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The exclusion of pregnant populations, women of reproductive age, and the fetus from clinical trials of therapeutics is a major global public health issue. It is also a problem of inequity in medicines development, as pregnancy is a protected characteristic. The current regulatory requirements for drugs in pregnancy are being analyzed by a number of agencies worldwide. There has been considerable investment in developing expertise in pregnancy clinical trials (for the pregnant person and the fetus) such as the Obstetric-Fetal Pharmacology Research Centers funded by the National Institute of Child Health and Human Development. Progress has also been made in how to define and grade clinical trial safety in pregnant women, the fetus, and neonate. Innovative methods to model human pregnancy physiology and pharmacology using computer simulations are also gaining interest. Novel ways to assess fetal well-being and placental function using magnetic resonance imaging, computerized cardiotocography, serum circulating fetoplacental proteins, and mRNA may permit better assessment of the safety and efficacy of interventions in the mother and fetus. The core outcomes in women’s and newborn health initiative is facilitating the consistent reporting of data from pregnancy trials. Electronic medical records integrated with pharmacy services should improve the strength of pharmacoepidemiologic and pharmacovigilance studies. Incentives such as investigational plans and orphan disease designation have been taken up for obstetric, fetal, and neonatal diseases. This review describes the progress that is being made to better understand the extent of the problem and to develop applicable solutions.

OBJECTIVE: Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions. METHOD: Existing severity grading for pregnant AEs and definitions/indicators of 'severe' and 'life-threatening' conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives. RESULTS: Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus. CONCLUSIONS: This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety. ispartof: PRENATAL DIAGNOSIS vol:42 issue:1 pages:15-26 ispartof: location:England status: published

