Selective modulation of monocyte and neutrophil responses with activated protein C in preterm infants.

BACKGROUND: Inflammation is associated with many disorders of preterm infants including periventricular leukomalacia, chronic lung disease, and necrotizing enterocolitis. Activated protein c (APC) has shown positive immunomodulatory effects. OBJECTIVES: We aimed to study neutrophil and monocyte function in response to lipopolysaccharide (LPS) and APC stimulation ex vivo in preterm infants <32 weeks gestation over the first week of life compared to neonatal and adult controls. METHODS: Peripheral blood was taken on day 1, 3, and 7 and stimulated with LPS in the absence or presence of APC. Expression of toll-like receptor 4 (TLR4) and CD11b and reactive oxygen intermediate (ROI) release from neutrophils and monocytes was examined by flow cytometry. RESULTS: LPS induced neutrophil ROI in adults and preterm infants and was significantly reduced by APC. Baseline and LPS-induced monocyte ROI production in preterm neonates was increased compared to adult and term controls. Neutrophil TLR4 baseline expression was higher in term controls compared to preterm infants. CONCLUSION: Increased systemic ROI release in preterm infants may mediate tissue damage, ROI was reduced by APC. However, due to the high risk of hemorrhage further examination of APC mutant forms with anti-inflammatory but decreased anticoagulant properties is merited.

High-Grade Fetal Vascular Malperfusion Is Associated With Diffuse Chorionic Hemosiderosis.

INTRODUCTION: Diffuse chorionic hemosiderosis (DCH) is an abnormality of the placental membranes characterized by the deposition of iron pigment. It is usually secondary to recurrent venous bleeding in early pregnancy. In many papers, it is associated with pre-term delivery. Fetal vascular malperfusion (FVM) is an abnormality of the feto-placental circulation that may be seen at any stage of gestation, but most often in the third trimester. It may be graded as low grade (LGFVM) or high grade (HGFVM). No link has been identified in the placental literature between DCH and FVM, but we have noted the 2 co-existing in placentas submitted for analysis. This study explored a possible association of these 2 entities. METHODS: Laboratory records were searched for singleton cases coded as DCH based on diagnosis on H&E stain over a 6-year period. Of 4478 placentas reported, 66 cases were coded as DCH (1.5%). These were classified as showing HGFVM, LGFVM, or no FVM. Controls (n = 132) were gestational age-matched cases without DCH. Cord length, coiling, insertion, or other abnormalities were noted. Membranes were classified as normal or circumvallate. Results were analyzed using Graphpad. RESULTS: Gestation ranged between 16 and 41 weeks gestation. 14/66 (21%) cases of DCH showed HGFVM and 2/66 (3%) showed LGFVM. 16/132 (12%) controls showed HGFVM and 21/132 (15.9%) had LGFVM. Where FVM is present, high-grade FVM is significantly associated with DCH versus controls (P < .0031 Fischer's Test). DISCUSSION: HGFVM occurs significantly more often in placentas with DCH than in controls. Both FVM and DCH are associated with adverse perinatal outcomes, and a possible relationship between the 2 remains to be clarified.

Sexual dimorphism and the placenta - results from the ROLO kids study.

BACKGROUND/AIMS: To assess the association between placental morphology and neonatal and infant anthropometry, including analysis by sex. STUDY DESIGN: Data from the ROLO Kids [Randomized COntrol Trial of LOw Glycaemic Index in Pregnancy] study were analyzed including placental weight and morphology. Placental, anthropometric and skinfold measurements were recorded as markers of adiposity in 196 neonates and 215 infants at 6 months of age. Ratios including subscapular-to-triceps skinfold ratio and waist-to-height ratio were used as markers of central adiposity, while the sum of all skinfolds and subscapular plus triceps skinfolds were used as markers of general adiposity. Analysis was performed for total groups and by sex. RESULTS: On simple linear regression placental weight was associated with neonatal and infant anthropometric measurements. On multiple regression, the placental weight was associated with birth weight. In the neonatal period placental weight was associated with general adiposity in males only (sum of skinfolds (B 0.007, p < .001) and subscapular + triceps skinfolds a marker of general adiposity (B 0.004 p < .001)). At 6 months of age placental length was positively associated with central adiposity in the total group (B 0.006, p .036) and maximum cord diameter was inversely associated with infant central adiposity (B - 0.309 p .043) in males only. CONCLUSION: The placental phenotype is associated with anthropometry at birth and this association persists to early infancy with a stronger relationship noted in this cohort amongst males. This suggests sexual dimorphism may play a role in the impact of the placenta on infant anthropometry.

