Gross and Histologic Placental Abnormalities Associated With Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To elucidate particular placental pathology findings that are associated with hypoxic ischemic encephalopathy (HIE) and determine which patterns are associated with adverse fetal/neonatal outcomes. STUDY DESIGN: Multi-institutional retrospective case-control study of newborns with HIE (2002-2022) and controls. Four perinatal pathologists performed gross and histologic evaluation of placentas of cases and controls. RESULTS: A total of 265 placentas of neonates with HIE and 122 controls were examined. Infants with HIE were more likely to have anatomic umbilical cord abnormalities (19.7% vs 7.4%, P = .003), fetal inflammatory response in the setting of amniotic fluid infection (27.7% vs 13.9%, P = .004), and fetal vascular malperfusion (30.6% vs 9.0%, P = <.001) versus controls. Fetal vascular malperfusion with maternal vascular malperfusion was more common in those who died of disease (P = .01). CONCLUSION: Placental pathology examination of neonates with HIE may improve our understanding of this disorder and its adverse outcomes.

Criteria for placental examination for obstetrical and neonatal providers.

Pathologic examination of the placenta can provide insight into likely (and unlikely) causes of antepartum and intrapartum events, diagnoses with urgent clinical relevance, prognostic information for mother and infant, support for practice evaluation and improvement, and insight into advancing the sciences of obstetrics and neonatology. Although it is true that not all placentas require pathologic examination (although alternative opinions have been expressed), prioritization of placentas for pathologic examination should be based on vetted indications such as maternal comorbidities or pregnancy complications in which placental pathology is thought to be useful for maternal or infant care, understanding pathophysiology, or practice modifications. Herein we provide placental triage criteria for the obstetrical and neonatal provider based on publications and expert opinion of 16 placental pathologists and a pathologists' assistant, formulated using a modified Delphi approach. These criteria include indications in which placental pathology has clinical relevance, such as pregnancy loss, maternal infection, suspected abruption, fetal growth restriction, preterm birth, nonreassuring fetal heart testing requiring urgent delivery, preeclampsia with severe features, or neonates with early evidence of multiorgan system failure including neurologic compromise. We encourage a focused gross examination by the provider or an attendant at delivery for all placentas and provide guidance for this examination. We recommend that any placenta that is abnormal on gross examination undergo a complete pathology examination. In addition, we suggest practice criteria for placental pathology services, including a list of critical values to be used by the relevant provider. We hope that these sets of triage indications, criteria, and practice suggestions will facilitate appropriate submission of placentas for pathologic examination and improve its relevance to clinical care.

Recurrent Second Trimester Fetal Demise Caused by Hypercoiled Umbilical Cords.

BACKGROUND: Umbilical cord flow impairment accounts for a majority of fetal vascular malperfusion (FVM). Hypercoiled umbilical cords are one cause of impaired fetal blood flow that may, in severe cases, result in intrauterine fetal demise (IUFD). Although the factors involved in umbilical cord patterning are incompletely understood, a limited number of reports have described recurrent intra-familial hypercoiling leading to death in the second trimester, suggesting a subset may have a genetic etiology. CASE REPORTS: Herein, we report two additional cases of recurrent second trimester IUFD secondary to FVM due to umbilical cord hypercoiling and briefly discuss all published cases. CONCLUSION: Our cases add to a small, but growing, body of literature that suggests a genetic etiology to a subset of hypercoiled umbilical cords.

Fetal Vascular Malperfusion Due To Long and Hypercoiled Umbilical Cords Resulting in Recurrent Second Trimester Pregnancy Loss: A Case Series and Literature Review.

BACKGROUND: Intrauterine fetal demise due to fetal vascular malperfusion in mid-gestation is a rare occurrence. Abnormally long and hypercoiled umbilical cords are associated with an increased risk of umbilical cord blood flow restriction, which in turn can result in adverse perinatal and maternal outcomes. The factors that regulate umbilical cord development, specifically umbilical cord length and coiling, are poorly understood. METHODS: Maternal history, along with fetal and placental findings (post-mortem, pathological, and molecular), were reviewed for a series of 3 consecutive pregnancies that ended in second trimester intrauterine fetal demise. RESULTS: All 3 umbilical cords were exceptionally long and hypercoiled, and all placentas showed evidence of high-grade fetal vascular malperfusion. At fetopsy, all 3 fetuses were developmentally normal for gestational age and lacked congenital anomalies. Maternal medical history and antenatal testing (including an extensive work-up for maternal hypercoagulability syndromes) were normal and/or noncontributory. CONCLUSION: Although excessively long and hypercoiled cords are generally thought of as sporadic, nongenetic events, rare examples of recurrent intrauterine fetal demise secondary to such exist have been reported. This intrafamilial clustering of a rare event is suggestive that at least a subset of hypercoiled, long umbilical cords may have an underlying genetic etiology.

Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms.

AIMS: The classification of paediatric spindle mesenchymal tumours is evolving, and the spectrum of so-called 'infantile fibrosarcoma' has expanded to include tumours with NTRK, BRAF and MET gene fusions. RET-rearranged paediatric spindle cell neoplasms are an emerging group; there is sparse literature on their clinical, pathological and genetic features, and their nosological place in the canon of soft tissue tumours is uncertain. In this study, we report five RET-rearranged paediatric spindle cell tumours with fusion partners MYH10, KIAA1217 and CLIP2. METHODS AND RESULTS: The tumours occurred in the pelvic region, paraspinal region, kidney and subcutaneous tissue of hand and abdomen. The patients' ages ranged from 6 months to 13 years (median 1 year). The tumours were composed of monomorphic spindle cells arranged in a fascicular pattern. Lesional cells had minimally atypical ovoid or tapered nuclei and pale cytoplasm with indistinct borders. Necrosis was not identified. Mitoses numbered three to 12 per 10 high-power field. Cases showed inconsistent and variable expression of S100, CD34 and SMA. Clinical behaviour ranged from small lesions potentially cured by simple resection to large lesions exhibiting metastasis, but responsive to kinase inhibitor therapy. CONCLUSIONS: Our findings help to define RET-rearranged spindle cell tumours. Although it is likely that these tumours comprise part of the morphological and clinical spectrum of infantile fibrosarcoma (IFS), identification of RET gene alteration is important for its unique therapeutic implications.

Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma.

Congenital hemangioma is a rare vascular tumor that forms in utero. Postnatally, the tumor either involutes quickly (i.e., rapidly involuting congenital hemangioma [RICH]) or partially regresses and stabilizes (i.e., non-involuting congenital hemangioma [NICH]). We hypothesized that congenital hemangiomas arise due to somatic mutation and performed massively parallel mRNA sequencing on affected tissue from eight participants. We identified mutually exclusive, mosaic missense mutations that alter glutamine at amino acid 209 (Glu209) in GNAQ or GNA11 in all tested samples, at variant allele frequencies (VAF) ranging from 3% to 33%. We verified the presence of the mutations in genomic DNA using a combination of molecular inversion probe sequencing (MIP-seq) and digital droplet PCR (ddPCR). The Glu209 GNAQ and GNA11 missense variants we identified are common in uveal melanoma and have been shown to constitutively activate MAPK and/or YAP signaling. When we screened additional archival formalin-fixed paraffin-embedded (FFPE) congenital cutaneous and hepatic hemangiomas, 4/8 had GNAQ or GNA11 Glu209 variants. The same GNAQ or GNA11 mutation is found in both NICH and RICH, so other factors must account for these tumors' different postnatal behaviors.

Ectopic Fetal Hepatic Tissue in the Placenta.

When an unusual intraplacental lesion is identified during pathologic examination, it becomes of substantial import to determine whether it represents a normal structure, metastasis from the mother, or a primary benign tumor, including those secondary to abnormal embryologic development versus a primary malignant placental tumor. In this case report, we identified an incidental nest of intraplacental cells with nondiagnostic morphology and negative initial Glypican-3 stain in a healthy 35-wk gestation. This negative result prompted a broadening of the differential before ultimately determining this lesion was indeed ectopic liver with positive Arginase-1 and HepPar-1 staining. This may represent the mature hepatocyte phenotype within the lesional cells of this near-term birth, a dichotomy not previously discussed in the literature, which focuses on the fetal hepatocyte phenotype, also rarely seen. In this report, we summarize the previous literature regarding intraplacental ectopic liver, and we propose a sensitive approach to suspected ectopic liver of the placenta that may be sufficient to capture both the fetal and mature hepatocyte immunophenotypes. This approach may extend to other related pathologies including assessment of suspected intraumbilical hepatocytes.

