Exome sequencing in every pregnancy? Results of trio exome sequencing in structurally normal fetuses.

OBJECTIVE: This study aimed to assess the detection rate of clinically significant results of prenatal exome sequencing (pES) in low-risk pregnancies and apparently normal fetuses in non-consanguineous couples. METHODS: A retrospective analysis of pES conducted at a single center from January 2020 to September 2023 was performed. Genetic counseling was provided, and detailed medical histories were obtained. High-risk pregnancies were excluded due to major ultrasound anomalies, sonographic soft markers, abnormal maternal biochemical screening, or family history suggestive of monogenic diseases as well as cases with pathogenic and likely pathogenic (P/LP) chromosomal microarray results. Exome analysis focused on ∼2100 genes associated with Mendelian genetic disorders. Variant analysis and classification followed the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Among 1825 pES conducted, 1020 low-risk cases revealed 28 fetuses (2.7%) with potentially clinically significant variants indicating known monogenic diseases, primarily de novo dominant variants (64%). Among these 28 cases, 9 fetuses (0.9%) had the potential for severe phenotypes, including shortened lifespan and intellectual disability, and another 12 had the potential for milder phenotypes. Seven cases were reported with variants of uncertain significance (VUS) that, according to the ACMG criteria, leaned toward LP, constituting 0.7% of the entire cohort. Termination of pregnancy was elected in 13 out of 1020 cases (1.2%) in the cohort, including 7/9 in the severe phenotypes group, 2/12 in the milder phenotype group, and 4/7 in the VUS group. CONCLUSION: The 2.7% detection rate highlights the significant contribution of pES in low-risk pregnancies. However, it necessitates rigorous analysis, and comprehensive genetic counseling before and after testing.

Exploring inheritance, and clinical penetrance of distal Xq28 duplication syndrome: insights from 47 new unpublished cases.

BACKGROUND: Distal Xq28 duplication, or int22h1/int22h2-mediated Xq28 duplication syndrome, leads to cognitive impairment, neurobehavioral issues, and facial dysmorphisms. Existing literature has limited information on clinical traits and penetrance. METHODS: We identified cases of distal Xq28 duplication (chrX: 154,126,575-154,709,680, GRCh37/hg19) through a review of clinical records and microarray reports from five centers, encompassing both postnatal and prenatal cases, with no prior family knowledge of the duplication. RESULTS: Our search found 47 cases across 26 families, with duplications ranging from 208 to 935 Kb. In total, 8 out of 26 index cases featured a 200-300 kb partial duplication, mainly from Armenian/Caucasian Jewish backgrounds. Most prenatal cases showed no major fetal ultrasound malformations. Of cases with known inheritance mode (15 out of 26), maternal inheritance was more common (80%). The study identified seven male carriers of the duplication from six unrelated families, indicating partial penetrance in males. CONCLUSION: Our study provides key insights into distal Xq28 duplication. Most prenatal tests showed no major fetal ultrasound issues. Maternal inheritance was common, with unaffected mothers. In the postnatal group, a balanced gender distribution was observed. Among male family members, two fathers had ADHD, one was healthy, and one brother had mild symptoms, indicating partial penetrance in males.

The Diagnostic Yield of Chromosomal Microarray Analysis in Third-Trimester Fetal Abnormalities.

OBJECTIVE: This study aimed to determine the diagnostic yield of chromosomal microarray analysis (CMA) performed in cases of fetal abnormalities detected during the third trimester of pregnancy. STUDY DESIGN: A retrospective review of medical records was conducted for women who underwent amniocentesis at or beyond 28 weeks of gestation between January 2017 and February 2023. CMA results of pregnancies with abnormal sonographic findings not detected before 28 weeks were included. RESULTS: A total of 482 fetuses met the inclusion criteria. The average maternal age was 31.3 years, and the average gestational age at amniocentesis was 32.3 weeks. The overall diagnostic yield of CMA was 6.2% (30 clinically significant copy number variations [CNVs]). The yield was 16.4% in cases with two or more fetal malformations, while cases with a single anomaly revealed a diagnostic yield of 7.3%. Cases presenting isolated polyhydramnios or isolated fetal growth restriction had a lower yield of 9.3 and 5.4%, respectively. Of the 30 clinically significant cases, 19 (or 63.4%) exhibited recurrent CNVs. The remaining 11 cases (or 36.6%) presented unique CNVs. The theoretical yield of Noninvasive Prenatal Testing (NIPT) in our cohort is 2% for aneuploidy, which implies that it could potentially miss up to 70% of the significant findings that could be identified by CMA. In 80% of the fetuses (or 24 out of 30) with clinically significant CNVs, the structural abnormalities detected on fetal ultrasound examinations corresponded with the CMA results. CONCLUSION: The 6.2% detection rate of significant CNVs in late-onset fetal anomalies confirms the value of CMA in third-trimester amniocentesis. The findings underscore the necessity of CMA for detecting CNVs potentially overlooked by NIPT and emphasize the importance of thorough genetic counseling. KEY POINTS: · CMA yields 6.2% for third-trimester anomalies.. · NIPT may miss 70% of CMA findings.. · Ultrasound matched 80% of CMA results..

