Non-hypertensive gestational diabetes mellitus: Placental histomorphology and its association with perinatal outcomes.

INTRODUCTION: Gestational diabetes mellitus (GDM) exerts a great impact on the placenta and reflects changes on placentas both morphological and functionally. The aims of this study are to evaluate the prevalence of placental histopathological lesions in pregnancies complicated by GDM compared to gestational age-matched controls, and their association with maternal and fetal complications. METHODS: Fifty-four singleton GDM-complicated pregnancies were recruited and compared to 33 consecutive normal pregnancies. Two pathologists, blinded to all clinical data, reviewed and evaluated all histological samples of the placentas in accordance with Amsterdam criteria. Relevant demographic, clinical data and primary birth outcomes were recorded. RESULTS: A myriad of histomorphological abnormalities, including chronic inflammation (n = 9/54, p = 0.031), histological chorioamnionitis (n = 23/54, p < 0.001), umbilical/chorionic vasculitis (n = 9/54, p = 0.031), changes related to maternal vascular malperfusion (n = 22/54, p = 0.003), chorangiosis (n = 10/54, p = 0.046) and villous dysmaturity (n = 9/54, p = 0.012) were observed more frequently in the GDM placentas compared to the controls. Additionally, GDM significantly increased the risk of fetal complications, including macrosomia/fetal growth restriction (n = 13/54, p = 0.004). DISCUSSION: Histoarchitectural abnormalities were observed more frequently in placentas of GDM pregnancies compared to the controls. Our findings support the hypothesis that diabetic-induced damage in the placental function may be associated with the increased in fetal growth disorders in GDM-complicated pregnancies.

Diagnostic Utility of TSSC3 and RB1 Immunohistochemistry in Hydatidiform Mole.

The general notion of complete hydatidiform moles is that most of them consist entirely of paternal DNA; hence, they do not express p57, a paternally imprinted gene. This forms the basis for the diagnosis of hydatidiform moles. There are about 38 paternally imprinted genes. The aim of this study is to determine whether other paternally imprinted genes could also assist in the diagnostic approach of hydatidiform moles. This study comprised of 29 complete moles, 15 partial moles and 17 non-molar abortuses. Immunohistochemical study using the antibodies of paternal-imprinted (RB1, TSSC3 and DOG1) and maternal-imprinted (DNMT1 and GATA3) genes were performed. The antibodies' immunoreactivity was evaluated on various placental cell types, namely cytotrophoblasts, syncytiotrophoblasts, villous stromal cells, extravillous intermediate trophoblasts and decidual cells. TSSC3 and RB1 expression were observed in all cases of partial moles and non-molar abortuses. In contrast, their expression in complete moles was identified in 31% (TSSC3) and 10.3% (RB1), respectively (p < 0.0001). DOG1 was consistently negative in all cell types in all cases. The expressions of maternally imprinted genes were seen in all cases, except for one case of complete mole where GATA3 was negative. Both TSSC3 and RB1 could serve as a useful adjunct to p57 for the discrimination of complete moles from partial moles and non-molar abortuses, especially in laboratories that lack comprehensive molecular service and in cases where p57 staining is equivocal.

Gardnerella vaginalis infection in pregnancy: Effects on placental development and neonatal outcomes.

INTRODUCTION: Gardnerella vaginalis (GV)-associated bacterial vaginosis is recognised for its detrimental effects on pregnancy resulting in poor obstetric and neonatal outcomes. There is limited knowledge of the effects on placental histomorphology following GV infection in pregnancy. We investigated the effects of GV infection on the placenta, particularly with regards to the syncytiotrophoblasts and vascular development, and related these to neonatal outcomes. METHODS: A prospective cohort study involving GV-positive pregnant women presented with abnormal vaginal discharge, with gestational age-matched healthy pregnant women controls. Placental sampling was performed upon delivery and examined histologically. Vascular endothelial growth factor-A (VEGF-A) and hypoxia-inducible factor-1α (HIF-1α) mRNA and protein expression were analysed by real-time PCR and immunohistochemistry respectively. The standard measures in neonatal outcomes were recorded. RESULTS: Placentas from GV-positive mothers were found to have significant histological evidence of maternal and/or fetal inflammatory response compared with the controls (17/28: 60.7% vs 2/20: 10%) (p = 0.0011). There was an increase in the percentage of syncytial nuclear aggregates (SNAs) per villus (47.4 ± 11.09%) in placentas from GV-positive mothers (p < 0.0001). VEGF-A was significantly increased in specifically, the villous endothelial cells of placentas with GV infection, but no difference in the immunoexpression of HIF-1α in these cells between groups. However, these were not associated with adverse neonatal outcomes. DISCUSSION: Increased placental VEGF-A expression associated with increased SNAs in pregnant women with GV infection of the genital tract may be an intrauterine response towards placental vascular remodeling, that may also serve as a protective role in moderating birth outcomes.