Placental Pathology in Neonatal Stroke: A Retrospective Case-Control Study.

OBJECTIVE: To assess the association of placental abnormalities with neonatal stroke. STUDY DESIGN: This retrospective case-control study at 3 academic medical centers examined placental specimens for 46 children with neonatal arterial or venous ischemic stroke and 99 control children without stroke, using a standard protocol. Between-group comparisons used χ2 and Fisher exact t test. Correlations used Spearman correlation coefficient. RESULTS: Case placentas were more likely than controls to meet criteria for ≥1 of 5 major categories of pathologic abnormality (89% vs 62%; OR, 5.1; 95% CI, 1.9-14.0; P = .0007) and for ≥2 categories (38% vs 8%; OR, 7.3; 95% CI, 2.9-19.0; P < .0001). Fetal vascular malperfusion occurred in 50% of cases and 17% of controls (OR, 4.8; 95% CI, 2.2-10.5; P = .0001). Amniotic fluid inflammation occurred in 46% of cases with arterial ischemic stroke vs 25% of controls (OR, 2.6; 95% CI, 1.1-6.1; P = .037). There was evidence of a "stress response" (meconium plus elevated nucleated red blood cells) in 24% of cases compared with 1% of controls (OR, 31; 95% CI, 3.8-247.0; P < .0001). CONCLUSIONS: Placental abnormality was more common in children with neonatal stroke compared with controls. All placental findings represent subacute-to-chronic intrauterine stressors. Placental thrombotic processes were associated with both arterial and venous stroke. Our findings provide evidence for specific mechanisms that may predispose to acute perinatal stroke. Amniotic fluid inflammation associated with neonatal arterial ischemic stroke deserves further investigation.

Early-onset neonatal sepsis in Dhaka, Bangladesh: risk associated with maternal bacterial colonisation and chorioamnionitis.

OBJECTIVE: To estimate the risk of early-onset neonatal sepsis among newborns of mothers with chorioamnionitis and/or bacterial colonisation in Dhaka. METHODS: We conducted a cohort study at a maternity centre following 600 mother-newborn pairs. Women with a positive bacterial vaginal culture or positive Group B streptococcus (GBS) rectal culture during labour were classified as colonised. Women with placental histopathology demonstrating signs of maternal or foetal inflammation were classified as having chorioamnionitis. Newborns were followed over the first 7 days of life. The primary outcome measure was physician or community health worker diagnosis of neonatal sepsis following modified World Health Organization Integrated Management of Childhood Illnesses criteria. Survival analysis was conducted with non-parametric, parametric and semiparametric models. RESULTS: Of the 600 mother-newborn pairs, 12.8% of newborns were diagnosed with early-onset sepsis. Five hundred and forty-three women had both colonisation and chorioamnionitis data, 55.4% of mothers were non-exposed, 31.7% were only colonised and 12.9% had chorioamnionitis regardless of colonisation status. After adjusting for birthweight, sex, maternal characteristics and wealth, newborns of only colonised mothers developed sepsis 63% faster and had a 71% higher risk of developing sepsis than their non-exposed counterparts (RT = 0.37, 95% CI 0.14-1.03; RH = 1.71, 95% CI 1.00-2.94). Newborns of mothers with chorioamnionitis developed sepsis 74% faster and had a 111% higher risk of developing sepsis (RT = 0.26, 95% CI 0.07-0.94; RH = 2.11, 95% CI 1.06-4.21). CONCLUSIONS: Newborns born to mothers with colonisation or chorioamnionitis developed sepsis faster and were at higher risk of developing sepsis in Dhaka.

Association of Placental Histology with the Pulsatility Index of Fetal and Uteroplacental Vessels during Pregnancy and with Birthweight Z-Score.