Mid-luteal uterine artery Doppler indices in the prediction of pregnancy outcome in nulliparous women undergoing assisted reproduction.

Traditionally, the assessment of endometrial receptivity at transvaginal ultrasound scan has been based on the thickness and the morphological appearance of the endometrium. The objective of this study was to prospectively evaluate endometrial thickness (ET), endometrial morphology and uterine artery Doppler parameters prior to assisted reproduction treatment (ART) in the prediction of pregnancy outcome. This was a prospective cohort study. ET, morphology and uterine artery Doppler (UtAD) pulsatility index (PI) and resistance index (RI) were measured in the mid-luteal stage of the menstrual cycle ultrasonographically, timed with urinary luteinizing hormone testing. A total of 50 women were included in the analysis. The clinical pregnancy rate (CPR) per embryo transfer was 42.0% (n = 21/50). Twenty nine women (58.0%) had an unsuccessful outcome. There were no differences in mean ± SD endometrial thickness (ET) (10.0 ± 1.8 mm vs. 10.5 ± 2.4; p = 0.43), or endometrial morphology (100% (n = 21) vs 100% (n = 29); p = 1.00) between the pregnant and not pregnant groups. Similarly, there were no differences in mean ± SD UtAD PI (2.17 ± 0.83 vs. 2.07 ± 0.81; p = 0.67 or mean ± SD UtAD RI (0.84 ± 0.10 vs. 0.81 ± 0.10; p = 0.30). Ultrasonographic endometrial assessment did not differentiate between those who would have a subsequent clinical pregnancy.

The etiology of stillbirth over 30 years: A cross-sectional study in a tertiary referral unit.

INTRODUCTION: Stillbirth remains an often unpredictable and devastating pregnancy outcome, and despite thorough investigation, the number of stillbirths attributable to unexplained causes remains high. Placental examination has become increasingly important where access to perinatal autopsy is limited. We aimed to examine the causes of stillbirth in normally formed infants over 30 years and whether a declining autopsy rate has affected our ability to determine a cause for stillbirths. MATERIAL AND METHODS: All cases of normally formed singleton infants weighing ≥500 g that died prior to the onset of labor from 1989 to 2018 were examined. Trends for specific causes and uptake of perinatal autopsy were analyzed individually. RESULTS: In all, 229 641 infants were delivered, with 840 stillbirths giving a rate of 3.66/1000. The rate of stillbirth declined from 4.84/1000 in 1989 to 2.51 in 2018 (P < .001). There was no difference in the rate of stillbirth between nulliparous and multiparous women (4.25 vs 3.66 per 1000, P = .026). Deaths from placental abruption fell (1.13/1000 in 1989 to 0 in 2018, P < .001) and the relative contribution of placental abruption to the incidence of stillbirth also fell, from 23.3% (7/30) in 1989 to 0.0% (0/19) in 2018 (P < .001). Stillbirth attributed to infection remained static (0.31/1000 in 1989 to 0.13 in 2018, P = .131), while a specific causal organism was found in 79.2% (42/53) of cases. Unexplained stillbirths decreased from 2.58/1000 (16/6200) in 1989 to 0.13 (1/7581) in 2018 (P < .001) despite a fall in the uptake of perinatal autopsy (96.7% [29/30] in 1989 to 36.8% (7/19) in 2018; P < .001). Placental disease emerged as a significant cause of stillbirth from 2004 onwards (89.5% [17/19] in 2018). CONCLUSIONS: The present analysis is one of the largest single-center studies on stillbirth published to date. Stillbirth rates have fallen across the study period across parity. A decrease in deaths secondary to placental abruption contributed largely to this. Infection-related deaths are static; however, in one-fifth of cases a causative organism was not found. Despite a decreasing autopsy rate, the number of unexplained stillbirths continues to fall as the importance of placental pathology is increasingly recognized.

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.

