Fetal Deaths in Ireland Due to SARS-CoV-2 Placentitis Caused by SARS-CoV-2 Alpha.

CONTEXT.­: A severe third wave of COVID-19 disease affected Ireland in the first 3 months of 2021. In this wave, 1 second-trimester miscarriage and 6 stillbirths were observed in the Irish population because of placental insufficiency as a result of SARS-CoV-2 placentitis. This observation was at odds with the country's previous experience with COVID-19 disease in pregnant mothers. OBJECTIVE.­: To describe the clinical and pathologic features of these pregnancy losses. DESIGN.­: Retrospective review of clinical and pathologic data of cases of second-trimester miscarriage, stillbirth, or neonatal death identified by perinatal pathologists as being due to SARS-CoV-2 placentitis during the third wave of COVID-19 in Ireland. RESULTS.­: Clinical and pathologic data were available for review in 6 pregnancies. Sequencing or genotyping of the virus identified SARS-CoV-2 alpha (B.1.1.7) in all cases. Three of the 6 cases had maternal thrombocytopenia, and fetal growth restriction was not prominent, suggesting a rapidly progressive placental disease. CONCLUSIONS.­: The identification of SARS-CoV-2 alpha in all these cases suggests that the emergence of the variant was associated with an increased risk of fetal death due to SARS-CoV-2 placentitis when compared with the original virus. Maternal thrombocytopenia may have potential as a clinical marker of placentitis, but other inflammatory markers need investigation. Three of the 6 women had been assessed for reduced fetal movements in hospital some days before the fetal deaths actually occurred; this could suggest that there may be a window for intervention in some cases.

Biallelic CYP24A1 variants presenting during pregnancy: clinical and biochemical phenotypes.

INTRODUCTION: Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants. METHODS: The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine. RESULTS: The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL: 2.30) mmol/L), suppressed iPTH (<6 ng/L), elevated 25(OH)D (264 (URL: 55) nmol/L) and elevated 1,25(OH)D (293 (URL: <280) pmol/L). Ionized calcium was 1.55 (URL: 1.28) mmol/L. Sanger sequencing revealed two heterozygous missense variants in the CYP24A1: p.(Arg439Cys), R439C and p.(Trp275Arg), W275R. The proband's brother and sister had the same genotype. The brother had intermittent hypercalcaemia and hypervitaminosis D. Only the sister had a history of nephrolithiasis. The proband's daughter and two nephews were heterozygous for the R439C variant. The proband and her brother frequently had elevated 25(OH)D:24,25(OH)2D ratios (>50) during follow-up. CONCLUSIONS: W275R is a new pathogenic CYP24A1 mutation in compound heterozygotic form with R439C in this family.

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.

The correlation of ultrasonographic placental architecture with placental histology in the low-risk primigravid population.

AIM: To determine the association, if any, between placental architecture findings assessed ultrasonographically at 22 and 36 weeks and placental histology. METHODS: There was prospective recruitment of 1011 low-risk primigravids from the antenatal clinic at the Rotunda Hospital, Dublin, Ireland. Ultrasound of the placenta was performed at 22 and 36 weeks and histological assessment was made of the placenta of all participants. RESULTS: Complete data pertaining to ultrasound and placental histology was available for 810 women (80%). Placental calcification on ultrasound in the third trimester was associated with a higher incidence of placental infarction identified following placental histology (80.0% vs. 21.5%; P=0.009: r=0.115). The placental thickness on ultrasound in the second trimester was less in cases complicated by chorioamnionitis (2.62 cm vs. 3.07 cm; P=0.039: r=-0.176). Chronic villitis was associated with a statistically significant increased incidence of antenatal placental infarction identified on ultrasound in the third trimester (10.7% vs. 1.9%; P=0.020: r=0.113). Intervillous thrombi occurred more frequently in cases with reduced placental thickness on ultrasound in the second trimester (3.0 cm vs. 3.3 cm; P=0.035: r=-0.171). CONCLUSIONS: Antenatal ultrasound of the placenta may aid detection of placental disease, particularly in the identification of placental infarction.

Placental pathology, birthweight discordance, and growth restriction in twin pregnancy: results of the ESPRiT Study.

OBJECTIVE: We sought to evaluate the association between placental histological abnormalities and birthweight discordance and growth restriction in twin pregnancies. STUDY DESIGN: We performed a multicenter, prospective study of twin pregnancies. Placentas were examined for evidence of infarction, retroplacental hemorrhage, chorangioma, subchorial fibrin, or abnormal villus maturation. Association of placental lesions with chorionicity, birthweight discordance, and growth restriction were assessed. RESULTS: In all, 668 twin pairs were studied, 21.1% monochorionic and 78.9% dichorionic. Histological abnormalities were more frequent in placentas of smaller twins of birthweight discordant pairs (P = .02) and in placentas of small for gestational age infants (P = .0001) when compared to controls. The association of placental abnormalities with both birthweight discordance and small for gestational age was significant for dichorionic twins (P = .01 and .0001, respectively). No such association was seen in monochorionic twins. CONCLUSION: In a large, prospective, multicenter study, we observed a strong relationship between abnormalities of placental histology and birthweight discordance and growth restriction in dichorionic, but not monochorionic, twin pregnancies.

