Knowledge, Attitude and Perceptions Around Perinatal Mental Health Among Doctors in an Obstetrics and Gynaecology Academic Department in Singapore.

Background Frontline healthcare professionals who provide regular care to women in the antenatal and postnatal period play a critical role in the early detection and management of maternal perinatal mental health (PMH). This study aimed to assess the knowledge, attitudes, and perceptions of doctors around perinatal mental health in an obstetrics and gynaecology (O&G) department in Singapore. Methods Using an online survey, data was collected from 55 doctors who participated in the Doctor's Knowledge, Attitudes and Perceptions of Perinatal Mental Health (I-DOC) study. The survey questions assessed the knowledge, attitudes, perceptions and practices in relation to PMH among doctors in the O&G specialty. Descriptive data was presented as means and standard deviations (SDs), or frequency and percentages. Results Out of the 55 doctors, more than half (60.0%) were not aware of the adverse impacts of poor PMH; 83.7% of doctors were not confident in providing PMH advice and 65.5% did not routinely screen patients for PMH disorders. There was a lower percentage of doctors (10.9% vs. 34.5%, p<0.001) who discussed PMH issues in the antenatal period compared to the postnatal period and this was statistically significant. Majority of doctors (98.2%) agreed that having standardised PMH guidelines will be useful. All doctors agreed on the benefits of having PMH guidelines, education and routine screening for patients. Conclusion There is inadequate PMH literacy among O&G doctors and lack of emphasis on antenatal PMH disorder. The findings highlighted the need for increased education and development of perinatal mental health guidelines.

First Trimester Circulating MicroRNA Biomarkers Predictive of Subsequent Preterm Delivery and Cervical Shortening.

Preterm birth (PTB) is the leading cause of infant death and disability worldwide. The onset of preterm uterine contractions is preceded by asymptomatic cervical remodelling and ripening, which can be seen on trans-vaginal ultrasound as cervical shortening. This study aimed to identify plasma miRNA biomarkers that predict preterm birth and/or cervical shortening. We collected serial plasma samples from pregnant women prospectively from 12 to 22 weeks gestation. The nCounter miRNA assay was used to identify differentially expressed miRNAs associated with spontaneous PTB and/or cervical shortening (n = 16 term no short, n = 13 preterm, n = 24 short). Predictive values of the miRNA biomarkers were confirmed in an independent validation cohort consisting of 96 women who delivered at term, 14 preterm and 21 early cervical shortening at <20 weeks gestation. Nine miRNAs (hsa-let-7a-5p, hsa-miR-374a-5p, hsa-miR-15b-5p, hsa-miR-19b-3p, hsa-miR-23a-3p, hsa-miR-93-5p, hsa-miR-150-5p, hsa-miR-185-5p and hsa-miR-191-5p) were differentially expressed (P < 0.001) in women subsequently experiencing PTB or cervical shortening. Hsa-miR-150-5p had the strongest ability to predict PTB (AUC = 0.8725) and cervical shortening (AUC = 0.8514). Plasma miRNAs in the first trimester can predict PTB and cervical shortening in women at risk of preterm delivery. This is a key period in pregnancy when early identification of PTB risk allows time to deliver outcome-modifying interventions.

Sulfasalazine augments a pro-inflammatory response in interleukin-1ß-stimulated amniocytes and myocytes.

Preterm birth occurs in 10% of pregnancies and is a major cause of neonatal morbidity and mortality. The majority of cases of early preterm labour are associated with infection/inflammation, which places the fetal central nervous system at risk. Targeting immune activation is therefore an appealing therapeutic strategy for the prevention of preterm labour and neonatal brain injury. The expression of many labour-associated and inflammatory-response genes is controlled by the transcription factors nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), which makes them therapeutic targets of interest. Sulfasalazine (SASP) has been shown to inhibit NF-κB and reduce lipopolysaccharide-induced cytokine concentrations in fetal membrane explants and reduce the rate of Escherichia coli-induced preterm labour in mice. Its effects upon AP-1 in the context of pregnancy are unknown. In this study the effect of SASP on interleukin-1ß (IL-1ß) -induced NF-κB and AP-1 activity, cytokine production and cyclo-oxygenase-2 (COX-2) expression was examined in amniocytes and myocytes. A supra-therapeutic concentration (5 mm) was required to inhibit IL-1ß-induced NF-κB (P < 0·0001) in amniocytes and IL-1ß-induced NF-κB (P < 0·01), AP-1 (P < 0·01) and COX-2 (P < 0·05) in myocytes. Despite inhibiting IL-1ß-induced cytokines, a basal increase in IL-6 (P < 0·01), IL-8 (P < 0·0001) and tumour necrosis factor-α (TNF-α) (P < 0·001) was seen with 5 mm SASP in amniocytes, and significant cytotoxic effects were seen in myocytes. The therapeutic concentration of 0·015 mm had no inhibitory effects on pro-inflammatory mediators, but led to an augmented response to IL-1ß-induced IL-6 (P < 0·01), IL-8 (P < 0·05) and TNF-α (P < 0·05) in amniocytes and IL-8 (P < 0·05) in myocytes. SASP is therefore an unlikely therapeutic candidate for the prevention of inflammation-induced preterm labour.