Aims: To compare macro- and microscopic features of the placenta with the pulsatility index (PI) of the uterine (UtA), umbilical (UA) and middle cerebral arteries at 20-24- and 34-38-weeks' gestation, and with birthweight z-scores (BWZS). Methods: Recruitment for the Safe Passage Study, which investigated the association of alcohol and tobacco use with stillbirth and sudden infant death syndrome, occurred from August 2007 to January 2015 at community clinics in Cape Town, South Africa. The population represents a predominantly homogenous population of pregnant women from a low socioeconomic residential area. This study is a further analysis of the data of the Safe Passage Study. It consists of 1205 singleton pregnancies for which placental histology was available, of whom 1035 had a known BWZS and 1022 and 979 had fetoplacental Doppler examinations performed at Tygerberg Academic Hospital at 20-24 and 34-38 weeks respectively. Features of the placenta were assessed according to international norms. Results: Significantly higher ORs for the presence of individual and combined features of maternal vascular malperfusion (MVM) were found with lower BWZS and higher UtA PI values, more consistently than with higher UA PI values. Strongest associations were for a small placenta for gestational age (UtA OR 4.86 at 20-24 and 5.92 at 34-38 weeks; UA OR 5.33 at 20-24 and 27.01 at 34-38 weeks; low BWZS OR 0.31), for accelerated maturation (UtA OR 11.68 at 20-24 weeks and 18.46 at 34-38 weeks; low BWZS 0.61), for macroscopic infarction (UtA OR 6.08 at 20-24 weeks; UA OR 17.02 at 34-38 weeks; low BWZS OR 0.62) and for microscopic infarction (UtA OR 6.84 at 20-24 and 10.9 at 34-38 weeks; low BWZS OR 0.62). Conclusion: There is considerable variability in the associations between individual features of MVM and increased UtA or UA PI and low BWZS. Although all MVM features currently carry equal weight in defining the condition of MVM, our data suggest that some should carry more weight than others. Macroscopic examination of the placenta may be helpful in identifying placental insufficiency as a small placenta for gestational age and macroscopic infarction were the features most strongly associated with outcomes.

Placental pathology in spontaneous and iatrogenic preterm birth: Different entities with unique pathologic features.

INTRODUCTION: Placental pathology is an important contributor to the understanding of preterm birth and reveals major differences between spontaneous preterm birth (SPTB) and iatrogenic preterm birth (IPTB). The aim of this study was to investigate these relationships. METHODS: Research midwives collected placentas from 1101 women with singleton pregnancies who were enrolled in the Safe Passage Study. Trained pathology technologists prepared and processed placenta specimens for macroscopic and microscopic examination by designated pathologists. Statistical analyses were done with STATISTICA version 13. RESULTS: In SPTB we found more cases of accelerated villous maturation; however, the other features of maternal vascular malperfusion (MVM) were not present. The prevalence rate of funisitis was also increased. In IPTB, multiple features of MVM - accelerated villous maturation, distal villous hypoplasia, decidual arteriopathy, increased syncytial knots, increased perivillous fibrin, and prominent extravillous trophoblast were increased, as were features of fetal vascular malperfusion (FVM) - umbilical cord vessel thrombosis, avascular villi, and fetal vascular thrombosis. Increased syncytial knots were found in 26% of preterm stillbirths and in 29% of preterm infant demises as compared to 81% of IPTB infants alive at one year. DISCUSSION: SPTB and IPTB differ. The detected "abnormal" accelerated villous maturation pattern in SPTB and preterm demises, suggests an inability of the placenta to adapt and may be a trigger for SPTB. Funisitis was the only inflammatory response significant for SPTB. MVM and FVM are implicated in IPTB, but not an inflammatory process.

Graves' disease in a five-month-old boy with an unusual treatment course.

OBJECTIVES: Graves' disease (GD) is rare in children under age five years. Antithyroid drugs are typically first-line therapy but carry the risks of agranulocytosis and liver dysfunction. CASE PRESENTATION: A male infant with multiple congenital anomalies, left ventricular hypertrophy, and neurologic dysfunction developed GD at five months of life. The presence of chronic hepatitis complicated medical management. Potassium iodide was effective temporarily, but urgent thyroidectomy was required at nine months of age. Postoperatively, the patient developed a thyroid function pattern consistent with impaired pituitary sensitivity to thyroid hormone (TH) that responded to the addition of liothyronine. Exome sequencing revealed a heterozygous de novo duplication of the ATAD3 gene cluster, suggesting a possible mitochondrial disorder. CONCLUSIONS: This case describes the youngest child to date to be diagnosed with endogenous GD and to successfully undergo definitive treatment with thyroidectomy. An underlying defect in mitochondrial function is suspected, suggesting a potential novel pathophysiologic link to early-onset thyroid autoimmunity. Additionally, this case illustrated the development of impaired pituitary sensitivity to TH following thyrotoxicosis of postnatal onset, which may contribute to our understanding of hypothalamic-pituitary-thyroid (HPT) axis development.

Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by 125I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in 125I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002-0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, 125I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on 125I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla-a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

Association of Prenatal Exposure to Maternal Drinking and Smoking With the Risk of Stillbirth.

Importance: Prenatal smoking is a known modifiable risk factor for stillbirth; however, the contribution of prenatal drinking or the combination of smoking and drinking is uncertain. Objective: To examine whether prenatal exposure to alcohol and tobacco cigarettes is associated with the risk of stillbirth. Design, Setting, and Participants: The Safe Passage Study was a longitudinal, prospective cohort study with data collection conducted between August 1, 2007, and January 31, 2015. Pregnant women from Cape Town, South Africa, and the Northern Plains region of the US were recruited and followed up throughout pregnancy. Data analysis was performed from November 1, 2018, to November 20, 2020. Exposure: Maternal consumption of alcohol and tobacco cigarettes in the prenatal period. Main Outcomes and Measures: The main outcomes were stillbirth, defined as fetal death at 20 or more weeks' gestation, and late stillbirth, defined as fetal death at 28 or more weeks' gestation. Self-reported alcohol and tobacco cigarette consumption was captured at the recruitment interview and up to 3 scheduled visits during pregnancy. Participants were followed up during pregnancy to obtain delivery outcome. Results: Of 11663 pregnancies (mean [SD] gestational age at enrollment, 18.6 [6.6] weeks) in 8506 women for whom the pregnancy outcome was known by 20 weeks' gestation or later and who did not terminate their pregnancies, there were 145 stillbirths (12.4 per 1000 pregnancies) and 82 late stillbirths (7.1 per 1000 pregnancies). A total of 59% of pregnancies were in women from South Africa, 59% were in multiracial women, 23% were in White women, 17% were in American Indian women, and 0.9% were in women of other races. A total of 8% were older than 35 years. In 51% of pregnancies, women reported no alcohol or tobacco cigarette exposure (risk of stillbirth, 4 per 1000 pregnancies). After the first trimester, 18% drank and smoked (risk of stillbirth, 15 per 1000 births), 9% drank only (risk of stillbirth, 10 per 1000 pregnancies), and 22% smoked only (risk of stillbirth, 8 per 1000 pregnancies). Compared with the reference group (pregnancies not prenatally exposed or without any exposure after the first trimester), the adjusted relative risk of late stillbirth was 2.78 (98.3% CI, 1.12-6.67) for pregnancies prenatally exposed to drinking and smoking, 2.22 (98.3% CI, 0.78-6.18) for pregnancies prenatally exposed to drinking only after the first trimester, and 1.60 (98.3% CI, 0.64-3.98) for pregnancies prenatally exposed to smoking only after the first trimester. The adjusted relative risk for all stillbirths was 1.75 (98.3% CI, 0.96-3.18) for dual exposure, 1.26 (98.3% CI, 0.58-2.74) for drinking only, and 1.27 (98.3% CI, 0.69-2.35) for smoking only compared with the reference group. Conclusions and Relevance: These results suggest that combined drinking and smoking after the first trimester of pregnancy, compared with no exposure or quitting before the end of the first trimester, may be associated with a significantly increased risk of late stillbirth.

Associations of maternal smoking and drinking with fetal growth and placental abruption.

OBJECTIVE: To investigate pregnant women from the Safe Passage Study for the individual and combined effects of smoking and drinking during pregnancy on the prevalence of clinical placental abruption. STUDY DESIGN: The aim of the original Safe Passage Study was to investigate the association of alcohol use during pregnancy with stillbirths and sudden infant deaths. Recruitment for this longitudinal study occurred between August 2007 and October 2016. Information on smoking and drinking was collected prospectively at up to 4 occasions during pregnancy where a modified timeline follow-back method was used to assess the exposure to alcohol. Placentas were examined histologically in a subset of pregnant women. For this study we examined the effects of smoking and drinking on fetal growth and the prevalence rate of placental abruption. High smoking constituted of 10 or more cigarettes per day and high drinking of four or more binge drinking episodes or 32 and more standard drinks during pregnancy. Placental abruption was diagnosed in two ways, by the clinical picture or the macroscopic and microscopic examination of the placenta. RESULTS: When compared to the non-drinking/non-smoking group, the high drinking/high smoking group were significantly older, had a higher gravidity, had a lower household income and booked later for prenatal care; fewer of them were employed and had toilet and running water facilities in their houses. Clinical placental abruption was diagnosed in 49 (0.87 %) of 5806 pregnancies. Histological examination was done in 1319 placentas; macroscopic and microscopic diagnosis of placental abruption was made in 8.2 % and 11.9 % of placentas respectively. These 49 cases were then correlated with seven smoking/drinking patterns during pregnancy. When compared to rates for no smoking/no drinking (0.11 %) and low smoking/no drinking (0.55 %), the prevalence rate of placental abruption was significantly higher (p < .005) in the low smoking/low drinking group (1.25 %). There was also a significant relationship between low maternal employment and methamphetamine use with placental abruption. CONCLUSION: As many conditions and habits are associated with placental abruption, it is impossible to single out one specific cause but concomitant drinking and smoking seem to increase the risk of placental abruption.

