Imaging and outcomes of fetal adrenal hemorrhage: A systematic review.

OBJECTIVE: To describe prenatal and postnatal imaging findings of fetal adrenal hemorrhage (FAH) and its associated perinatal outcomes, including frequency of postnatal surgical intervention. METHOD: A systematic literature review of seven electronic databases was conducted from inception until January 2022, with 2008 articles identified reporting prenatally identified fetal adrenal masses. Studies with confirmed FAH diagnosis were included. Quality and risk assessment were evaluated. RESULTS: Thirty-five studies, including 102 FAH cases, were analyzed. FAH was commonly described as cystic (28/90, 31%), anechoic (25/90, 28%), or mixed echogenic (14/90, 16%) on ultrasound. Outcome data were available for 65 cases (64%) of FAH: 9% (6/65) resolved prenatally, 35% (23/65) resolved postnatally, 34% (22/65) regressed in size after birth, and 22% (14/65) persisted postnatally. Overall, 25% (16/65) of cases underwent postnatal surgical intervention. Neuroblastoma was suspected in all 16 surgical cases. Only one case (1/16, 6%) confirmed a cystic hematoma with microscopic islets of neuroblastoma in situ on pathology. CONCLUSION: Prenatal diagnosis of FAH is challenging due to the significant heterogeneity of ultrasound findings. Final pathology did not support the need for surgical intervention. Persistent postnatal FAH warrants shared decision making for further management based on the clinical presentation.

MicroRNA analysis in maternal blood of pregnancies with preterm premature rupture of membranes reveals a distinct expression profile.

OBJECTIVE: To determine the expression profile of microRNAs in the peripheral blood of pregnant women with preterm premature rupture of membranes (PPROM) compared to that of healthy pregnant women. STUDY DESIGN: This was a pilot study with case-control design in pregnant patients enrolled between January 2017 and June 2019. Patients with healthy pregnancies and those affected by PPROM between 20- and 33+6 weeks of gestation were matched by gestational age and selected for inclusion to the study. Patients were excluded for multiple gestation and presence of a major obstetrical complication such as preeclampsia, diabetes, fetal growth restriction and stillbirth. A total of ten (n = 10) controls and ten (n = 10) patients with PPROM were enrolled in the study. Specimens were obtained before administration of betamethasone or intravenous antibiotics. MicroRNA expression was analyzed for 800 microRNAs in each sample using the NanoString nCounter Expression Assay. Differential expression was calculated after normalization and log2- transformation using the false discovery rate (FDR) method at an alpha level of 5%. RESULTS: Demographic characteristics were similar between the two groups. Of the 800 miRNAs analyzed, 116 were differentially expressed after normalization. However, only four reached FDR-adjusted statistical significance. Pregnancies affected by PPROM were characterized by upregulation of miR-199a-5p, miR-130a-3p and miR-26a-5p and downregulation of miR-513b-5p (FDR adjusted p-values <0.05). The differentially expressed microRNAs participate in pathways associated with altered collagen and matrix metalloprotease expression in the extracellular matrix. CONCLUSION: Patients with PPROM have a distinct peripheral blood microRNA profile compared to healthy pregnancies as measured by the NanoString Expression Assay.

Genetics of non-isolated hemivertebra: A systematic review of fetal, neonatal, and infant cases.

Hemivertebra is a congenital vertebral malformation caused by unilateral failure of formation during embryogenesis that may be associated with additional abnormalities. A systematic review was conducted to investigate genetic etiologies of non-isolated hemivertebra identified in the fetal, neonatal, and infant periods using PubMed, Cochrane database, Ovid Medline, and ClinicalTrials.gov from inception through May 2022 (PROSPERO ID CRD42021229576). The Human Phenotype Ontology database was accessed May 2022. Studies were deemed eligible for inclusion if they addressed non-isolated hemivertebra or genetic causes of non-isolated hemivertebra identified in the fetal, neonatal, or infant periods. Cases diagnosed clinically without molecular confirmation were included. Systematic review identified 23 cases of non-isolated hemivertebra with karyotypic abnormalities, 2 cases due to microdeletions, 59 cases attributed to single gene disorders, 18 syndromic cases without known genetic etiology, and 14 cases without a known syndromic association. The Human Phenotype Ontology search identified 49 genes associated with hemivertebra. Non-isolated hemivertebra is associated with a diverse spectrum of cytogenetic abnormalities and single gene disorders. Genetic syndromes were notably common. Frequently affected organ systems include musculoskeletal, cardiovascular, central nervous system, genitourinary, gastrointestinal, and facial dysmorphisms. When non-isolated hemivertebra is identified on prenatal ultrasound, the fetus must be assessed for associated anomalies and genetic counseling is recommended.

