancy is a relative contraindication to colonoscopy. Once diagnosed, pregnant women often have more advanced disease. Due to its rarity, treatment is often based on case reports and limited studies. A multidisciplinary team is important in the optimization of treatment. We present a case of a 29-year-old African-American primigravid with chronic gastrointestinal symptoms diagnosed with colorectal adenocarcinoma at 17 weeks of gestation. She delayed surgical intervention for several weeks due to fear of miscarriage, and ultimately underwent exploratory laparotomy with hemicolectomy and colostomy placement at 20 weeks. Abdominal ultrasound and magnetic resonance imaging revealed non-specific hepatic lesions concerning for metastatic disease, but the patient refused biopsy due to concern for radiation harm to the fetus. Chemotherapy was considered, but postponed until the postpartum period, for fear of fetal harm. Computed tomography imaging after delivery noted an increased number of hepatic lesions, representing progression of her disease. She received two rounds of chemotherapy in the postpartum period, but remained non-compliant with treatment recommendations and ultimately was lost to follow-up.  This case presents a delayed diagnosis of colorectal cancer in pregnancy, as well as delayed treatment due to concerns for fetal harm with current therapies. It emphasizes the diagnostic challenges and the complexity and ethical issues involved when a pregnant patient faces a life-threatening terminal illness. This case adds to the growing body of literature on colorectal cancer in pregnancy and highlights the importance of clinical suspicion, informed patient centered decision making, and tailored treatment goals.

Effects of Melatonin on the Defense to Acute Hypoxia in Newborn Lambs.

Neonatal lambs, as other neonates, have physiologically a very low plasma melatonin concentration throughout 24 h. Previously, we found that melatonin given to neonates daily for 5 days decreased heart weight and changed plasma cortisol and gene expression in the adrenal and heart. Whether these changes could compromise the responses to life challenges is unknown. Therefore, firstly, we studied acute effects of melatonin on the defense mechanisms to acute hypoxia in the neonate. Eleven lambs, 2 weeks old, were instrumented and subjected to an episode of acute isocapnic hypoxia, consisting of four 30 min periods: normoxia (room air), normoxia after an i.v. bolus of melatonin (0.27 mg kg-1, n = 6) or vehicle (ethanol 1:10 NaCl 0.9%, n = 5), hypoxia (PaO2: 30 ± 2 mmHg), and recovery (room air). Mean pulmonary and systemic blood pressures, heart rate, and cardiac output were measured, and systemic and pulmonary vascular resistance and stroke volume were calculated. Blood samples were taken every 30 min to measure plasma norepinephrine, cortisol, glucose, triglycerides, and redox markers (8-isoprostane and FRAP). Melatonin blunted the increase of pulmonary vascular resistance triggered by hypoxia, markedly exacerbated the heart rate response, decreased heart stroke volume, and lessened the magnitude of the increase of plasmatic norepinephrine and cortisol levels induced by hypoxia. No changes were observed in pulmonary blood pressure, systemic blood pressures and resistance, cardiac output, glucose, triglyceride plasma concentrations, or redox markers. Melatonin had no effect on cardiovascular, endocrine, or metabolic variables, under normoxia. Secondly, we examined whether acute melatonin administration under normoxia could have an effect in gene expression on the adrenal, lung, and heart. Lambs received a bolus of vehicle or melatonin and were euthanized 30 min later to collect tissues. We found that melatonin affected expression of the immediate early genes egr1 in adrenal, ctgf in lung, and nr3c1, the glucocorticoid receptor, in adrenal and heart. We speculate that these early gene responses may contribute to the observed alterations of the newborn defense mechanisms to hypoxia. This could be particularly important since the use of melatonin is proposed for several diseases in the neonatal period in humans.

Delayed-Interval Delivery of Twin Gestation via Cesarean Section: A Case Report.

BACKGROUND Multifetal pregnancies are at high risk for preterm delivery. Under certain circumstances, delayed vaginal delivery of the second twin is performed to improve morbidity and mortality. Most of the information on optimal management of delayed-interval delivery comes from published case reports in which the first twin was delivered vaginally. This case report is unique in that twin A was delivered via cesarean section. CASE REPORT Our patient was a 21-year-old G2P1, with dichorionic diamniotic twins of unknown gestational age, with prenatal care at a different facility, who presented with preterm prelabor rupture of membranes and cord prolapse. Twin A, with an estimated weight by ultrasound of 528 g, was delivered via cesarean section and twin B was left in utero until the patient went into preterm labor 10 days later. Obstetrical management included tocolytic protocol from the Management of Myelomeningocele Study trial, preterm prelabor rupture of membrane antibiotics with broad-spectrum coverage, and judicious use of fetal lung maturity steroids and magnesium sulfate. CONCLUSIONS This case is important as we have demonstrated that cesarean section in the setting of delayed-interval delivery may be an option to improve survival at the limits of viability. We also discussed our treatment approach and how we delayed delivery of the second twin by 10 days. Unexpectedly, the surviving twin was the one born first, at 22 4/7 weeks determined 2 days after birth by prenatal records.