A Review of Placenta and Umbilical Cord-Derived Stem Cells and the Immunomodulatory Basis of Their Therapeutic Potential in Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a devastating lung disorder of preterm infants as a result of an aberrant reparative response following exposures to various antenatal and postnatal insults. Despite sophisticated medical treatment in this modern era, the incidence of BPD remains unabated. The current strategies to prevent and treat BPD have met with limited success. The emergence of stem cell therapy may be a potential breakthrough in mitigating this complex chronic lung disorder. Over the last two decades, the human placenta and umbilical cord have gained increasing attention as a highly potential source of stem cells. Placenta-derived stem cells (PDSCs) and umbilical cord-derived stem cells (UCDSCs) display several advantages such as immune tolerance and are generally devoid of ethical constraints, in addition to their stemness qualities. They possess the characteristics of both embryonic and mesenchymal stromal/stem cells. Recently, there are many preclinical studies investigating the use of these cells as therapeutic agents in neonatal disease models for clinical applications. In this review, we describe the preclinical and clinical studies using PDSCs and UCDSCs as treatment in animal models of BPD. The source of these stem cells, routes of administration, and effects on immunomodulation, inflammation and regeneration in the injured lung are also discussed. Lastly, a brief description summarized the completed and ongoing clinical trials using PDSCs and UCDSCs as therapeutic agents in preventing or treating BPD. Due to the complexity of BPD, the development of a safe and efficient therapeutic agent remains a major challenge to both clinicians and researchers.

The Effects of COVID-19 on Placenta and Pregnancy: What Do We Know So Far?

The current coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has inflicted a serious health crisis globally. This virus is associated with a spectrum of respiratory illness ranging from asymptomatic, mild to severe pneumonia, and acute respiratory distress syndrome. Accumulating evidence supports that COVID-19 is not merely a respiratory illness per se, but potentially affects other organ systems including the placenta. SARS-CoV-2 gains access to human cells via angiotensin-converting enzyme 2 (ACE-2). The abundance of ACE-2 on the placental cell surface, especially the syncytiotrophoblasts, could potentially contribute to vertical transplacental transmission to the fetus following maternal COVID-19 infection. Intriguingly, despite the placentas being tested positive for SARS-CoV-2, there are very few newborns that manifest virus-induced diseases. The protective effects of the placental barrier to viral infection, limiting the spread of the virus to newborn infants, remain a mystery. The detrimental role of COVID-19 in pregnancies is largely debatable, although COVID-19 maternal infection has been implicated in unfavorable pregnancy outcomes. In this review, we summarize the pathological features manifested in placenta due to COVID-19 maternal infection that have been previously reported, and relate them to the possible disease manifestation. The potential mechanistic pathways associated with transplacental viral transmission and adverse pregnancy outcomes are also discussed.

A multi-centre, open label, randomised, parallel-group, superiority Trial to compare the efficacy of URsodeoxycholic acid with RIFampicin in the management of women with severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC randomised trial.

BACKGROUND: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. METHODS: We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. DISCUSSION: Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. TRIAL IDENTIFIERS: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

Consensus Definition of Fetal Growth Restriction in Intrauterine Fetal Death: A Delphi Procedure.