The vaginal microbiome during pregnancy and the postpartum period in a European population.

The composition and structure of the pregnancy vaginal microbiome may influence susceptibility to adverse pregnancy outcomes. Studies on the pregnant vaginal microbiome have largely been limited to Northern American populations. Using MiSeq sequencing of 16S rRNA gene amplicons, we characterised the vaginal microbiota of a mixed British cohort of women (n = 42) who experienced uncomplicated term delivery and who were sampled longitudinally throughout pregnancy (8-12, 20-22, 28-30 and 34-36 weeks gestation) and 6 weeks postpartum. We show that vaginal microbiome composition dramatically changes postpartum to become less Lactobacillus spp. dominant with increased alpha-diversity irrespective of the community structure during pregnancy and independent of ethnicity. While the pregnancy vaginal microbiome was characteristically dominated by Lactobacillus spp. and low alpha-diversity, unlike Northern American populations, a significant number of pregnant women this British population had a L. jensenii-dominated microbiome characterised by low alpha-diversity. L. jensenii was predominantly observed in women of Asian and Caucasian ethnicity whereas L. gasseri was absent in samples from Black women. This study reveals new insights into biogeographical and ethnic effects upon the pregnancy and postpartum vaginal microbiome and has important implications for future studies exploring relationships between the vaginal microbiome, host health and pregnancy outcomes.

Anti-inflammatory prostaglandins for the prevention of preterm labour.

Preterm birth occurs in 10-12% of pregnancies and is the primary cause of neonatal mortality and morbidity. Tocolytic therapies have long been the focus for the prevention of preterm labour, yet they do not significantly improve neonatal outcome. A direct causal link exists between infection-induced inflammation and preterm labour. As inflammation and infection are independent risk factors for poor neonatal outcome, recent research focus has been shifted towards exploring the potential for anti-inflammatory strategies. Nuclear factor kappa B (NFκB) is a transcription factor that controls the expression of many labour-associated genes including PTGS2 (COX2), prostaglandins (PGs) and the oxytocin receptor (OXTR) as well as key inflammatory genes. Targeting the inhibition of NFκB is therefore an attractive therapeutic approach for both the prevention of preterm labour and for reducing neonatal exposure to inflammation. While PGs are considered to be pro-labour and pro-inflammatory, the cyclopentenone PG 15-deoxy-Δ(12,14)PGJ2 (15d-PGJ2) exhibits anti-inflammatory properties via the inhibition of NFκB in human amniocytes, myocytes and peripheral blood mononuclear cells in vitro. 15d-PGJ2 also delays inflammation-induced preterm labour in the mouse and significantly increases pup survival. This review examines the current understanding of inflammation in the context of labour and discusses how anti-inflammatory PGs may hold promise for the prevention of preterm labour and improved neonatal outcome.

Characterization of neutrophil subsets in healthy human pregnancies.

We have previously shown that in successful pregnancies increased arginase activity is a mechanism that contributes to the suppression of the maternal immune system. We identified the main type of arginase-expressing cells as a population of activated low-density granulocytes (LDGs) in peripheral blood mononuclear cells and in term placentae. In the present study, we analyzed the phenotype of LDGs and compared it to the phenotype of normal density granulocytes (NDGs) in maternal peripheral blood, placental biopsies and cord blood. Our data reveal that only LDGs but no NDGs could be detected in placental biopsies. Phenotypically, NDGs and LDGs from both maternal and cord blood expressed different levels of maturation, activation and degranulation markers. NDGs from the maternal and cord blood were phenotypically similar, while maternal, cord and placental LDGs showed different expression levels of CD66b. LDGs present in cord blood expressed higher levels of arginase compared to maternal and placental LDGs. In summary, our results show that in maternal and cord blood, two phenotypically different populations of neutrophils can be identified, whereas in term placentae, only activated neutrophils are present.