Pregnancies Complicated by Familial Hypertriglyceridemia: A Case Report.

Background Although rare, familial hypertriglyceridemia can cause acute and life-threatening complications in pregnancy. Cases The first patient's pregnancy was complicated by multiple admissions for pancreatitis due to hypertriglyceridemia and noncompliance with gemfibrozil. In her second pregnancy, she was compliant with gemfibrozil and only experienced pancreatitis episodes toward the end of pregnancy. The second patient had diabetes mellitus and familial hypertriglyceridemia. She required multiple hospitalizations for diabetic ketoacidosis secondary to insulin noncompliance. In both pregnancies, she was compliant with gemfibrozil and had no complications related to hypertriglyceridemia. Conclusion Treatment with gemfibrozil in pregnancies complicated by hypertriglyceridemia may prevent complications without adverse maternal or fetal effects and could be considered in treating pregnant patients with severe hypertriglyceridemia. These cases also demonstrate the importance of medication compliance in the prevention of poor outcomes.

Developmental Programming of Capuchin Monkey Adrenal Dysfunction by Gestational Chronodisruption.

In the capuchin monkey (Cebus apella), a new-world nonhuman primate, maternal exposure to constant light during last third of gestation induces precocious maturation of the fetal adrenal and increased plasma cortisol in the newborn. Here, we further explored the effects of this challenge on the developmental programming of adrenal function in newborn and infant capuchin monkeys. We measured (i) plasma dehydroepiandrosterone sulphate (DHAS) and cortisol response to ACTH in infants with suppressed endogenous ACTH, (ii) plasma DHAS and cortisol response to ACTH in vitro, and (iii) adrenal weight and expression level of key factors in steroid synthesis (StAR and 3ß-HSD). In one-month-old infants from mothers subjected to constant light, plasma levels of cortisol and cortisol response to ACTH were twofold higher, whereas plasma levels of DHAS and DHAS response to ACTH were markedly reduced, compared to control conditions. At 10 months of age, DHAS levels were still lower but closer to control animals, whereas cortisol response to ACTH was similar in both experimental groups. A compensatory response was detected at the adrenal level, consisting of a 30% increase in adrenal weight and about 50% reduction of both StAR and 3ß-HSD mRNA and protein expression and the magnitude of DHAS and cortisol response to ACTH in vitro. Hence, at birth and at 10 months of age, there were differential effects in DHAS, cortisol production, and their response to ACTH. However, by 10 months of age, these subsided, leading to a normal cortisol response to ACTH. These compensatory mechanisms may help to overcome the adrenal alterations induced during pregnancy to restore normal cortisol concentrations in the growing infant.

Deciphering the Function of the Blunt Circadian Rhythm of Melatonin in the Newborn Lamb: Impact on Adrenal and Heart.

Neonatal lambs, as with human and other neonates, have low arrhythmic endogenous levels of melatonin for several weeks until they start their own pineal rhythm of melatonin production at approximately 2 weeks of life. During pregnancy, daily rhythmic transfer of maternal melatonin to the fetus has important physiological roles in sheep, nonhuman primates, and rats. This melatonin rhythm provides a circadian signal and also participates in adjusting the physiology of several organs in preparation for extrauterine life. We propose that the ensuing absence of a melatonin rhythm plays a role in neonatal adaptation. To test this hypothesis, we studied the effects of imposing a high-amplitude melatonin rhythm in the newborn lamb on (1) clock time-related changes in cortisol and plasma variables and (2) clock time-related changes of gene expression of clock genes and selected functional genes in the adrenal gland and heart. We treated newborn lambs with a daily oral dose of melatonin (0.25 mg/kg) from birth to 5 days of age, recreating a high-amplitude melatonin rhythm. This treatment suppressed clock time-related changes of plasma adrenocorticotropic hormone, cortisol, clock gene expression, and functional genes in the newborn adrenal gland. In the heart, it decreased heart/body weight ratio, increased expression of Anp and Bnp, and resulted in different heart gene expression from control newborns. The interference of this postnatal melatonin treatment with the normal postnatal pattern of adrenocortical function and heart development support a physiological role for the window of flat postnatal melatonin levels during the neonatal transition.

