Paul Downey

Novel placental ultrasound assessment: Potential role in pre-gestational diabetic pregnancy

OBJECTIVES Management of women with pre-gestational diabetes continues to be challenging for clinicians. This study aims to determine if 3D power Doppler (3DPD) analysis of placental volume and flow, and calculation of placental calcification using a novel software method, differ between pregnancies with type 1 or type 2 diabetes and normal controls, and if there is a relationship between these ultrasound placental parameters and clinical measures in diabetics. METHODS This was a prospective cohort study of 50 women with diabetes and 250 controls (12-40 weeks gestation). 3DPD ultrasound was used to evaluate placental volume, vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI). Placental calcification was calculated by computer analysis. Results in diabetics were compared with control values, and correlated with early pregnancy HbA1c, Doppler results and placental histology. RESULTS Placental calcification and volume increased with advancing gestation in pre-gestational diabetic placentae. Volume was also found to be significantly higher than in normal placentae. VI and VFI were significantly lower in diabetic pregnancies between 35 and 40 weeks gestation. A strong relationship was seen between a larger placental volume and both increasing umbilical artery pulsatility index and decreasing middle cerebral artery pulsatility index. FI was significantly lower in cases which had a booking HbA1c level ≥6.5%. Ultrasound assessed placental calcification was reduced with a histology finding of delayed villous maturation. No other correlation with placental histology was found. CONCLUSIONS This study shows a potential role for 3D placental evaluation, and computer analysis of calcification, in monitoring pre-gestational diabetic pregnancies.

Cardiomyopathy in Offspring of Pregestational Diabetic Mouse Pregnancy

Purpose. To investigate cardiomyopathy in offspring in a mouse model of pregestational type 1 diabetic pregnancy. Methods. Pregestational diabetes was induced with STZ administration in female C57BL6/J mice that were subsequently mated with healthy C57BL6/J males. Offspring were sacrificed at embryonic day 18.5 and 6-week adolescent and 12-week adult stages. The size and number of cardiomyocyte nuclei and also the extent of collagen deposition within the hearts of diabetic and control offspring were assessed following cardiac tissue staining with either haematoxylin and eosin or Picrosirius red and subsequently quantified using automated digital image analysis. Results. Offspring from diabetic mice at embryonic day 18.5 had a significantly higher number of cardiomyocyte nuclei present compared to controls. These nuclei were also significantly smaller than controls. Collagen deposition was shown to be significantly increased in the hearts of diabetic offspring at the same age. No significant differences were found between the groups at 6 and 12 weeks. Conclusions. Our results from offspring of type 1 diabetic mice show increased myocardial collagen deposition in late gestation and have increased myocardial nuclear counts (hyperplasia) as opposed to increased myocardial nuclear size (hypertrophy) in late gestation. These changes normalize postpartum after removal from the maternal intrauterine environment.

An open-label randomized-controlled trial of low dose aspirin with an early screening test for pre-eclampsia and growth restriction (TEST): Trial protocol

OBJECTIVE Pre-eclampsia remains a worldwide cause of maternal and perinatal morbidity and mortality. Low dose aspirin (LDA) can reduce the occurrence of pre-eclampsia in women with identifiable risk factors. Emerging screening tests can determine the maternal risk of developing placental disease, such as pre-eclampsia from the first trimester of pregnancy. The aim of this study is to determine if it is more beneficial in terms of efficacy and acceptability to routinely prescribe LDA to nulliparous low-risk women compared to test indicated LDA on the basis of a positive screening test for placental disease. METHODS We propose a three armed multi-center open-labeled randomized control trial of; (i) routine LDA, (ii) no aspirin, and (iii) LDA on the basis of a positive first trimester pre-eclampsia screening test. LDA (75mg once daily) shall be given from the first trimester until 36-week gestation. The primary outcome measures include; (i) the proportion of eligible women that agree to participate (acceptability), (ii) compliance with study protocol (acceptability and feasibility), (iii) the proportion of women in whom it is possible to obtain first trimester trans-abdominal uterine artery Doppler examination (feasibility) and (iv) the proportion of women with a completed screening test that are issued the screening result within one week of having the test performed (feasibility). CONCLUSION This will be the first clinical trial to determine the efficacy and acceptability in low-risk women of taking routine LDA versus no aspirin versus LDA based on a positive first trimester screening test for the prevention of placental disease.