Does the combination of four OGTT values enhance the prediction of adverse pregnancy outcomes? Insights from a retrospective cohort study.

AIM: To explore the correlation between a singular value of additive OGTT scores and adverse maternal and neonatal outcomes. We postulated that a higher additive OGTT score would predict poorer maternal and neonatal outcomes. METHODS: In this retrospective cohort study, data were collected from all women with a documented complete OGTT result and subsequent diagnosis of GDM. The additive OGTT score was calculated by adding each individual hourly glucose measurement. Maternal demographics, pregnancy and labor characteristics, and neonatal outcomes were compared between the lower-sum and higher-sum OGTT groups. A multivariate regression analysis was performed to identify confounders associated with adverse outcomes. RESULTS: In this study, a total of 1497 patients were assessed. The group with higher-sum OGTT scores was characterized by increased rates of GDMA2 (p = 0.008), higher insulin doses (p = 0.009), and higher rates of composite maternal and neonatal adverse outcomes (p = 0.021 and p = 0.030, respectively) compared to the lower-sum OGTT group. CONCLUSION: The additive OGTT score may aid in predicting the need for insulin treatment, labor course, and neonatal outcomes in GDM patients.

Chromosomal microarray testing yield in 829 cases of microcephaly: a clinical characteristics-based analysis for prenatal and postnatal cases.

INTRODUCTION: Microcephaly, characterized by abnormal head growth, can often serve as an initial indicator of congenital, genetic, or acquired disorders. In this study, we sought to evaluate the effectiveness of chromosomal microarray (CMA) testing in detecting abnormalities in both prenatal and postnatal cases of microcephaly. MATERIALS AND METHODS: CMA Testing: We conducted CMA testing on 87 prenatally-detected microcephaly cases and 742 postnatal cases at a single laboratory. We evaluated the CMA yield in relation to specific clinical characteristics. RESULTS: In prenatal cases, pathogenic and likely pathogenic (LP) results were identified in 4.6% of cases, a significantly higher rate compared to low-risk pregnancies. The male-to-female ratio in this cohort was 3, and the CMA yield was not influenced by gender or other clinical parameters. For postnatal cases, the CMA yield was 15.0%, with a significantly higher detection rate associated with dysmorphism, hypotonia, epilepsy, congenital heart malformations (CHM), learning disabilities (LD), and a history of Fetal growth restriction (FGR). No specific recurrent copy number variations (CNVs) were observed, and the rate of variants of unknown significance was 3.9%. CONCLUSIONS: The yield of CMA testing in prenatal microcephaly is lower than in postnatal cases (4.6% vs. 15%). The presence of microcephaly, combined with dysmorphism, hypotonia, epilepsy, CHD, LD, and FGR, significantly increases the likelihood of an abnormal CMA result.

Improved neonatal outcomes in pregnancies with coexisting gestational diabetes and preeclampsia in normal birthweight neonates- insights from a retrospective cohort study.