CONTEXT.­: Fetal growth restriction is a risk factor for intrauterine fetal death. Currently, definitions of fetal growth restriction in stillborns are heterogeneous. OBJECTIVES.­: To develop a consensus definition for fetal growth restriction retrospectively diagnosed at fetal autopsy in intrauterine fetal death. DESIGN.­: A modified online Delphi survey in an international panel of experts in perinatal pathology, with feedback at group level and exclusion of nonresponders. The survey scoped all possible variables with an open question. Variables suggested by 2 or more experts were scored on a 5-point Likert scale. In subsequent rounds, inclusion of variables and thresholds were determined with a 70% level of agreement. In the final rounds, participants selected the consensus algorithm. RESULTS.­: Fifty-two experts participated in the first round; 88% (46 of 52) completed all rounds. The consensus definition included antenatal clinical diagnosis of fetal growth restriction OR a birth weight lower than third percentile OR at least 5 of 10 contributory variables (risk factors in the clinical antenatal history: birth weight lower than 10th percentile, body weight at time of autopsy lower than 10th percentile, brain weight lower than 10th percentile, foot length lower than 10th percentile, liver weight lower than 10th percentile, placental weight lower than 10th percentile, brain weight to liver weight ratio higher than 4, placental weight to birth weight ratio higher than 90th percentile, histologic or gross features of placental insufficiency/malperfusion). There was no consensus on some aspects, including how to correct for interval between fetal death and delivery. CONCLUSIONS.­: A consensus-based definition of fetal growth restriction in fetal death was determined with utility to improve management and outcomes of subsequent pregnancies.

Interventions for investigating and identifying the causes of stillbirth.

BACKGROUND: Identification of the causes of stillbirth is critical to the primary prevention of stillbirth and to the provision of optimal care in subsequent pregnancies. A wide variety of investigations are available, but there is currently no consensus on the optimal approach. Given their cost and potential to add further emotional burden to parents, there is a need to systematically assess the effect of these interventions on outcomes for parents, including psychosocial outcomes, economic costs, and on rates of diagnosis of the causes of stillbirth. OBJECTIVES: To assess the effect of different tests, protocols or guidelines for investigating and identifying the causes of stillbirth on outcomes for parents, including psychosocial outcomes, economic costs, and rates of diagnosis of the causes of stillbirth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (31 August 2017), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (15 May 2017). SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs), quasi-RCTs, and cluster-RCTs. We planned to include studies published as abstract only, provided there was sufficient information to allow us to assess study eligibility. We planned to exclude cross-over trials.Participants included parents (including mothers, fathers, and partners) who had experienced a stillbirth of 20 weeks' gestation or greater.This review focused on interventions for investigating and identifying the causes of stillbirth. Such interventions are likely to be diverse, but could include:* review of maternal and family history, and current pregnancy and birth history;* clinical history of present illness;* maternal investigations (such as ultrasound, amniocentesis, antibody screening, etc.);* examination of the stillborn baby (including full autopsy, partial autopsy or noninvasive components, such as magnetic resonance imaging (MRI), computerised tomography (CT) scanning, and radiography);* umbilical cord examination;* placental examination including histopathology (microscopic examination of placental tissue); and* verbal autopsy (interviews with care providers and support people to ascertain causes, without examination of the baby).We planned to include trials assessing any test, protocol or guideline (or combinations of tests/protocols/guidelines) for investigating the causes of stillbirth, compared with the absence of a test, protocol or guideline, or usual care (further details are presented in the Background, see Description of the intervention).We also planned to include trials comparing any test, protocol or guideline (or combinations of tests/protocols/guidelines) for investigating the causes of stillbirth with another, for example, the use of a limited investigation protocol compared with a comprehensive investigation protocol. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility independently. MAIN RESULTS: We excluded five studies that were not RCTs. There were no eligible trials for inclusion in this review. AUTHORS' CONCLUSIONS: There is currently a lack of RCT evidence regarding the effectiveness of interventions for investigating and identifying the causes of stillbirth. Seeking to determine the causes of stillbirth is an essential component of quality maternity care, but it remains unclear what impact these interventions have on the psychosocial outcomes of parents and families, the rates of diagnosis of the causes of stillbirth, and the care and management of subsequent pregnancies following stillbirth. Due to the absence of trials, this review is unable to inform clinical practice regarding the investigation of stillbirths, and the specific investigations that would determine the causes.Future RCTs addressing this research question would be beneficial, but the settings in which the trials take place, and their design, need to be given careful consideration. Trials need to be conducted with the utmost care and consideration for the needs, concerns, and values of parents and families. Assessment of longer-term psychosocial variables, economic costs to health services, and effects on subsequent pregnancy care and outcomes should also be considered in any future trials.

Interventions for supporting parents' decisions about autopsy after stillbirth.