The impact of accurately timed mid-luteal endometrial injury in nulligravid women undergoing their first or second embryo transfer.

INTRODUCTION: Endometrial injury or 'scratch' preceding an assisted reproductive therapy (ART) cycle has recently been shown not to improve livebirth rates among women undergoing ART. The objective of this study was to compare pregnancy outcomes in nulliparous women who underwent an accurately timed mid-luteal scratch biopsy prior to ART with those who did not. METHODS: This was a prospective cohort study. Women were recruited between October 2016 and February 2018 inclusive. Women who met the inclusion criteria and who did not undergo an endometrial scratch in the study period were used as a comparison group. Patients underwent a cycle of ART in the menstrual cycle following endometrial scratch. RESULTS: Ninety-eight women were eligible for participation in the study. There were no differences in rates of implantation (35.7% (n = 20/56) vs. 35.4% (n = 17/48); p = 1.00), clinical pregnancy (40.0% (n = 20/50) vs. 39.5% (n = 17/43); p = 1.00) or live birth (34.0% (n = 17/50) vs. 25.6% (n = 11/43); p = 0.50) per embryo transfer between those who underwent a scratch and those who did not. CONCLUSION: Endometrial scratch is a simple, inexpensive and low-risk procedure. However, in this relatively small cohort study, no differences in rates of implantation, clinical pregnancy or live birth in women with primary infertility were determined between those who underwent a scratch and those who did not.

Histological chorioamnionitis is predicted by early infant C-reactive protein in preterm infants and correlates with neonatal outcomes.

AIM: Histological chorioamnionitis (HCA) is associated with preterm birth and adverse neonatal outcomes. We evaluated the rise in C-reactive protein (CRP) in preterm infants as a predictor of HCA severity and outcomes. METHODS: Consecutive preterm infants, born January 2009 to January 2014 in the National Maternity Hospital, Dublin, under 32 weeks' gestation or <1.5 kg birthweight, were included. Histological chorioamnionitis was staged as maternal inflammatory response, foetal inflammatory response and non-HCA. RESULTS: Preterm infants (n = 518) were included with a mean gestational age 28.5 ± 2.8 weeks, birthweight 1.1 ± 0.3 kg, and 53.5% were male. Histological chorioamnionitis was found in 25.4%. Histological chorioamnionitis was present in 93.7% when CRP > 5 mg/L, 65.2% when CRP 1-5 mg/L and in 19.4% when CRP < 1 mg/L. When both the immature to total neutrophil (IT) ratio was >0.2 and the CRP > 1 mg/L the positive predictive value and negative predictive value for HCA were 92.5% and 84.9%, respectively. Histological chorioamnionitis was associated with more resuscitation and respiratory distress syndrome (both P < .001). A CRP > 10 mg/L was associated with a foetal inflammatory response and increased early-onset sepsis. CONCLUSION: Higher early CRP was a surrogate predictor of HCA and correlated with the severity of HCA. Higher CRP and HCA were associated with adverse early outcomes.

Placental weights from normal deliveries in Ireland.

BACKGROUND: The weight of the delivered placenta gives a useful representation of placental function in utero. In the absence of Irish data, many pathologists rely on data from other populations, many of which are now 15 to 30 years old. The development of a population-specific nomogram would aid in the examination of placentas after delivery, allowing pathologists and medical scientists to more easily distinguish between placental physiological changes and pathology. AIMS: To record placental weights among women having a singleton delivery in Dublin and to establish median placental weights for each gestational age after 37 weeks. METHODS: Prospective cohort study in a Tertiary level University Hospital. All singleton pregnancies were included; stillbirths, multiple gestations, and cases with obstetric complications involving the placenta were excluded. The placentas were weighed both untrimmed and trimmed with standard scales. Demographic features including birth weight and maternal parity were also recorded. RESULTS: Four hundred thirty placentas were weighed over a 6-week period. A median term placental weight based on gestational age was established, with a range from the tenth to ninetieth centiles. CONCLUSION: The weight of the placenta is one of several measurements that are easy to acquire, and when recorded in a systematic fashion, provide information not just on an individual, but also on a population basis. Birth weights have increased over the last century, and this study provides national data helping distinction between placental physiology and pathology.