INTRODUCTION: We aimed to assess neonatal and maternal outcomes in appropriate-for-gestational-weight (AGA) neonates of mothers with both gestational diabetes mellitus (GDM) and preeclampsia (PET). METHODS: Medical records of women diagnosed with GDM or PET were reviewed. Women with AGA neonates were divided into three groups- GDM, PET, and GDM + PET and maternal neonatal and placental outcomes were compared. The primary outcome was a composite of adverse neonatal outcomes, including intensive care unit admission (NICU), neurological morbidity, hypoglycemia, ventilation, respiratory distress syndrome (RDS), phototherapy, sepsis, blood transfusion, and neonatal death. Post-hoc analysis was performed to determine between-group significance. RESULTS: Composite adverse neonatal outcomes are significantly lower in women with multiple morbidities compared to women with confined PET (p = 0.015), and a similar trend is observed when comparing neonatal outcomes between women with GDM to those with GDM + PET, yet these results are underpowered (18.9 % vs. 12.8 % respectively, p = 0.243). Placentas of women with GDM + PET were larger, with a lower rate of placentas below the 10th percentile as compared to placentas of women with isolated PET (p < 0.001), but with similar rates of MVM lesions. DISCUSSION: While maternal and placental outcomes in patients of the GDM + PET group resemble the characteristics of the PET group, surprisingly, the neonatal outcomes in this group are significantly better compared to isolated morbidities. The paradoxical benefit attributed to the coexistence of GDM + PET may be explained by a balance of the opposing trends characterizing these morbidities-the reduced blood and nutrient supply characterizing PET vs. chronic overflow and abundance typical of GDM. CLINICAL TRIAL REGISTRATION: approval of local ethics committee WOMC-19-0152.

The effect of watching an informational video prior amniocentesis on maternal anxiety: a randomized controlled trail.

PURPOSE: This randomized controlled trial aimed to ascertain the effect of a pre-procedure informational video on anxiety, pain perception, and satisfaction levels in patients undergoing amniocentesis. METHODS: Patients were randomized into two groups: a video group who watched an informational video prior to the procedure, and a control group who received standard care. Anxiety was gauged both pre- and post-procedure via the State-Trait Anxiety Inventory (STAI) score. Post-procedure, patients' perceived pain, anxiety, and satisfaction levels were evaluated using the Visual Analog Scale questionnaire (VAS). RESULTS: Of 110 randomized patients, 100 completed the study and were included in the final analysis. No significant difference was noted in overall anxiety levels between the study and control groups. However, in-procedure anxiety was significantly lower in the video group compared to the control group (p = 0.04). Among patients undergoing amniocentesis for the first time, the subgroup analysis revealed reduced levels of anxiety during the procedure and diminished pain 10 min after the procedure in the video group compared to the control group. (p = 0.041 and p = 0.025, respectively). CONCLUSION: A pre-procedural informational video could help in alleviating anxiety and mitigating pain during amniocentesis. CLINICAL TRIAL REGISTRATION: The study was registered at 27.3.2022 in clinical-trials.gov (identifier NCT05463549).

Potential Founder Variants in COL4A4 Identified in Bukharian Jews Linked to Autosomal Dominant and Autosomal Recessive Alport Syndrome.

BACKGROUND: Alport syndrome is a hereditary disorder caused by pathogenic variants in the COL4A gene, which can be inherited in an autosomal recessive, dominant, or X-linked pattern. In the Bukharian Jewish population, no founder pathogenic variant has been reported in COL4A4. METHODS: The cohort included 38 patients from 22 Bukharian Jewish families with suspected Alport syndrome who were referred the nephrogenetics clinic between 2012 and 2022. The study collected demographic, clinical, and genetic data from electronic medical records, which were used to evaluate the molecular basis of the disease using Sanger sequencing, and next-generation sequencing. RESULTS: Molecular diagnosis was confirmed in 20/38 patients, with each patient having at least one of the three disease-causing COL4A4 variants detected: c.338GA (p.Gly1008Arg), and c.871-6T>C. In addition, two patients were obligate carriers. Overall, there were 17 heterozygotes, 2 compound heterozygotes, and 3 homozygotes. Each variant was detected in more than one unrelated family. All patients had hematuria with/without proteinuria at referral, and the youngest patient with proteinuria (age 5 years) was homozygous for the c.338G>A variant. End-stage renal disease was diagnosed in two patients at the age of 38 years, a compound heterozygote for c.338G>A and c.871-6T>C. Hearing deterioration was detected in three patients, the youngest aged 40 years, all of whom were heterozygous for c.338G>A. CONCLUSION: This study unveils three novel disease-causing variants, c.3022G>A, c.871-6T>C, and c.338G>A, in the COL4A4 gene that are recurrent among Jews of Bukharian ancestry, and cause Alport syndrome in both dominant and recessive autosomal inheritance patterns.