The contribution of massive fetomaternal hemorrhage to antepartum stillbirth: a 25‐year cross‐sectional study

Fatal antepartum fetomaternal hemorrhage is a relatively uncommon clinical presentation, though one that appears quickly and without warning. The pathophysiology of this disease is unclear, and the incidence does not appear to be decreasing in line with overall antepartum mortality. This study was undertaken to analyse trends in antepartum fetal death from fetomaternal hemorrhage over a 25‐year period in a single maternity hospital in Dublin, Ireland.

A case of recurrent familial male miscarriages with hypercoiled umbilical cord: a possible X-linked association?

Introduction The umbilical cord represents the vascular connection between the developing foetus and the maternal placenta. By way of its anatomy it is at risk for traction, kinking and compression. The normal umbilical cord is spiralled along its length, thus providing resistance to compression and aiding venous return to the foetus. A coil is defined as a complete spiral of 3601 of the umbilical vessels around each other (De Laat et al., 2005). The degree of cord coiling is quantified by the umbilical cord index (UCI), which is calculated by dividing the number of complete coils present in the cord by the total length of the cord in centimetres (Strong et al., 1994a), with a mean value of 0.20 from various studies (Khong, 2010). A hypercoiled cord is one in which the UCI is greater than the 90th centile (De Laat et al., 2007). Emerging literature has shown a relationship between hypercoiled umbilical cords and adverse perinatal outcomes, including polyhydramnios, congenital abnormalities and perinatal death (Hermann et al., 1991; Strong et al., 1993; Strong et al., 1994b; Degani et al., 1995; Rana et al., 1995; Ezimokhai et al., 2000; Machin et al., 2000; De Laat et al., 2005, 2007; Chitra et al., 2012). To date the mechanism underlying cord hypercoiling is not completely understood and the risk of recurrence is not clear. We report a case with two consecutive pregnancy losses of male infants with hypercoiled cords, raising the possibility of an underlying X-linked or possible autosomal association.

Umbilical artery thrombosis is a rare but clinically important finding: a series of 7 cases with clinical outcomes.

Umbilical artery thrombosis is a rare occurrence and is associated with poor neonatal outcomes. We present a series of 7 cases occurring over a 13-year period. The National Maternity Hospital is a tertiary referral center with approximately 10 000 births per annum. Cases were identified by a keyword search on the laboratory computer system. Seven cases were retrieved over a 13-year period (from an estimated 116 000 births): 5 cases from 7306 placentas and 2 cases from 1174 autopsies performed. Only cases with isolated umbilical artery thrombosis were included in the study. Placental histology from all cases was examined, placental gross findings were recorded, and clinical information and Doppler findings were obtained. Two infants were stillborn, and an additional 3 of the 7 cases were small for dates. All liveborn infants had a complicated neonatal course: 1 infant had a caudate infarction, 1 was born with partial acrania and schizencephaly, and 1 had a prolonged intensive care unit admission for low birth weight and jaundice. One case had absent end diastolic flow on Doppler ultrasound. Three cases had a cord diameter narrower than that expected for gestational age. All cases showed evidence of placental hypoperfusion. Umbilical artery thrombosis is a rare occurrence and carries a poor prognosis.

Neutrophil and monocyte Toll-Like Receptor 4, CD11b and Reactive Oxygen Intermediates and Neuroimaging Outcomes in Preterm Infants

Background:Activated leukocytes and infection are implicated in neonatal brain injury. Leukocyte surface receptors are increased in stroke models and may be targets for future adjunctive therapies.Methods:Serial blood samples were analyzed from preterm infants (n = 51; <32 wk gestation) on days 0, 1, 2, and 7 of life. Monocyte and neutrophil activation were evaluated via flow cytometry at baseline and following endotoxin stimulation ex vivo by measuring CD11b (activation), toll-like receptor 4 (TLR-4; endotoxin recognition) expression, and intracellular reactive oxygen intermediate (ROI) production (function).Results:Control preterm infants with normal neuroimaging had elevated baseline CD11b and TLR-4 expression and ROI production compared with adults as well as a robust immune response following endotoxin stimulation. Preterm infants with abnormal neuroimaging had increased neutrophil TLR-4 and ROI compared with all controls.Conclusion:Preterm infants have a robust immune response compared with adults. Increased TLR-4 expression in preterm infants with abnormal neuroimaging is similar to findings in adult stroke. In addition, ROI production may cause tissue injury. The modulation of these responses may be beneficial in preterm inflammatory disorders.