Chemoattractant receptor homologous to the T helper 2 cell (CRTH2) is not expressed in human amniocytes and myocytes.

BACKGROUND: 15-deoxy-Δ 12,14- Prostaglandin J2 (15dPGJ2) inhibits Nuclear factor kappa B (NF-κB) in human myocytes and amniocytes and delays inflammation induced preterm labour in the mouse. 15dPGJ2 is a ligand for the Chemoattractant Receptor Homologous to the T helper 2 cell (CRTH2), a G protein-coupled receptor, present on a subset of T helper 2 (Th2) cells, eosinophils and basophils. It is the second receptor for Prostaglandin D2, whose activation leads to chemotaxis and the production of Th2-type interleukins. The cellular distribution of CRTH2 in non-immune cells has not been extensively researched, and its identification at the protein level has been limited by the lack of specific antibodies. In this study we explored the possibility that CRTH2 plays a role in 15dPGJ2-mediated inhibition of NF-κB and would therefore represent a novel small molecule therapeutic target for the prevention of inflammation induced preterm labour. METHODS: The effect of a small molecule CRTH2 agonist on NF-κB activity in human cultured amniocytes and myocytes was assessed by detection of p65 and phospho-p65 by immunoblot. Endogenous CRTH2 expression in amniocytes, myocytes and peripheral blood mononuclear cells (PBMCs) was examined by PCR, western analysis and flow cytometry, with amniocytes and myocytes transfected with CRTH2 acting as a positive control in flow cytometry studies. RESULTS: The CRTH2 agonist had no effect on NF-κB activity in amniocytes and myocytes. Although CRTH2 mRNA was detected in amniocytes and myocytes, CRTH2 was not detectable at the protein level, as demonstrated by western analysis and flow cytometry. 15dPGJ2 inhibited phospho-65 in PBMC'S, however the CRTH2 antagonist was not able to attenuate this effect. In conclusion, CRTH2 is not expressed on human amniocytes or myocytes and plays no role in the mechanism of 15dPGJ2-mediated inhibition of NF-κB.

The Th1:th2 dichotomy of pregnancy and preterm labour.

Pregnancy is a unique immunological state in which a balance of immune tolerance and suppression is needed to protect the fetus without compromising the mother. It has long been established that a bias from the T helper 1 cytokine profile towards the T helper 2 profile contributes towards successful pregnancy maintenance. The majority of publications that report on aberrant Th1:Th2 balance focus on early pregnancy loss and preeclampsia. Over the last few decades, there has been an increased awareness of the role of infection and inflammation in preterm labour, and the search for new biomarkers to predict preterm labour continues. In this paper, we explore the evidence for an aberrant Th1:Th2 profile associated with preterm labour. We also consider the potential for its use in screening women at high risk of preterm labour and for prophylactic therapeutic measures for the prevention of preterm labour and associated neonatal adverse outcomes.

Changes in the Th1:Th2 cytokine bias in pregnancy and the effects of the anti-inflammatory cyclopentenone prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J2.

Pregnancy is a complex immunological state in which a bias towards T helper 2 (Th2) protects the fetus. Evidence suggests that proinflammatory cytokines increase the risk of poor neonatal outcome, independently of the direct effect of preterm labour. The anti-inflammatory prostaglandin 15-deoxy-Δ(12,14)-Prostaglandin J(2) (15dPGJ(2)) inhibits nuclear factor Kappa B (NF-κB) in amniocytes and myocytes in vitro and is a ligand for the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptor. Here we examine the Th1:Th2 cytokine bias in pregnancy and whether 15dPGJ(2) could be used to inhibit the production of the proinflammatory cytokines through inhibition of NF-κB while simultaneously promoting Th2 interleukin 4 (IL-4) synthesis via CRTH2 in T helper cells. Peripheral blood mononuclear cells (PBMCs) from women at 28 weeks, term pre-labour, term labour as well as non-pregnant female controls were cultured with 15dPGJ(2) or vehicle control and stimulated with phorbol myristyl acetate (PMA)/ionomycin. The percentage of CD4(+) cells producing interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) in response to PMA/ionomycin was significantly reduced in pregnancy. 15dPGJ(2) reduced IFN-γ and TNF-α production in stimulated T helper cells, but did not alter IL-4 production in CRTH2(+ve) cells. 15dPGJ(2) also reduced phospho-p65 in stimulated PBMCs. In summary, 15dPGJ(2) suppresses the Th1 response of PBMCs during pregnancy and active labour whilst maintaining the Th2 response suggesting a therapeutic benefit in reducing neonatal morbidity in inflammation-induced PTL.