Pregnancy and placental outcomes according to maternal BMI in women with preeclampsia: a retrospective cohort study.

PURPOSE: Obesity and preeclampsia share similar patho-mechanisms and can both affect placental pathology. We aimed to investigate pregnancy outcomes in correlation with placental pathology among pregnancies complicated by preeclampsia in three different maternal body mass index (BMI, kg/m2) groups. METHODS: In this retrospective cohort study, medical and pathological records of patients with preeclampsia and a singleton pregnancy delivered between 2008 and 2021 at a single tertiary medical center were reviewed. Study population was divided into three BMI groups: BMI < 22.6 kg/m2 (low BMI group), 22.7 ≤ BMI ≤ 28.0 kg/m2 (middle-range BMI group), and BMI > 28.0 kg/m2 (high BMI group). Data regarding maternal characteristics, neonatal outcomes, and placental histopathological lesions were compared. RESULTS: The study groups included a total of 295 patients diagnosed with preeclampsia-98, 99, and 98 in the low, middle-range, and high BMI groups respectively. Neonatal birth weight was significantly decreased in the low maternal BMI group compared to both middle and high BMI groups (p = 0.04) with a similar trend seen in placental weight (p = 0.03). Villous changes related to maternal malperfusion were more prevalent in the low and high BMI groups compared to middle-range BMI group (p < 0.01) and composite maternal vascular malperfusion lesions were also more prevalent in the groups of BMI extremities compared to the middle-range BMI group (p < 0.01). CONCLUSION: Maternal BMI might influence neonatal outcomes and placental pathology in pregnancies complicated by preeclampsia. Both extremes of BMI were associated with higher rates of placental maternal vascular malperfusion. Balanced BMI in women at risk for preeclampsia may reduce the incidence of placental lesions.

The homodimer interfaces of costimulatory receptors B7 and CD28 control their engagement and pro-inflammatory signaling.

BACKGROUND: The inflammatory response is indispensable for protective immunity, yet microbial pathogens often trigger an excessive response, 'cytokine storm', harmful to the host. Full T-cell activation requires interaction of costimulatory receptors B7-1(CD80) and B7-2(CD86) expressed on antigen-presenting cells with CD28 expressed on the T cells. We created short peptide mimetics of the homodimer interfaces of the B7 and CD28 receptors and examined their ability to attenuate B7/CD28 coligand engagement and signaling through CD28 for inflammatory cytokine induction in human immune cells, and to protect from lethal toxic shock in vivo. METHODS: Short B7 and CD28 receptor dimer interface mimetic peptides were synthesized and tested for their ability to attenuate the inflammatory cytokine response of human peripheral blood mononuclear cells, as well as for their ability to attenuate B7/CD28 intercellular receptor engagement. Mice were used to test the ability of such peptides to protect from lethal superantigen toxin challenge when administered in molar doses far below the toxin dose. RESULTS: B7 and CD28 homodimer interfaces are remote from the coligand binding sites, yet our finding is that by binding back into the receptor dimer interfaces, short dimer interface mimetic peptides inhibit intercellular B7-2/CD28 as well as the tighter B7-1/CD28 engagement, attenuating thereby pro-inflammatory signaling. B7 mimetic peptides exhibit tight selectivity for the cognate receptor in inhibiting intercellular receptor engagement with CD28, yet each diminishes signaling through CD28. In a prominent example of inflammatory cytokine storm, by attenuating formation of the B7/CD28 costimulatory axis, B7-1 and CD28 dimer interface mimetic peptides protect mice from lethal toxic shock induced by a bacterial superantigen even when administered in doses far submolar to the superantigen. CONCLUSIONS: Our results reveal that the B7 and CD28 homodimer interfaces each control B7/CD28 costimulatory receptor engagement and highlight the protective potential against cytokine storm of attenuating, yet not ablating, pro-inflammatory signaling via these receptor domains.

Proximal 1q21 duplication: A syndrome or a susceptibility locus?