Cumulative oxytocin dose during induction of labor according to maternal body mass index.

OBJECTIVE: To determine the cumulative oxytocin dose needed to achieve vaginal delivery among obese and non-obese women. METHODS: A retrospective study was undertaken of women with singleton, term (≥37 weeks) pregnancies who delivered at an institution in California, USA, between May 1 and July 31, 2012. Women were deemed to be obese when their body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) was 30 or above. Cumulative oxytocin doses were calculated for women who achieved vaginal delivery. RESULTS: Overall, 413 women were included. Among 357 women for whom BMI data were available, 204 (57.1%) were obese. Vaginal delivery was achieved in 379 women. Among women who received augmentation after spontaneous labor onset, obese women trended towards more cumulative oxytocin (minimum: 24.7 ± 100.5 mU among women with a BMI of 18.50-24.99; maximum: 1580.5 ± 2530.5 mU among women with a BMI of 35.00-39.99; P=0.086). Women who underwent induction of labor required significantly more oxytocin with increasing BMI class (P<0.001), despite no difference in length of labor. CONCLUSION: Obese women required a larger cumulative oxytocin dose to achieve vaginal birth during labor induction, but not during augmentation of labor. The physiology of spontaneous labor could supersede or influence the metabolic derangement facing obese patients undergoing induction of labor.

Impact of Maternal Melatonin Suppression on Amount and Functionality of Brown Adipose Tissue (BAT) in the Newborn Sheep.

In human and sheep newborns, brown adipose tissue (BAT) accrued during fetal development is used for newborn thermogenesis. Here, we explored the role of maternal melatonin during gestation on the amount and functionality of BAT in the neonate. We studied BAT from six lambs gestated by ewes exposed to constant light from 63% gestation until delivery to suppress melatonin (LL), six lambs gestated by ewes exposed to LL but receiving daily oral melatonin (12 mg at 1700 h, LL + Mel) and another six control lambs gestated by ewes maintained in 12 h light:12 h dark (LD). Lambs were instrumented at 2 days of age. At 4-6 days of age, they were exposed to 24°C (thermal neutrality conditions) for 1 h, 4°C for 1 h, and 24°C for 1 h. Afterward, lambs were euthanized and BAT was dissected for mRNA measurement, histology, and ex vivo experiments. LL newborns had lower central BAT and skin temperature under thermal neutrality and at 4°C, and higher plasma norepinephrine concentration than LD newborns. In response to 4°C, they had a pronounced decrease in skin temperature and did not increase plasma glycerol. BAT weight in LL newborns was about half of that of LD newborns. Ex vivo, BAT from LL newborns showed increased basal lipolysis and did not respond to NE. In addition, expression of adipogenic/thermogenic genes (UCP1, ADBR3, PPARγ, PPARα, PGC1α, C/EBPß, and perilipin) and of the clock genes Bmal1, Clock, and Per2 was increased. Remarkably, the effects observed in LL newborns were absent in LL + Mel newborns. Thus, our results support that maternal melatonin during gestation is important in determining amount and normal functionality of BAT in the neonate.

Impact of chronodisruption during primate pregnancy on the maternal and newborn temperature rhythms.

Disruption of the maternal environment during pregnancy is a key contributor to offspring diseases that develop in adult life. To explore the impact of chronodisruption during pregnancy in primates, we exposed pregnant capuchin monkeys to constant light (eliminating the maternal melatonin rhythm) from the last third of gestation to term. Maternal temperature and activity circadian rhythms were assessed as well as the newborn temperature rhythm. Additionally we studied the effect of daily maternal melatonin replacement during pregnancy on these rhythms. Ten pregnant capuchin monkeys were exposed to constant light from 60% of gestation to term. Five received a daily oral dose of melatonin (250 µg kg/body weight) at 1800 h (LL+Mel) and the other five a placebo (LL). Six additional pregnant females were maintained in a 14∶10 light:dark cycles and their newborns were used as controls (LD). Rhythms were recorded 96 h before delivery in the mother and at 4-6 days of age in the newborn. Exposure to constant light had no effect on the maternal body temperature rhythm however it delayed the acrophase of the activity rhythm. Neither rhythm was affected by melatonin replacement. In contrast, maternal exposure to constant light affected the newborn body temperature rhythm. This rhythm was entrained in control newborns whereas LL newborns showed a random distribution of the acrophases over 24-h. In addition, mean temperature was decreased (34.0±0.6 vs 36.1±0.2°C, in LL and control, respectively P<0.05). Maternal melatonin replacement during pregnancy re-synchronized the acrophases and restored mean temperature to the values in control newborns. Our findings demonstrate that prenatal melatonin is a Zeitgeber for the newborn temperature rhythm and supports normal body temperature maintenance. Altogether these prenatal melatonin effects highlight the physiological importance of the maternal melatonin rhythm during pregnancy for the newborn primate.