Background Concerns have been raised that a lack of senior obstetricians (“consultants”) on the labour ward outside normal hours may lead to worse outcomes among babies born during periods of reduced cover. Methods and Findings We carried out a multicentre cohort study using data from 19 obstetric units in the United Kingdom between 1 April 2012 and 31 March 2013 to examine whether rates of obstetric intervention and outcome change “out-of-hours,” i.e., when consultants are not providing dedicated, on-site labour ward cover. At the 19 hospitals, obstetric rotas ranged from 51 to 106 h of on-site labour ward cover per week. There were 87,501 singleton live births during the year, and 55.8% occurred out-of-hours. Women who delivered out-of-hours had slightly lower rates of intrapartum caesarean section (CS) (12.7% versus 13.4%, adjusted odds ratio [OR] 0.94; 95% confidence interval [CI] 0.90 to 0.98) and instrumental delivery (15.6% versus 17.0%, adj. OR 0.92; 95% CI 0.89 to 0.96) than women who delivered at times of on-site labour ward cover. There was some evidence that the severe perineal tear rate was reduced in out-of-hours vaginal deliveries (3.3% versus 3.6%, adj. OR 0.92; 95% CI 0.85 to 1.00). There was no evidence of a statistically significant difference between out-of-hours and “in-hours” deliveries in the rate of babies with a low Apgar score at 5 min (1.33% versus 1.25%, adjusted OR 1.07; 95% CI 0.95 to 1.21) or low cord pH (0.94% versus 0.82%; adjusted OR 1.12; 95% CI 0.96 to 1.31). Key study limitations include the potential for bias by indication, the reliance upon an organisational measure of consultant presence, and a non-random sample of maternity units. Conclusions There was no difference in the rate of maternal and neonatal morbidity according to the presence of consultants on the labour ward, with the possible exception of a reduced rate of severe perineal tears in out-of-hours vaginal deliveries. Fewer women had operative deliveries out-of-hours. Taken together, the available evidence provides some reassurance that the current organisation of maternity care in the UK allows for good planning and risk management. However there is a need for more robust evidence on the quality of care afforded by different models of labour ward staffing., In a multicenter cohort study, Hannah Knight and colleagues assess differences in birth-related outcomes associated with the presence of senior obstetricians on the labor ward., Editors' Summary Background In an ideal world, expert medical care would be available for anyone who needs it 24 hours a day, 7 days a week. But in the real world, a lower level of medical cover is often available in the evening and at weekends, a situation that potentially puts lives at risk. In the United Kingdom, for example, the National Health Service (NHS) does not currently provide consultant-level care or full laboratory and imaging services in the evenings and at weekends (in the UK, a consultant is a senior, hospital-based doctor who provides care in a medical or surgical specialty). Consequently, patients admitted out of normal hours have to wait to see a consultant and to have tests and scans done. Citing studies that suggest that people admitted to hospital at the weekend are more likely to die than those admitted on weekdays, the UK government recently made a pledge to improve access to consultants and other NHS services during evenings and weekends. Why Was This Study Done? Maternity care is a specialty in which a 24-hour hospital service is clearly required. Women can go into labor at any time of the day, and intrapartum emergencies (emergencies that arise during labor) can develop rapidly and without warning in previously uncomplicated pregnancies. Concerns have been raised that a lack of senior obstetricians (consultants who look after women during pregnancy, childbirth, and the postpartum period immediately after childbirth) on labor wards outside normal working hours may lead to worse outcomes among babies born during periods of reduced cover. However, few studies have examined the extent to which variation in consultant presence on labor wards affects maternal and neonatal (newborn) outcomes. In this multicenter cohort study, the researchers use data from UK obstetric units to evaluate the relationship between the presence of obstetric consultants on labor wards and the rates of obstetric interventions (surgical delivery by cesarean section and “instrumental” delivery using forceps or a vacuum) and of several maternal and neonatal outcomes. What Did the Researchers Do and Find? For their study, the researchers used electronic patient data collected over a 12-month period by 19 obstetric units and administrative data on obstetric rotas at the participating hospitals, which were mainly teaching hospitals. On-site labor ward cover by consultants ranged from 51 to 106 hours per week at the participating hospitals, where there were 87,501 singleton live births over the study period, 55.8% of which occurred “out-of-hours.” Women who delivered out-of-hours had slightly lower rates of intrapartum cesarean section (operations initiated after labor had started; 12.7% versus 13.4%) and of instrumental delivery (15.6% versus 17.0%) than women who delivered when there was on-site labor ward cover (“in-hours”). Moreover, whereas 3.6% of women who had an in-hours vaginal delivery had a severe perineal tear (damage to the soft tissue between the vagina and the anus), only 3.3% of women who delivered out-of-hours had a tear. Finally, there was no difference between out-of-hours and in-hours deliveries in the rate of babies with a low Apgar score 5 minutes after birth (a measure of newborn health) or a low cord pH (a measure of oxygen deprivation during birth) or in the rate of mothers with severe postpartum bleeding. What Do These Findings Mean? These findings show no association between maternal and neonatal outcomes and the presence of consultants on the labor ward, with the exception of weak evidence for a reduced likelihood of severe perineal tears following out-of-hours delivery. However, women who deliver out-of-hours may be less likely to have an obstetric intervention than women who deliver in-hours, possibly because obstetric teams will usually try to undertake operative deliveries during in-hours shifts. The accuracy of these findings may be limited by the use of administrative records to determine when consultants were present on labor wards and by the potential for “bias by indication.” That is, obstetric teams may have tried to ensure that women with a greater risk of a poor outcome delivered in-hours rather than out-of-hours. Nevertheless, these findings suggest that the current organization of maternity care in the UK allows for good planning and risk management. Thus, although further robust evidence on the quality of care delivered at all times of the week by UK maternity units is needed, politically driven efforts to increase senior obstetrician attendance “out-of-hours” may not lead to improved clinical outcomes for women and babies. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1002000. This study is further discussed in a PLOS Medicine Perspective by Jenny Myers and Edward Johnstone Information from the UK Department of Health on research into the weekend effect on hospital mortality and the UK government's plans to provide NHS 7-day services by 2020 is available; a news article from the BBC discusses an ongoing controversy about how the UK government has used a recent research study to back its case for more 7-day NHS care The UK National Health Service website provides information on current out-of-hours NHS services, labor and childbirth (including a video about giving birth in hospital), cesarean section, assisted delivery (including a video), and perineal tears The UK Royal College of Obstetricians and Gynaecologists provides patient information leaflets on all aspects of pregnancy and childbirth MedlinePlus provides links to sources of other information on childbirth

Since the controversies regarding the use of non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclo-oxygenase (COX)-2 antagonists for the treatment of preterm labour (PTL), more emphasis has been placed on investigating the terminal synthases involved in the production of prostaglandins (PGs) to allow more targeted therapy in PTL. Prostaglandin E(2) (PGE(2)) is synthesized by one of three enzymes, cytosolic prostaglandin E synthase (cPGES), microsomal PGES-1 (mPGES-1) and microsomal PGES-2 (mPGES-2). We have determined (i) the immuno-localization of all three PGES enzymes in lower segment pregnant human myometrium, (ii) the expression of PGES and COX-2 mRNA expression at term and preterm gestation with and without labour and (iii) the effect of interleukin (IL)-1beta on COX-2 and PGES mRNA and protein expression in human myometrial smooth muscle (HMSM) cell cultures. We show mPGES-1 protein located predominantly in myometrial and vascular smooth muscle cells (SMCs), whilst mPGES-2 protein is largely in stromal cells surrounding the SMC and cPGES is diffusely located throughout the myometrium. Expression of mPGES-2 mRNA increased with term labour and PTL and expression of COX-2 and mPGES-1 mRNA with term labour, whereas cPGES expression did not change. IL-1beta stimulated release of PGE(2) by HMSM cells and increased COX-2 and mPGES-1 mRNA and protein expression. Thus, COX-2 expression and mPGES-1 expression are co-ordinately up-regulated in lower segment myometrium with term labour and with IL-1beta treatment in HMSM cells.