Proximal 1q21 microduplication is an incomplete penetrance and variable expressivity syndrome. This study reports 28 new cases and summarizes data on phenotype, gender, and parental origin. Data on isolated proximal 1q21.1 microduplications (g. chr1:145,394,956-145,762,959 GRCh37/hg19) was retrieved in postnatal and prenatal "clinical cases" group, and prenatal "control group." The "clinical cases" cases included cases where chromosomal microarray (CMA) was performed due to congenital anomalies, autism spectrum disorder, seizures, and developmental delay/intellectual disability. The "control group" cases consisted of fetal CMA performed upon parental request despite normal nuchal translucency and anatomical second trimester fetal scans. We analyzed a local database of 27,990 cases and another cohort of 80,000 cases (including both indicated and non-indicated cases) for population frequency analysis. A total of 62 heterozygous cases were found, including 28 index cases and 34 family members. Among the index cases, 13 (9 males, 4 females) were identified in the "clinical cases" group, of which 10 had developmental abnormalities. Parental origin was tested in 9/13 cases, and all were found to be maternally inherited. In the "control group," which comprised non-affected cases, of 15 cases (10 males, 5 females), only 5/11 were maternally inherited. Four cases with clinical follow-up showed no reported neurodevelopmental abnormalities. No de-novo cases were detected, and the population frequency in both cohorts was 1:1000. Proximal 1q21.1 microduplication is a recurrent copy number variant, associated with neurodevelopmental abnormalities. It has a greater impact on males inheriting it from their mothers than females from their fathers.

Placental pathology in pregnancies with late fetal growth restriction and abnormal cerebroplacental ratio.

INTRODUCTION: Late fetal growth restriction (FGR) is associated with mild growth restriction and normal or mild abnormal doppler flows. The cerebroplacental ratio (CPR) has been demonstrated as more sensitive to hypoxia than its individual components in these fetuses. We hypothesized that abnormal CPR in late FGR is reflected in specific placental vascular malperfusion lesions. METHODS: Retrospective cohort study of late FGR newborns between 2012 and 2022 in a tertiary hospital. Overall, 361 cases were included: 104 with pathological CPR (study group), and 257 with normal doppler flows (control group). The primary outcome was a composite of maternal vascular malperfusion lesions (MVM) and fetal vascular malperfusion lesions (FVM). Secondary outcomes were macroscopic placental characteristics and various obstetrical and neonatal outcomes. RESULTS: The study group had lower birthweight compared with the normal CPR group (2063.5 ± 470.5 vs. 2351.6 ± 387.4 g. P < 0.0001), higher rates of composite adverse neonatal outcomes (34.2% vs. 22.5%, p < 0.0001), lower mean placental weight (318 ± 71.6 vs. 356.6 ± 76.5 g, p < 0.0001), as well as a higher prevalence of Vascular lesions of MVM (15.3% vs. 5.0%, p = 0.002), villous lesions of FVM (37.5% vs. 24.9%, p = 0.02), and composite FVM lesions (36.5% vs. 25.6%, p = 0.04). On multivariate regression analysis for MVM lesions and composite FVM lesions, abnormal CPR was found as an independent risk factor (aOR 2.17, 95% CI 1.63-4.19, and aOR 1.31, 95% CI 1.09-3.97, respectively). DISCUSSIONS: Abnormal CPR in late FGR is reflected in placental histopathologic vascular malperfusion lesions, and the incidence of these lesions is higher than in FGR placentas with normal CPR.

Perinatal outcomes and placental histology in small-for-gestational-age pregnancies-A comparison of population-based and universal growth charts.

OBJECTIVE: To assess obstetric, perinatal, and placental histologic findings in small-for-gestational-age (SGA) neonates according to different growth charts. METHODS: A retrospective cohort of singleton deliveries from 2008 to 2019 were divided into SGA neonates according to the local population-based chart, SGA according to universal standard growth charts (but appropriate for gestational age [AGA] according to local charts) and AGA deliveries according to both charts. RESULTS: A total of 626 local population SGA deliveries, 132 universal SGA and 468 AGA deliveries were compared. The local population SGA group had a significantly higher rate of preterm and cesarean deliveries. An adverse neonatal outcome occurred in 27.2% of the local population SGA group, 9.8% of the universal SGA group and 6.7% of the AGA group (P < 0.001). In the local population SGA group, placental weight was lower, birth weight to placental weight ratio was highest, and the rate of maternal malperfusion lesions was highest-55.4% versus 45.4% in the universal SGA group and 39.1% in the AGA group (P < 0.001). Villitis of unknown etiology was significantly more common and histologic chorioamnionitis was significantly less common in the local population SGA group. CONCLUSIONS: Our findings support the use of a local population-based growth chart for the diagnosis of fetal growth restriction.