Altered placental development in pregnancies resulting in sudden infant death syndrome (SIDS).

BACKGROUND: Sudden infant death syndrome (SIDS) is postulated to be a developmental disorder originating during fetal life in utero. Knowledge regarding the intrauterine environment in which SIDS infants develop is, however, inadequate and how the placenta develops prior to a SIDS event has not been studied. AIM: To investigate the morphological development of the placenta obtained from full-term infants who subsequently succumbed to SIDS. STUDY DESIGN: To estimate the percentage and total volumes of the chorionic villi and villous trophoblast membrane using stereological techniques. SUBJECTS: Placentas were obtained retrospectively from normal birthweight (SIDS-NBW n=18) and small-for-gestational age (SIDS-SGA, n=14) infants who had succumbed to SIDS, and compared to either control (n=8) or SGA placentas (n=7), respectively. RESULTS: SIDS-NBW placentas displayed evidence of augmented villous growth shown by significantly greater volumes of placental chorionic villi (gas-exchanging (GE) villi) in comparison to controls; this was not observed for SIDS-SGA placentas. However, both SIDS-NBW and SIDS-SGA placentas displayed significantly greater volumes of the cytotrophoblast (CT) (SIDS-NBW only), syncytiotrophoblast (SIDS-SGA only) and syncytial knots (SCT-K) and those displaying apoptotic syncytial nuclei (AP SCT-K). In contrast, SGA placentas displayed significantly reduced volumes of chorionic villi, GE villi and the villous trophoblast indicating a SIDS-specific effect associated with augmented placental growth. CONCLUSIONS: Our findings provide initial evidence that placental abnormality, although not necessarily causative, may precede a subset of SIDS cases supporting the hypothesis that the origins of SIDS begin during fetal life in utero.

The value of neonatal autopsy.

BACKGROUND AND OBJECTIVE: Neonatal autopsy rates were in decline internationally at the end of the last century. Our objective was to assess the current value of neonatal autopsy in providing additional information to families and healthcare professionals. METHODS: We conducted a review of neonatal autopsies performed in a tertiary perinatal centre over an 11-year period. Primary outcomes measured were the annual neonatal autopsy rates and concordance rates between clinical and autopsy diagnoses of the primary cause of death. Secondary outcomes were the clinical, genetic and audit value of the examinations. Findings were used to inform the consent process, and the effect this had on institutional post-mortem rates was assessed over the subsequent 5-year period. RESULTS: There was a marked decline in the annual neonatal autopsy rate from 73% in 1994 to 48% in 2004. 164 cases met the inclusion criteria for review. Complete concordance for cause of death was reached in 91% of cases. Previously unsuspected or unconfirmed clinical conditions, other than the primary cause of death, were uncovered at autopsy in 85 cases. Detailed information on inheritable conditions was obtained in 45 cases. Findings with perceived 'audit value' for clinical practice were identified in 29 cases. The dissemination of this information to staff and families contributed to the stabilisation of the consent rate in the following 5-year period. CONCLUSION: Neonatal autopsy remains a valuable diagnostic tool as it provides critical clinical and audit information for healthcare professionals and families.

Placental cord insertion and birthweight discordance in twin pregnancies: results of the national prospective ESPRiT Study.

OBJECTIVE: The purpose of this study was to evaluate the impact of noncentral placental cord insertion on birthweight discordance in twins. STUDY DESIGN: We performed a multicenter, prospective trial of twin pregnancies. Placental cord insertion was documented as central, marginal, or velamentous according to a defined protocol. Association of the placental cord insertion site with chorionicity, birthweight discordance, and growth restriction were assessed. RESULTS: Eight hundred sixteen twin pairs were evaluated; 165 pairs were monochorionic, and 651 pairs were dichorionic. Monochorionic twins had higher rates of marginal (P = .0068) and velamentous (P < .0001) placental cord insertion. Noncentral placental cord insertion was more frequent in smaller twins of discordant pairs than control pairs (29.8% vs 19.1%; P = .004). Velamentous placental cord insertion in monochorionic twins was associated significantly with birthweight discordance (odds ratio, 3.5; 95% confidence interval, 1.3-9.4) and growth restriction (odds ratio, 4; 95% confidence interval, 1.1-14.3). CONCLUSION: Noncentral placental cord insertion contributes to birthweight discordance in monochorionic twin pregnancies. Sonographic delineation of placental cord insertion may be of value in antenatal assessment of twin pregnancies.