Oxytocin receptor (OTR) expression is increased before the onset of labor in all models of parturition. However, the mechanisms responsible for the increase in OTR expression are uncertain. Animal data suggest that uterine stretch increases OTR mRNA expression. In primary cultures of human uterine smooth muscle cells obtained from nonpregnant (NP) women and pregnant women before (NL) and after (L) the onset of labor, we investigated the effect of stretch on the expression of OTR mRNA and DNA binding of activator protein-1 (AP-1), CCAAT/enhancer binding protein (C/EBP)β, and nuclear factor-κB transcription factors. OTR expression was least in NL, intermediate in NP, and greatest in L cells. Stretch of NL cells resulted in up-regulation of OTR mRNA expression associated with increased OTR gene promoter activity. Stretch of NP and L cells did not affect OTR mRNA expression. The increased promoter activity was associated with increased DNA binding of C/EBP and AP-1 but not nuclear factor-κB transcription factors. Overexpression of C/EBP, but not AP-1, increased OTR promoter activity. We conclude that stretch of NL cells results in increased OTR mRNA expression probably through increased C/EBPβ DNA binding. These data suggest that stretch contributes to the massive increase in OTR expression before the onset of human labor.

(2002). Secondary postpartum haemorrhage. Journal of Obstetrics and Gynaecology: Vol. 22, No. 2, pp. 119-122.

Editor – There are some significant misconceptions in the letter on UKMED by Best et al .1 UKMED is a partnership between data providers from across the health and education sectors to evaluate medical career progression. This will help to raise education standards by enabling us to assess the

Uterine activation is associated with increased oxytocin receptor (OXTR) expression and myometrial sensitivity to oxytocin. The OXTR promoter contains binding sites for CCAAT/enhancer-binding protein (CEBP) and nuclear factor-kappa B p65 (RELA). RELA and CEBP beta (CEBPB) play a synergistic role in OXTR promoter activation. We created deletions in a DNA construct consisting of 850 bp upstream of the transcription start site linked to luc reporter to identify the CIS element of the OXTR promoter responsible for the synergistic activation by RELA and CEBPB. Deletion from -712 to -692 bp eliminated synergy, demonstrating that the critical region lies within these 20 bp. Binding studies showed that this sequence binds both RELA and CEBPB. The 20-bp critical region for synergistic activation of OXTR requires full-length RELA but only the basic leucine zipper domain of CEBPB.

It is not known whether human labour is associated with increased fetal oxytocin production or transfer of oxytocin across the placenta. Previous reports are contradictory, due in part, to the influence of maternal analgesia on fetal production. We determined plasma oxytocin concentration in the umbilical artery and vein of women after vaginal delivery and after caesarean section with general anaesthesia before or after the onset of labour. The results demonstrate that fetal production of oxytocin is not influenced by general anaesthesia, thus enabling comparison of labour and nonlabour samples at caesarean section. Labour was not associated with an increase in fetal oxytocin production. Oxytocin was also measured in the umbilical artery and vein during maternal oxytocin infusion to assess placental transfer. The results do not support transfer of oxytocin across the placenta in women.

Background A number of tocolytics have been advocated for the treatment of threatened preterm labour in order to delay birth. The rationale is that a delay in birth may be associated with improved neonatal morbidity or mortality. Nitric oxide donors, such as nitroglycerin, have been used to relax the uterus. This review addresses their efficacy, adverse effects and influence on neonatal outcome. Objectives To determine whether nitric oxide donors administered in threatened preterm labour are associated with a delay in birth, adverse effects or improved neonatal outcome. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 December 2013). Selection criteria Randomised controlled trials of nitric oxide donors administered for tocolysis. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Main results Twelve trials, including a total of 1227 women at risk of preterm labour, contributed data to this updated review. The methodological quality of trials was mixed; trials comparing nitric oxide donors with other types of tocolytics were not blinded and this may have had an impact on findings.Three studies compared nitric oxide donors (glyceryl trinitrate (GTN)) with placebo. There was no significant evidence that nitric oxide donors prolonged pregnancy beyond 48 hours (average risk ratio (RR) 1.19, 95% confidence interval (CI) 0.74 to 1.90, two studies, 186 women), and although for most adverse effects there was no significant difference between groups, women in the active treatment group in one study were at higher risk of experiencing a headache. For infant outcomes there was no significant evidence that nitric oxide donors reduced the risk of neonatal death or serious morbidity (stillbirth RR 0.36, 95% CI 0.01 to 8.59, one study, 153 infants; neonatal death RR 0.43, 95% CI 0.06 to 2.89, two studies, 186 infants). One study, using a composite outcome, reported a reduced risk of serious adverse outcomes for infants in the GTN group which approached statistical significance (RR 0.29, 95% CI 0.08 to 1.00, 153 infants). Overall, these studies were underpowered to identify differences between groups for most outcomes.When nitric oxide donors were compared with other tocolytic drugs there was no significant evidence that nitric oxide donors performed better than other tocolytics (betamimetics, magnesium sulphate, a calcium channel blocker or a combination of tocolytics) in terms of pregnancy prolongation, although nitric oxide donors appeared to be associated with a reduction in most adverse effects, apart from headache. There was no significant difference between groups for infant morbidity or mortality outcomes. Authors' conclusions There is currently insufficient evidence to support the routine administration of nitric oxide donors in the treatment of threatened preterm labour.