The association of placental histopathological lesions and adverse obstetric outcomes in patients with Müllerian anomalies.

INTRODUCTION: An increased risk of an unfavorable obstetric outcome has been reported in relation with Müllerian anomalies (MA). We evaluated whether placental lesions are more frequent among patients with MA and correlates with adverse pregnancy outcomes. METHODS: The medical records and placental histopathologyy of consecutive patients with MA between 2007 and 2020 were reviewed. A control group matched for maternal age and pregnancy complications was selected in a 1:1 ratio. Characteristics were then compared between the MA and control groups. RESULTS: The study group included 110 patients with MA. Patients in the MA group gave birth at earlier gestational age as (35.8 ± 3.3 vs 39.1 ± 1.3 weeks, respectively, P < 0.001). Placental weight <10th percentile was significantly more frequent in the MA cohort compared with controls (31% vs. 6%, respectively, p < 0.001). Higher rates of vascular and villous lesions of maternal vascular malperfusion (MVM) were also detected in the MA group (P = 0.04, P = 0.01, respectively). On multivariable analysis the presence of MA was an independent predictor of composite placental MVM lesions (OR 3.9, 95% CI 2.2, 6, p = 0.04). Using multivariate logistic regression models, the presence of MA was also found to be an independent predictor of small for gestational age (SGA), (OR 4.2, 95% CI 2.7, 11.7, p = 0.01). DISCUSSION: MA are associated with placental MVM lesions and SGA independent of background confounders including gestational age - suggesting a placental involvement in the association between MA and adverse pregnancy outcomes. Prospective studies among larger cohorts are needed to corroborate our results.

Self-Efficacy and External Locus of Control as Predictors of Participant Roles in Relational Aggression.

We examined the extent to which the perceived behavioral control factors of pro-social, emotional, or verbal-social self-efficacy (SE) as well as external locus of control (LOC) explain the variance between different participant roles: relational aggressors, relational victims, relational aggressive-victims, and bystanders. Participants included 1,518 adolescents (61.6% boys and 38.4% girls) from 15 Israeli middle and high schools. Multinomial logistic regression models indicated relational aggressors, and aggressive-victims had lower pro-social SE and higher verbal-social SE than relational victims and bystanders. Relational aggressors, aggressive-victims, and victims had more extensive external LOC than bystanders. The theoretical contribution of verbal-social SE is discussed, and practical implications are highlighted, in particular, regarding the relational aggressive-victim, who exhibits high-risk behaviors.

The thrifty phenotype hypothesis: The association between ultrasound and Doppler studies in fetal growth restriction and the development of adult disease.

Barker pioneered the idea that the epidemic of coronary heart disease in Western countries in the 20th century, which paradoxically coincided with improved standards of living and nutrition, has its origin in fetal life. Indeed, there is substantial evidence associating low birthweight because of fetal growth restriction with an increased risk of vascular disease in later adult life. These conclusions led to the second part of the Barker hypothesis, the thrifty phenotype, in which adaptation to undernutrition in fetal life leads to permanent metabolic and endocrine changes. Such changes are beneficial if the undernutrition persists after birth but may predispose the individual to obesity and impaired glucose tolerance if conditions improve. The hypothesis assumes that a poor nutrient supply during a critical period of in utero life may "program" a permanent structural or functional change in the fetus, thereby altering the distribution of cell types, gene expression, or both. The fetus, in response to placental undernutrition and to maintain sufficient vascular supply to the brain, decreases resistance to blood flow in the middle cerebral artery. Simultaneously, because of the limited blood supply to the fetus, the arterial redistribution process is accompanied by increased resistance to flow to other fetal vital organs, such as the heart, kidneys, liver, and pancreas. It may explain why individuals exposed to ischemic changes in utero develop dyslipidemia, lower nephron number, and impaired glucose tolerance, all factors contributing to metabolic syndrome later in life. Nevertheless, support for the hypotheses comes mainly from studies in rodents and retrospective epidemiologic studies. This review focused on ultrasound and Doppler studies of human fetal growth restriction in several fetal organs: the placenta, fetal circulation, brain, heart, kidneys, adrenal glands, liver, and pancreas. Support for the hypothesis was provided by animal studies involving conditions that create fetuses with growth restriction with effects on various fetal organs and by human studies that correlate impaired fetal circulation with the in utero development and function of fetal organs.