Inflammatory Protein Expression in Adolescent and Adult Offspring of Type 1 Diabetic Mice

AIMS To measure inflammatory markers in offspring of pregestational type 1 diabetic mothers. METHODS Type 1 diabetes was induced in female C57BL6/J mice using streptozotocin. Offspring from control C57BL6/J and type 1 diabetic mothers were followed up to adulthood and blood was collected at 6 and 12 weeks of age, representing adolescent and adult stages respectively. Five well-established inflammatory markers; Matrix metalloproteinase 9, soluble E-selectin, sICAM-1, sVCAM-1, and total plasminogen activator inhibitor-1 (PAI-1) were measured on an inflammatory multiplex assay in plasma. RESULTS Blood plasma from adolescent offspring from diabetic mothers displayed an increase in all five inflammatory markers when compared to controls, and there was a highly significant increase in sVCAM-1 (64.56 ± 20.1 vs. 33.8 ± 20.75; p < 0.01) and tPAI-1 (0.05 ± 0.02 vs. 0.02 ± 0.01; p < 0.01) expression. CONCLUSION Our findings show that inflammatory markers are increased in offspring of pregestational diabetic mothers. This may represent a mechanism for increased risk of cardiovascular disease evident in these offspring.

Clinical disparity of haemolytic disease of the fetus and newborn in twin pregnancy

Dear Sir, A 32-year-old Caucasian woman, blood group O RhD-negative (cde/cde, rr), gravida 4 para 2, presented to our institution for management of a spontaneously conceived dichorionic twin pregnancy. Her previous pregnancy was affected by Haemolytic Disease of the Fetus and Newborn (HDFN), necessitating induction at 38 weeks gestation for elevated and rising levels of anti-D and the baby required phototherapy after delivery. This current pregnancy was a dichorionic twin pregnancy. Both anti-D and anti-G antibodies were detected through indirect antiglobulin testing in a maternal sample at 13 weeks gestation. Anti-D antibody levels were quantified using the Astoria Pacific International 300 (API 300) continuous flow analyser (CFA) using group O R1R1 (CCDDee) reagent cells (Marsh et al., 1968) and are measured in IU mL−1. The following levels of anti-D were used to guide management; <4 (HDFN unlikely), 4–15 (moderate risk of HDFN), >15 (risk of severe HDFN) (Gooch et al., 2007). Anti-D quantitation levels are provided in Table 1. The patient underwent surveillance for fetal anaemia with middle cerebral artery (MCA) Doppler studies once and subsequently twice weekly from 24 weeks gestation. Owing to increasing MCA Doppler Peak systolic velocity values (PSVs) as shown in Table 1, twin A required three intrauterine transfusions (IUTs) by cordocentesis of packed red blood cells (PRCs) of 100, 60 and 160 mL at 27, 29 and 34 weeks gestation, respectively. Anti-D antibody levels rose dramatically to 330 IU/mL following the first IUT. While twin B had evidence of mild intrauterine fetal anaemia (PSV 1·5 MoMs), this did not persist and an IUT was not required. There was no evidence of hydrops or fetal compromise in either twin throughout the pregnancy. The twins were delivered via caesarean section at 34 weeks and 3 days of gestation for the indication of suspected chorioamnionitis. Twin A was 2·4 kg with Apgar scores of nine at 1 and 5 min. Twin A was blood group O RhD-positive (R2r phenotype) cDE/cde, with a strongly positive direct antiglobulin test (DAT) (4+, IgG), haemoglobin of 16·9 g/dL, reticulocytes 222× 109 L−1 (4·2%) and bilirubin of 132 μmol L−1. On the first day of life this infant received intravenous immunoglobulin, phototherapy and a subsequent double volume exchange transfusion using irradiated whole O RhD-negative blood at 8 hours of life in addition

An audit of healthcare professionals’ knowledge regarding perinatal autopsy

BackgroundPerinatal autopsy is one the most valuable investigations to ascertain the cause of death (Nijkamp et al., Seminars in Fetal & Neonatal Medicine. 22:167-175, 2017; Korteweg et al., AJOG 53, e1-12, 2012; Late Interuterine Death and Stillbirth’ RCOG Green-top Guideline No.55, 2015). Discussions about perinatal autopsy can be difficult for parents and healthcare professionals. Perinatal staff need a good level of knowledge and understanding regarding perinatal autopsy in order to discuss the procedure with parents. This study aims to investigate healthcare professionals’ knowledge regarding perinatal autopsy.MethodsAn audit conducted in a large teaching hospital using a questionnaire was developed and distributed to healthcare professionals in the hospital.ResultsSeventy healthcare professionals participated in the audit. Of those surveyed, 64% (n = 45) have discussed perinatal autopsy with a mother and the majority of healthcare professionals (67%) found this difficult. Self-reported levels of understanding were found to be low with just 10% reporting ‘excellent understanding’.ConclusionsThe results of this audit highlight the need for further education among all healthcare professionals working with bereaved families.