Timed maternal melatonin treatment reverses circadian disruption of the fetal adrenal clock imposed by exposure to constant light.

Surprisingly, in our modern 24/7 society, there is scant information on the impact of developmental chronodisruption like the one experienced by shift worker pregnant women on fetal and postnatal physiology. There are important differences between the maternal and fetal circadian systems; for instance, the suprachiasmatic nucleus is the master clock in the mother but not in the fetus. Despite this, several tissues/organs display circadian oscillations in the fetus. Our hypothesis is that the maternal plasma melatonin rhythm drives the fetal circadian system, which in turn relies this information to other fetal tissues through corticosterone rhythmic signaling. The present data show that suppression of the maternal plasma melatonin circadian rhythm, secondary to exposure of pregnant rats to constant light along the second half of gestation, had several effects on fetal development. First, it induced intrauterine growth retardation. Second, in the fetal adrenal in vivo it markedly affected the mRNA expression level of clock genes and clock-controlled genes as well as it lowered the content and precluded the rhythm of corticosterone. Third, an altered in vitro fetal adrenal response to ACTH of both, corticosterone production and relative expression of clock genes and steroidogenic genes was observed. All these changes were reversed when the mother received a daily dose of melatonin during the subjective night; supporting a role of melatonin on overall fetal development and pointing to it as a 'time giver' for the fetal adrenal gland. Thus, the present results collectively support that the maternal circadian rhythm of melatonin is a key signal for the generation and/or synchronization of the circadian rhythms in the fetal adrenal gland. In turn, low levels and lack of a circadian rhythm of fetal corticosterone may be responsible of fetal growth restriction; potentially inducing long term effects in the offspring, possibility that warrants further research.

Melatonina inhibe la respuesta de cortisol a ACTH: posible mediación a través del gen reloj Per1 / Melatonin inhibition of the cortisol response to ACTH may be exerted through period circadian protein homolog 1 (Per1)

Background: Circadian cortisol production results from the interaction of the circadian production of ACTH, the autonomic nervous system and intrinsic factors within the gland. An additional regulator is the neuro-hormone melatonin. In human adrenal gland cultures, melatonin inhibited ACTH stimulated cortisol production and Per1 mRNA expression. ACTH actions on the adrenal involve early and late responses. Aim: To investigate the effects of melatonin on the time course of ACTH stimulated cortisol production and of Per1 expression in the lamb adrenal gland. Material and Methods: Adrenal glands and plasma of five newborn lambs were obtained. Adrenal glands were cut in 15 mg explants. Three of these explants were stored for RNA extraction. The rest of explants were using in different culture protocols with ACTH and melatonin. Results: Lambs had an in vivo a circadian variation in plasma cortisol and in adrenal Per1 expression. In vitro, ACTH stimulated an early and late increase in cortisol production and an early increase in Per1 expression reaching a maximum at 3 hours of treatment. Melatonin inhibited the early Per1 response to ACTH without affecting the early ACTH stimulated cortisol production. However, melatonin inhibited the late response of cortisol production to ACTH. Conclusions: The inhibitory actions of melatonin on Per1 response to ACTH may contribute to the inhibitory effects of melatonin on adrenal steroidogenic response to ACTH.

Circadian rhythms in the fetus.

Throughout gestation, the close relationship between mothers and their progeny ensures adequate development and a successful transition to postnatal life. By living inside the maternal compartment, the fetus is inevitably exposed to rhythms of the maternal internal milieu such as temperature; rhythms originated by maternal food intake and maternal melatonin, one of the few maternal hormones that cross the placenta unaltered. The fetus, immature by adult standards, is however perfectly fit to accomplish the dual functions of living in the uterine environment and developing the necessary tools to "mature" for the next step, i.e. to be a competent newborn. In the fetal physiological context, organ function differs from the same organ's function in the newborn and adult. This may also extend to the developing circadian system. The information reviewed here suggests that the fetal circadian system is organized differently from that of the adult. Moreover, the fetal circadian rhythm is not just present simply as the initial immature expression of a mechanism that has function in the postnatal animal only. We propose that the fetal suprachiasmatic nucleus (SCN) of the hypothalamus and fetal organs are peripheral maternal circadian oscillators, entrained by different maternal signals. Conceptually, the arrangement produces internal temporal order during fetal life, inside the maternal compartment. Following birth, it will allow for postnatal integration of the scattered fetal circadian clocks into an adult-like circadian system commanded by the SCN.