Evaluation of the Effect of Low-Dose Aspirin on Biochemical and Biophysical Biomarkers for Placental Disease in Low-Risk Pregnancy: Secondary Analysis of a Multicenter RCT.

OBJECTIVE: To assess the effect of aspirin use in low-risk pregnancy on: (1) pregnancy-associated plasma protein-A (PAPP-A) and placental-like growth factor (PLGF); (2) urinary albumin-to-creatinine ratio (ACR) and blood pressure; (3) fetal growth parameters; and (4) placental histopathology. STUDY DESIGN: This secondary analysis from the T rial of low-dose aspirin with an E arly S creening T est for preeclampsia and growth restriction randomized controlled trial was based on low-risk nulliparous women randomized at 11 weeks to (1) aspirin 75 mg; (2) no aspirin; and (3) aspirin based on the preeclampsia Fetal Medicine Foundation screening test. At baseline, women underwent assessment of blood pressure, PAPP-A, PLGF, and ACR, repeated 9 to 10 weeks postaspirin, in addition to fetal growth assessment. Gross and histopathological placental analyses were performed in line with Amsterdam criteria. RESULTS: A total of 445 subjects were included (aspirin n = 163 [36.6%]; no aspirin n = 282 [63.4%]). Although the fetal-to-placental weight ratio was significantly greater in the aspirin group (7.5 [±1.3] vs. 7.3 [±1.4], p = 0.045), as was change in ultrasound assessed estimated fetal weight from second to third trimesters (1,624.5 g [±235.1] vs. 1,606.2 [±189.4], p = 0.042), this was invalidated by the lack of a difference in birth weight. Aspirin did not significantly impact on change in serum or urine preeclampsia biomarkers, maternal blood pressure, or placental histopathology. CONCLUSION: Aspirin use in low-risk pregnancy does not appear to impact on preeclampsia biomarkers, fetal growth, or placental pathology.

Placental disease and abnormal umbilical artery Doppler waveforms in trisomy 21 pregnancy: A case-control study.

INTRODUCTION: The objectives of this study were firstly to determine the proportion of placental pathology in fetuses affected by trisomy 21 (T21) using current pathological descriptive terminology and secondly to examine if a correlation existed between the finding of an abnormal umbilical artery Doppler (UAD) waveform, the presence of T21 and defined placental pathological categories. METHODS: This case-control study assessed singleton fetuses with karyotypically confirmed trisomy 21 where placental histopathology had been conducted from 2003 to 2015 inclusive, within a university tertiary obstetric centre. This was compared with unselected normal singleton control pregnancies matched within a week of gestation at delivery. Data included birthweight centiles and placental histopathology. Comparisons of Doppler findings across placental pathological categories were performed using statistical analysis. RESULTS: 104 cases were analysed; 52 cases of trisomy 21 and 52 controls. Fetal vascular malperfusion (48.1% vs. 5.8%, p = 0.001) and maturation defects (39.2% vs. 15.7%, p = 0.023) were more common in trisomy 21 placentas. Compared with controls, trisomy 21 fetuses were more likely to have shorter umbilical cords (p = 0.001) and had more UAD abnormalities. Amongst T21 pregnancies, umbilical artery Doppler abnormalities are associated with the presence of maternal vascular malperfusion. DISCUSSION: Fetal vascular malperfusion and maturation defects are more common in trisomy 21 placentas. Abnormal umbilical artery Doppler waveforms are more common in T21 and are associated with maternal vascular malperfusion. Placental disease may explain the increased rate of intrauterine death in T21.

Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement.

CONTEXT: -The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories. OBJECTIVE: -To establish an agreed-upon protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community. DATA SOURCES: -Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible. CONCLUSIONS: -The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous maturation, patterns of ascending intrauterine infection, and villitis of unknown etiology were agreed upon. Topics requiring further discussion were highlighted. Ongoing developments in our understanding of the pathology of the placenta, scientific bases of the maternofetoplacental triad, and evolution of the clinical significance of defined lesions may necessitate further refinements of these consensus guidelines. The proposed structure will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes.

Umbilical cord shortening: quantification postdelivery and postfixation.