To investigate labour-associated changes in: 1. the myometrial contractile response to arginine vasopressin compared with oxytocin in vitro 2. fetal production of arginine vasopressin and 3. myometrial vasopressin V1a receptor mRNA.The contractile response to vasopressin (compared with oxytocin) was investigated in paired myometrial strips in vitro. Blood was taken from the umbilical artery and vein at delivery and arginine vasopressin measured by radio-immunoassay. V1a receptor mRNA was determined by in situ hybridisation.Myometrium was more sensitive to arginine vasopressin than oxytocin (P0.05 for frequency, amplitude and activity integral in paired strips) after, but not before labour. There was a marked umbilical arteriovenous difference in arginine vasopressin concentration at delivery suggesting fetal production which was not influenced by labour. Myometrial vasopressin V1a receptor mRNA was not increased after the onset of labour.The human uterus is extremely sensitive to arginine vasopressin in vitro. Arginine vasopressin is produced by the fetus but fetal formation is not increased during labour.

OBJECTIVE To determine the effect of early labour, maternal analgesia and fetal hypoxia on circulating fetal oxytocin concentrations. DESIGN Prospective observational study. SETTING Delivery suite in a District General Hospital. SUBJECTS Fifty women at term who did not require oxytocin administration or more than one form of analgesia. Study groups: vaginal delivery with (1) no analgesia, (2) pethidine, or (3) epidural analgesia. Caesarean section under regional analgesia (4) prior to, and (5) after the onset of labour. INTERVENTIONS Samples of blood were collected from the umbilical artery (UA) and umbilical vein (UV) immediately after fetal delivery prior to placental separation or oxytocic administration. MAIN OUTCOME MEASURES Plasma oxytocin (OT) concentration, umbilical vein pH, cystine aminopeptidase activity. RESULTS The geometric mean UA-OT was significantly greater than UV-OT in all groups and was not altered by pethidine; however, epidural administration increased the UA-UV difference. The UA-UV difference at caesarean section was not significantly altered by the onset of labour. There was no correlation between UV pH and UA-UV plasma oxytocin. Cystine aminopeptidase activity was not detectable in UA and UV plasma. CONCLUSIONS Fetal OT production is increased by epidural but not by pethidine analgesia. It is not influenced by the onset of labour or fetal hypoxia.

In normal humans, arginine vasopressin and oxytocin are released acutely from the posterior pituitary gland in response to hypoglycemia, and their release may assist counterregulation. The responses of these hormones to insulin-induced hypoglycemia were measured in 16 insulin-dependent diabetic patients with no autonomic neuropathy (8 patients who had been diabetic less than 5 yr and 8 patients who had been diabetic greater than 15 yr) and in 6 normal subjects. The time of the onset of hypoglycemia and the mean blood glucose nadirs were similar in all groups, but the blood glucose recovery was delayed in the diabetic patients. In the normal subjects plasma arginine vasopressin rose from a mean basal value of 0.4 +/- 0.2 (+/- SE) pmol/L to a maximum of 1.3 +/- 0.6 pmol/L, and plasma oxytocin rose from 0.7 +/- 0.1 pmol/L to a maximum of 1.2 +/- 0.2 pmol/L 30 min after the onset of hypoglycemia. The plasma arginine vasopressin and oxytocin concentrations after hypoglycemia were significantly higher in both of the diabetic groups compared with those in the normal group. Arginine vasopressin and oxytocin rose in all control subjects after hypoglycemia. The individual hormonal profiles in the diabetic patients were variable, with an exaggerated rise of oxytocin in some diabetic patients and no rise in others. The arginine vasopressin responses were exaggerated in all of the diabetic patients. There was no correlation between the hormonal responses and the duration of diabetes. The exaggerated plasma arginine vasopressin and oxytocin responses to hypoglycemia in diabetic patients may indicate the failure of a normal inhibitory mechanism which modulates hormonal secretion or a compensatory response to impaired glucose recovery.