Prevention of preterm labour via the modulation of inflammatory pathways.

Pregnancy is characterized by a complex interplay of inflammatory events regulated by both the innate and acquired immune systems. Similarly, parturition can be viewed as the activation of "pro-labour" inflammatory pathways, which drive cervical ripening and myometrial activation. Premature activation of these pathways, for example, by infection, can lead to preterm labour and birth. Nuclear factor κß is a key modulator of these pathways and functions by regulating the expression of prostaglandins, chemokines and pro-inflammatory cytokines involved in both term and preterm labour. Future design of therapeutics that target key mediators of inflammation and immune activation would therefore be a rational approach for preventing preterm labour and immune-mediated neonatal brain damage.

Endocrine problems in pregnancy.

This paper aims to describe the pathophysiology and management of the main endocrine complications of pregnancy. For each endocrine dysfunction, the issues with the fetus, the mother, obstetric complications, and the long term prognosis for the disease itself need to be considered. Key management issues are highlighted with each condition. Thyroid dysfunction and goitre are common while management is relatively straightforward. Adrenal, pituitary, and parathyroid diseases present less commonly in pregnancy. Early recognition of endocrine disease in pregnancy and appropriate management has the potential to improve outcome for the mother and fetus in the short and long term.

Obesity in pregnancy: a major healthcare issue.

The prevalence of maternal obesity is rising, up to 20% in some antenatal clinics, in line with the prevalence of obesity in the general population. Maternal obesity poses significant risks for all aspects of pregnancy. There are risks to the mother with increased maternal mortality, pre-eclampsia, diabetes and thromboembolic disorders. There is increased perinatal mortality, macrosomia and congenital malformation. The obstetric management, with increased operative delivery rate, and increased difficulty of anaesthesia, carry risk for the obese mother. Long term complications associated with maternal obesity include increased likelihood of maternal weight retention and exacerbation of obesity. This review aims to discuss these risks with a view to suggesting management to ensure the best outcome for both the mother and the offspring.

Three case reports of maternal primary hyperparathyroidism in each trimester and a review of optimal management in pregnancy.

Primary hyperparathyroidism (PHPT) during pregnancy is associated with significant maternal and fetal risks. Prompt diagnosis and effective management during pregnancy can improve both maternal and fetal outcomes. However, there is no consensus with regard to conservative versus surgical management especially in the first and third trimester. We report three cases of PHPT associated with pregnancy that underwent parathyroidectomy each in a different trimester. Cases 1 and 2 were found to have hypercalcaemia and elevated parathyroid hormone levels in the second and first trimesters, respectively. Case 3 was known to have PHPT prenatally but previously declined parathyroidectomy. All three cases underwent parathyroidectomies during pregnancy without significant postoperative complications and all achieved favourable maternal and neonatal outcomes. Maternal hyperparathyroidism represents a preventable cause of maternal morbidity, with fetal morbidity and mortality. The benefits of parathyroidectomy with normalization of serum calcium in the mothers outweigh the risks of hypercalcaemia and suppression of the fetal parathyroid, especially where maternal vitamin D concentration is low.

Anorectal symptoms during pregnancy: how important is trimester?

PURPOSE: The frequency of anorectal symptoms amongst pregnant women has not been objectively investigated in the United Kingdom. The aim of this study was to determine the frequency of anorectal symptoms during each trimester of pregnancy. METHODS: Women attending the antenatal clinics at a London teaching hospital were asked to complete a questionnaire. The presence or absence of common anorectal symptoms experienced both before and during the current pregnancy together with demographic and pregnancy data was collected. Statistical analysis was performed using Fisher's exact test. RESULTS: Two hundred seventeen patients (first trimester n=75, second trimester n=70 and third trimester n=72) participated. A significant increase in the frequency of symptoms was observed in the third (43.1%) compared to the first (16.0%, p<0.001) and second (22.9%, p=0.013) trimesters. The incidence of per rectal bleeding was significantly greater in the third trimester (30.6%) compared to the first (10.6%, p=0.004) and the second (12.9%, p=0.014) trimesters. Similarly, anal pain was significantly more frequent in the third trimester (34.7%) compared to the first (13.3%, p=0.003) and the second (12.9%, p=0.003) trimesters. CONCLUSION: The frequency of anorectal symptom reporting appears to increase as pregnancy progresses. Further investigation and research is warranted to determine the configuration of services that may be required to treat those affected.