BACKGROUND: Stillbirth remains one of the least understood areas of infant death and accurate data on the causes of stillbirth are the cornerstone of stillbirth prevention. An autopsy examination remains the gold standard post-mortem investigation for stillbirth. However, decisions about post-mortem investigations, particularly autopsy are difficult. The purpose of this review is to examine the effectiveness of methods to help parents who have experienced a stillbirth decide whether to have post-mortem investigations, including whether to have an autopsy performed. OBJECTIVES: The primary objectives were a) to examine the effectiveness of interventions to support parents' decisions about autopsy consent after a stillbirth on outcomes for parents, and b) to determine autopsy rates. Secondary objectives were to identify issues related to the acceptability of any interventions to parents and the feasibility of their implementation. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (29 October 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10), MEDLINE (1966 to 24 July 2012) and EMBASE (1980 to 24 July 2012), Current Controlled Trials metaRegister (mRCT) (18 September 2012) and the WHO International Clinical Trials Registry Platform Search Portal (ICTRP) (18 September 2012). We also searched the websites of the Stillbirth and Neonatal Death Charity (SANDS) and International Stillbirth Alliance (ISA) (18 September 2012) and then subsequently searched the websites of all the ISA member organisations. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions designed specifically to support parents who have experienced a stillbirth make decisions about their options for post-mortem investigations including all investigations after stillbirth compared with usual care. DATA COLLECTION AND ANALYSIS: Two review authors independently screened citations against the selection criteria.  MAIN RESULTS: No studies meeting the review inclusion criteria were identified. A search of 40 websites associated with supporting parents who experience stillbirth also found little reference to, or information about autopsy or other post-mortem examinations. AUTHORS' CONCLUSIONS: Support for parents making decisions about autopsy or other post-mortem examinations after stillbirth must rely on the ad hoc knowledge and experience of those involved at the time.

Lung disease associated with periventricular nodular heterotopia and an FLNA mutation.

X-linked periventricular nodular heterotopia (PH) is a neuronal migration disorder caused by mutations in the gene encoding filamin A (FLNA). High phenotypic diversity, ranging from PH to otopalatodigital syndrome and frontometaphyseal dysplasia has been described in association with FLNA mutations. Extra-neurological features including cardiovascular abnormalities, coagulopathy, skeletal dysplasia and joint hypermobility have sometimes been described in patients with PH. Respiratory manifestations have not been associated with FLNA disorders with the exception of tracheal stenosis and pulmonary hypoplasia associated with frontometaphyseal dysplasia and Melnick-Needles syndrome. Here, we report on a male patient aged 6 years presenting with a mosaic nonsense mutation c.994delG within the FLNA gene, PH and severe congenital lung disease comprising bilateral atelectasis, lung cysts, tracheobronchomalacia, pulmonary arterial hypertension and long-term oxygen dependence; histology of resected lung showed panpulmonary emphysema with marked reduction of bronchial cartilage. Rare male patients with PH and FLNA mutations have already been reported, usually with early lethality. These observations suggest the possibility of a link between FLNA mutations and congenital lung disease. A prospective study of patients with PH and FLNA mutations would be helpful in order to test this hypothesis.

Low perinatal autopsy rate in Malaysia: time for a change.

Our objectives were to determine the perinatal autopsy rate in a tertiary hospital in Malaysia and to quantify the value of the perinatal autopsy. All stillbirths, miscarriages, therapeutic abortions, and neonatal deaths between January 1, 2004, and August 31, 2009, were identified from the archives. The autopsy findings were compared with the clinical diagnoses. The autopsy reports were also reviewed to determine if it would be possible to improve the quality of the autopsies. There were 807 perinatal deaths, of which 36 (4.5%) included an autopsy. There were ethnic differences in the rate of autopsy, with the lowest rate among the Malays. The autopsy provided the diagnosis, changed the clinical diagnosis, or revealed additional findings in 58.3% of cases. Ancillary testing, such as microbiology, chromosomal analysis, and biochemistry, could improve the quality of the autopsy. This study provides further data on the perinatal autopsy rate from an emerging and developing country. It reaffirms the value of the perinatal autopsy. Attempts must be made to improve on the low autopsy rate while recognizing that the performance of autopsies can be enhanced through the use of ancillary testing.