Passively inhaled tobacco smoke - pregnancy and neonatal outcomes in correlation with placental histopathology.

INTRODUCTION: We aimed to investigate the effect of maternal passive smoking (MPS) during pregnancy-on placental pathology and pregnancy outcomes. METHODS: A prospective case-control study. We recruited low-risk laboring women at 37+0-41 + 0 weeks between 9/2019-7/2020. MPS was defined as exposure to in-house spouse tobacco smoking of >20 cigarettes/day in the absence of maternal active-smoking. In attempt to "purify" the effect of MPS on placental pathology-we excluded cases with preeclampsia, diabetes, suspected fetal growth restriction (FGR), preterm labor, and illicit drug use. Maternal characteristics, pregnancy outcomes, and placental pathology were compared between the MPS group and a control group matched for gestational age, maternal age, and delivery date. Placental lesions were classified according to the "Amsterdam" criteria. The study was powered to detect a 33% difference in placental malperfusion lesions. Multivariable regression was performed to identify independent associations with placental malperfusion lesions. RESULTS: In labor, the MPS group (n = 115) had higher rates of meconium stained amniotic fluid (MSAF, p < 0.001) and non-reassuring fetal heart-rate (NRFHR,p = 0.006), compared to controls (n = 115). Neonates in the MPS group had higher rates of undiagnosed FGR (p = 0.01) and NICU admissions (p = 0.004). The MPS group had higher rates of placental-hypoplasia (p = 0.02) and fetal vascular malperfusion (FVM) lesions (p = 0.04). In regression analysis MPS was associated with FVM lesions independent of background confounders (aOR = 1.24 95% CI 1.10-2.65). DISCUSSION: In otherwise low-risk pregnancies, MPS was associated with higher rates of MSAF, NRFHR, undiagnosed FGR, and NICU admissions, probably mediated via placental FVM. These worrisome findings mandate patient counseling and further investigation in larger population-based studies.

Histologic Chorioamnionitis in Pregnancies Complicated by Preeclampsia and the Effect on Neonatal Outcomes.

Histological chorioamnionitis (HC) is a common placental finding that represents acute/chronic inflammation and can affect neonatal outcomes. We aimed to examine the effect of HC on neonatal outcomes in pregnancies complicated by preeclampsia. All pregnancies with the diagnosis of preeclampsia at 24-42 weeks between 2008 and 2019 were reviewed. Placental lesions were classified according to the "Amsterdam" criteria. Composite adverse neonatal outcome included ≥1 early complication. Maternal and neonatal outcomes were compared between cases with and without HC. Multivariable regression analysis was performed to identify independent associations with adverse neonatal outcome. Compared to preeclampsia without HC (n=517), preeclampsia with HC (n=55) was characterized by a more advanced gestational age (p<0.001) and a higher rate of nulliparity (p=0.02). Diabetes was more prevalent in preeclampsia without HC (p=0.039) as was a history of previous preeclampsia (p=0.048). Neonates in the preeclampsia with HC group had higher rates of adverse neonatal outcome (p<0.001) and Apgar scores <7 at 5 min (p=0.034) despite a higher birthweight (p=0.005). Preeclampsia without HC was associated with smaller placentas and a higher rate of placental maternal vascular malperfusion lesions (p=0.014 and p<0.001 respectively). By multivariate analysis, gestational age and HC were independently associated with adverse neonatal outcome (aOR 0.88 95% CI 0.76-0.96, and aOR 1.33, 95% CI 1.11-3.09, respectively). In preeclampsia, concomitant HC was associated with adverse neonatal outcome despite a more advanced gestational age and higher neonatal birthweight. This inflammatory mechanism probably plays a role in a more severe subgroup of preeclampsia cases, causing an additional risk for the developing fetus.