The length of the umbilical cord is an important data item, and little is known about the effects of time and fixation on measurement. Such a change has implications for the diagnosis of a long and short cord. This study was conducted to examine the effects of time and formalin fixation on cord length in a routine practice setting. We measured 90 cords from singleton term pregnancies within 5 minutes of delivery, again in the fresh state at 1 to 2 hours, and again after 24 to 48 hours of formalin fixation. The mean cord length was 536.7 mm at delivery. Mean cord shortening was 17.6 mm (3% reduction in length) between delivery and measurement at 1 to 2 hours, and 62.2 mm (12% reduction) between delivery and measurement after 24 to 48 hours fixation. Both values were statistically significant (P < 0.001). Studies on cord length should include data on time of measurement and fixation status.

A survey of obstetricians' views on placental pathology reporting.

OBJECTIVE: To determine the opinion of clinical obstetricians regarding interpretation of placental reports, including a recently proposed Norwegian classification system. METHODS: Paper and online surveys were circulated to practicing obstetricians in Ireland. Data on clinician experience, clinical workload, and exposure to placental pathology reporting were collated. Additionally, clinicians' opinions regarding the Norwegian classification system were sought. Statistical analysis was performed using Statsdirect version 2.7.8. RESULTS: Sixty-two practicing clinical obstetricians completed the survey. Overall, 47 (75.8%) respondents had at least 5 years of experience in clinical obstetrics. The population surveyed had a high level of clinicopathologic exposure, with 55 (88.7%) regularly attending a perinatal morbidity conference and 57 (91.9%) reading placental pathology reports. A significantly higher proportion of experienced clinicians read placental pathology reports (46/47 [97.9%]) compared with clinicians with less experience (11/15 [73.3%]; P=0.01). Overall, 51 (82.3%) obstetricians believed that introduction of the Norwegian classification would improve interpretation of placental findings; this high acceptance rate was similar for both experienced and less experienced clinicians (P>0.99). CONCLUSION: The Norwegian classification system is a clinician-friendly system for placental pathology reporting.

Delayed villous maturation of the placenta: quantitative assessment in different cohorts.

Placental villous maturation is maximal in the 3rd trimester, with an abundance of terminal villi. Delayed villous maturation (DVM) of the placenta is associated with chromosomal abnormalities, gestational diabetes, and an adverse outcome. This study compares quantitative assessment of vasculo-syncytial membranes (VSM) in cases of liveborn infants, perinatal deaths, and controls. Cases were selected as follows: (1) liveborn infants with a qualitative diagnosis of DVM (n  =  15); (2) controls matched for gestational age whose placentas did not have DVM (n  =  15); (3) stillbirths (SB)/neonatal deaths (NND) showing DVM (n  =  13); and (4) SB from autopsies in which DVM was felt to be the cause of death (COD) (n  =  12). Vasculo-syncytial membranes were counted in 10 terminal villi in each of 10 consecutive high-power fields on 3 slides. Data analysis was carried out using SPSS. Liveborn cases with DVM showed statistically significantly less VSM than controls (mean 1.01 vs 2.42, P < 0.0001). The SB/NND group also showed significantly less VSM than the control group (mean 0.46 vs 2.42, P < 0.0001) and less than the liveborn DVM group (mean 0.46 vs 1.01, P  =  0.001). The COD group was significantly different from the control group (mean 0.42 vs 2.42, P < 0.0001) and the liveborn DVM group (mean 0.42 vs 1.01, P < 0.0001) but not significantly different from the SB/NND group. There is a quantitative reduction in VSM in cases of DVM compared to controls.

Isolated acute non-cystic white matter injury in term infants presenting with neonatal encephalopathy.

We discuss possible aetiological factors, MRI evolution of injury and neuro-developmental outcomes of neonatal encephalopathy (NE). Thirty-six consecutive infants diagnosed with NE were included. In this cohort, four infants (11%) were identified with injury predominantly in the deep white matter on MRI who were significantly of younger gestation, lower birthweight with higher Apgars at one and five minutes compared to controls. Placental high grade villitis of unknown aetiology (VUA) was identified in all four of these infants. Our hypothesis states VUA may induce white matter injury by causing a local inflammatory response and/or oxidative stress during the perinatal period. We underline the importance of continued close and systematic evaluation of all cases of NE, including examination of the placenta, in order to come to a better understanding of the clinical presentation, the patterns of brain injury and the underlying pathophysiological processes.