The impact of positive acquired thrombophilia serology on ultrasound, obstetric outcome and the placenta in a low-risk primigravid population.

Our aim was to determine the prevalence and sequelae of positive acquired thrombophilia serology in the asymptomatic low-risk primigravid population. We undertook a prospective blinded study of 1011 primigravid patients screening for lupus anticoagulant, anticardiolipin antibody, anti-ß 2 glycoprotein-1 and antinuclear antibody assessment at booking and 36 weeks gestation. Serial ultrasounds of the fetus with uterine and umbilical Dopplers and placental evaluation were performed at 24 and 36 weeks gestation. Antenatal course, labour and delivery outcome and placental histology were reviewed. The incidence of positive acquired thrombophilia serology was 27.4%. Overall, there was no difference in rates of fetal loss or maternal disease between women with positive acquired thrombophilia serology and the control population. Routine testing for acquired thrombophilic traits is therefore not warranted.

The impact of umbilical and uterine artery Doppler indices on antenatal course, labor and delivery in a low-risk primigravid population.

AIMS: To evaluate the impact of umbilical and uterine artery Doppler in the second and third trimester on antenatal course, labor and delivery in a low-risk primigravid population. METHODS: Prospective recruitment of 1011 low-risk primigravidas with uterine and umbilical artery Doppler assessment at 22-24 weeks and 36 weeks. All mothers and infants were reviewed postnatally with a retrospective analysis of ultrasound and clinical outcome data. RESULTS: Elevated uterine artery indices were associated with increased rates of threatened miscarriage, higher rates of pre-eclampsia (PET) and a higher incidence of fetal birth weight <2nd and 9th centile for gestation. Uterine artery pulsatility index (PI) >95th centile for gestation was associated with statistically higher rates of small-for-gestational age (SGA) infants. Elevated umbilical artery indices were associated with higher rates of induction of labor and a higher incidence of fetal birth weight infants <2nd and 9th centile for gestation. Umbilical artery PI >95th centile for gestation was associated with statistically higher rates of SGA infants. CONCLUSION: Elevated uterine and umbilical artery indices are associated with higher rates of maternal and fetal disease.

The impact of ultrasonographic placental architecture on antenatal course, labor and delivery in a low-risk primigravid population.

OBJECTIVE: To ascertain the impact of placental architecture on antenatal course and labor delivery in a low-risk primigravid population. METHODS: This study involves prospective recruitment of 1011 low-risk primigravids with placental ultrasound at 22?24 weeks and 36 weeks. Detailed postnatal review of all mothers and infants was undertaken. Retrospective analysis of ultrasound and clinical outcome data was performed. RESULTS: Eight hundred ten women with complete outcome data were available. Anterior placentation was statistically associated with intrauterine growth restriction (IUGR) and preterm birth and fundal placentation was significantly associated with a higher incidence of pregnancy-induced hypertension and infants with a birthweight less than the 9th centile. Placental infarcts in the third trimester was significantly increased in cases complicated by pre-eclampsia (PET) and in cases with fetal acidosis. Placental calcification was associated a 40-fold increase in the incidence of IUGR. Placental lakes in the second trimester were more prevalent in patients with threatened miscarriage. Increased placental thickness was associated with a higher rate of fetal acidosis. The Grannum grade of the placenta was higher with threatened first or second trimester loss, PET and in infants born less than 9th centile for gestation. CONCLUSION: Placental site and architecture impact on the incidence of maternal and fetal disease.

Parvovirus infects cardiac myocytes in hydrops fetalis.

Parvovirus infection during pregnancy is an important cause of hydrops fetalis. It is attributed to anemia caused by viral-induced destruction of red blood cells. Infection of other organs has been reported including the heart, liver, and lungs. Few of these reports, however, convincingly demonstrate virions within the functional parenchyma of the tissue. This is of particular concern regarding myocardium in the context of hydrops fetalis which is, in part, due to cardiac failure. The problem in routine pathology practice is that most fetuses with the infection are macerated. This, in part, probably explains the paucity of published information on cardiac involvement. This study examined five cases of fatal hydrops fetalis with variable maceration with serologically proven parvovirus B19 infection. Transmission electron microscopy of cardiac tissue demonstrated intranuclear virions in both erythroid precursor cells and in cardiac myocytes in three of these cases. In each of these, immuno-gold electron microscopy provided confirmatory evidence of parvovirus infection. Virions were not identifiable where maceration had caused disintegration of nuclei in the myocytes. In addition, virions were absent in the three negative control cases where retroplacental hemorrhage was confirmed as the cause of death. This study suggests that parvovirus infection of cardiac myocytes may play a more important role in causing hydrops fetalis than previously realized. It also demonstrates that maceration should not discourage the use of electron microscopy.