The effect of concomitant histologic chorioamnionitis in pregnancies complicated by fetal growth restriction.

INTRODUCTION: We aimed to investigate the effect of placental histologic chorioamnionitis (HC) on neonatal outcomes in pregnancies complicated by fetal growth restriction (FGR). METHODS: - The computerized medical files of all pregnancies diagnosed with FGR (birthweight <10th percentile) at 24-42 weeks of gestation between 2008 and 2019 were reviewed. Maternal and neonatal outcomes were compared between FGR with and without evidence of placental HC. Placental lesions were classified according to "Amsterdam" criteria. Composite adverse neonatal outcome-included any of the following complications: neurological morbidity, neonatal respiratory assistance, RDS, NEC, sepsis, blood transfusion, phototherapy, hypoglycemia, or neonatal death. Composite severe adverse neonatal outcome included any of the following complications - neurological morbidity, blood transfusion, NEC, sepsis, RDS, neonatal death. RESULTS: - Compared to FGR without HC (n = 446), FGR with HC (n = 57) was characterized by more advanced gestational age at delivery 39.2 (38.3-39.9) vs. 38.2 (36.9-39.2), weeks respectively, p < 0.001), higher rate of nulliparity (73.7% vs. 45.1%, p < 0.001), less vascular lesions of MVM (1.8% vs.11.2%, p = 0.02), higher rate of Apgar scores at 5 min <7 (10.5% vs. 2%, p = 0.004), increased neonatal death (7.0% vs. 0.9%, p = 0.007), higher rates of both composite adverse neonatal outcome (31.1% vs. 17.3% p = 0.02), and composite severe adverse neonatal outcome (16.3% vs. 8.2% p = 0.04). By multivariate regression analysis HC was found to be independently associated with composite adverse neonatal outcome (aOR = 1.21, 95% CI 1.08-2.38) and with severe composite adverse neonatal outcome (aOR = 1.39, 95% CI 1.16-3.76). CONCLUSIONS: Pregnancies complicated by FGR with concomitant HC were associated with higher rates of adverse neonatal outcomes.

Fetal Growth Restriction in Hypertensive vs. Heavy Smoking Women-Placental Pathology, Ultrasound Findings, and Pregnancy Outcomes.

We compared placental pathology, ultrasonographic findings, and obstetric outcomes, in gestations complicated by fetal growth restriction (FGR) with either a background of hypertensive disorder or heavy tobacco cigarette smoking. The medical records and placental pathology reports of pregnancies complicated with FGR (birthweight < 10th percentile) between December 2008 and May 2018 from a single tertiary center were reviewed. Placental pathology, ultrasound findings, and pregnancy outcomes were compared between hypertensive patients (HTN) and heavy smokers (SMO). We included 213 pregnancies: 129 (60.6%) in the SMO group and 84 (39.4%) in the HTN group. The HTN group was characterized by a higher BMI (p = 0.01), higher rates of Cesarean deliveries (p = 0.006), and a lower gestational age at delivery (35.6 ± 3.8 vs. 37.5 ± 2.9 weeks, p < 0.001). The HTN group had higher rates of placental weights < 10th percentile (p = 0.04) and maternal vascular malperfusion lesions (p < 0.001), while the SMO group had higher rates of inflammatory lesions (p = 0.04). On ultrasound, the HTN group had a higher head/abdomen circumference ratio (p < 0.001) and more abnormal Doppler studies (< 0.001). Neonates in the HTN group had lower birthweights (p < 0.001) and higher rates of NICU admissions (p = 0.002) and adverse neonatal outcome (p = 0.006). On multivariable analysis, gestational age at delivery (aOR = 0.65, 95%CI 0.55-0.87), hypertensive disorders (aOR = 1.8, 95%CI = 1.21-4.81), placental MVM lesions (aOR = 1.23, 95%CI = 1.08-5.02), and the combination of HTN+MVM (aOR = 2.63, 95%CI 1.78-7.30) were independently associated with adverse neonatal outcome. Hypertension and smoking may lead to FGR in different pathways as the two groups significantly differed in maternal characteristics, placental pathology, ultrasound findings, and neonatal outcomes. A hypertensive disorder probably represents a more hostile maternal environment than smoking and these pregnancies would probably benefit from closes monitoring.