Concurrent prenatal drinking and smoking increases risk for SIDS: Safe Passage Study report.

BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality. Although the rate has plateaued, any unexpected death of an infant is a family tragedy thus finding causes and contributors to risk remains a major public health concern. The primary objective of this investigation was to determine patterns of drinking and smoking during pregnancy that increase risk of SIDS. METHODS: The Safe Passage Study was a prospective, multi-center, observational study with 10,088 women, 11,892 pregnancies, and 12,029 fetuses, followed to 1-year post delivery. Subjects were from two sites in Cape Town, South Africa and five United States sites, including two American Indian Reservations. Group-based trajectory modeling was utilized to categorize patterns of drinking and smoking exposure during pregnancy. FINDINGS: One-year outcome was ascertained in 94·2% infants, with 28 SIDS (2·43/1000) and 38 known causes of death (3·30/1000). The increase in relative risk for SIDS, adjusted for key demographic and clinical characteristics, was 11·79 (98·3% CI: 2·59-53·7, p < 0·001) in infants whose mothers reported both prenatal drinking and smoking beyond the first trimester, 3.95 (98·3% CI: 0·44-35·83, p = 0·14), for drinking only beyond the first trimester and 4·86 (95% CI: 0·97-24·27, p = 0·02) for smoking only beyond the first trimester as compared to those unexposed or reported quitting early in pregnancy. INTERPRETATION: Infants prenatally exposed to both alcohol and cigarettes continuing beyond the first trimester have a substantially higher risk for SIDS compared to those unexposed, exposed to alcohol or cigarettes alone, or when mother reported quitting early in pregnancy. Given that prenatal drinking and smoking are modifiable risk factors, these results address a major global public health problem. FUNDING: National Institute on Alcohol Abuse and Alcoholism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Deafness and Other Communication Disorders.

Multicenter pre-operative assessment of pediatric ovarian malignancy.

PURPOSE: The purpose of this study was to develop a pre-operative risk assessment tool for childhood and adolescent ovarian malignancy, in order to guide operative management of pediatric ovarian masses. METHODS: We conducted a retrospective analysis of patients <18 years old who underwent ovarian surgery at two quaternary care pediatric centers over 4 years (1/1/13-12/31/16). Probability of malignancy was estimated based on imaging characteristics (simple cyst, heterogeneous, or solid), maximal diameter, and tumor markers (α-fetoprotein, ß-human chorionic gonadotropin). RESULTS: Among 188 children with ovarian masses, 11% had malignancies. For simple cysts, there were no malignancies (0/24, 95% CI = 0-17%). Among solid lesions, 44% (15/34, 95% CI = 28-62%) were malignant. Among marker-elevated heterogeneous masses, 40% (2/5, 95% CI = 12-77%) were malignant. Conversely, small (≤10 cm) and large (>10 cm) marker-negative heterogeneous lesions had malignancy proportions of 0% (0/39, 95% CI = 0-11%) and 5% (2/40, 95% CI = 1-18%), respectively. CONCLUSIONS: Given the malignancy estimates identified from these multi-institutional data, we recommend an attempt at ovarian-sparing resection for simple cysts or tumor marker-negative heterogeneous lesions ≤10 cm. Oophorectomy is recommended for solid masses or heterogeneous lesions with elevated markers. Finally, large (>10 cm) heterogeneous masses with non-elevated markers warrant a careful discussion of ovarian-sparing techniques. Complete surgical staging is mandatory regardless of operative procedure. TYPE OF STUDY: Study of Diagnostic Test. LEVEL OF EVIDENCE: Level I.