Characterizing placental stiffness using ultrasound shear-wave elastography in healthy and preeclamptic pregnancies.

PURPOSE: To measure the stiffness of the placenta in healthy and preeclamptic patients in the second and third trimesters of pregnancy using ultrasound shear-wave elastography (SWE). We also aimed to evaluate the effect of age, gestational age, gravidity, parity and body mass index (BMI) on placental stiffness and a possible correlation of stiffness with perinatal outcomes. METHODS: In a case-control study, we recruited a total of 47 singleton pregnancies in the second and third trimesters of which 24 were healthy and 23 were diagnosed with preeclampsia. In vivo placental stiffness was measured once at the time of recruitment for each patient. Pregnancies with posterior placentas, multiple gestation, gestational hypertension, chronic hypertension, diabetes, autoimmune disease, fetal growth restriction and congenital anomalies were excluded. RESULTS: The mean placental stiffness was significantly higher in preeclamptic pregnancies compared to controls in the third trimester (difference of means = 16.8; 95% CI (9.0, 24.5); P < 0.001). There were no significant differences in placental stiffness between the two groups in the second trimester or between the severe preeclampsia and preeclampsia without severe features groups (difference of means = 9.86; 95% CI (-5.95, 25.7); P ≥ 0.05). Peripheral regions of the placenta were significantly stiffer than central regions in the preeclamptic group (difference of means = 10.67; 95% CI (0.07, 21.27); P < 0.05), which was not observed in the control group (difference of means = 0.55; 95% CI (- 5.25, 6.35); P > 0.05). We did not identify a correlation of placental stiffness with gestational age, maternal age, gravidity or parity. However, there was a statistically significant correlation with BMI (P < 0.05). In addition, pregnancies with higher placental stiffness during the 2nd and 3rd trimesters had significantly reduced birth weight (2890 ± 176 vs. 2420 ± 219 g) and earlier GA (37.8 ± 0.84 vs. 34.3 ± 0.98 weeks) at delivery (P < 0.05). CONCLUSION: Compared to healthy pregnancies, placentas of preeclamptic pregnancies are stiffer and more heterogeneous. Placental stiffness is not affected by gestational age or the severity of preeclampsia but there is a correlation with higher BMI and poor perinatal outcomes.

De novo ACTG2 mutations cause congenital distended bladder, microcolon, and intestinal hypoperistalsis.

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is characterized by prenatal-onset distended urinary bladder with functional intestinal obstruction, requiring extensive surgical intervention for survival. While it is believed to be an autosomal recessive disorder, most cases are sporadic. Through whole-exome sequencing in a child with MMIHS, we identified a de novo mutation, p.R178L, in the gene encoding the smooth muscle gamma-2 actin, ACTG2. We subsequently detected another de novo ACTG2 mutation, p.R178C, in an additional child with MMIHS. Actg2 transcripts were primarily found in murine urinary bladder and intestinal tissues. Structural analysis and functional experiments suggested that both ACTG2 mutants interfere with proper polymerization of ACTG2 into thin filaments, leading to impaired contractility of the smooth muscle. In conclusion, our study suggests a pathogenic mechanism for MMIHS by identifying causative ACTG2 mutations.

Esophageal Achalasia: An Uncommon Complication during Pregnancy Treated Conservatively.

A 38-year-old Caucasian woman, gravida 3 para 2, was admitted at 29 weeks of gestation because of vomiting, dysphagia for solids and liquids, and loss of weight. An enlargement of the anterior left neck region was noted on the palpation of the thyroid gland. An MRI of the neck showed a marked esophageal dilatation with the presence of food remnants along its length and the displacement of the trachea to the right. The findings of the upper gastrointestinal endoscopy and manometry were suggestive of esophageal achalasia. Conservative management with total parenteral nutrition (TPN) through a peripheral line proved to be successful. A healthy male baby was born by a cesarean section at 37 weeks. The patient underwent laparoscopic esophageal myotomy and fundoplication seven days postpartum.

Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia.

KBG syndrome is characterized by intellectual disability associated with macrodontia of the upper central incisors as well as distinct craniofacial findings, short stature, and skeletal anomalies. Although believed to be genetic in origin, the specific underlying defect is unknown. Through whole-exome sequencing, we identified deleterious heterozygous mutations in ANKRD11 encoding ankyrin repeat domain 11, also known as ankyrin repeat-containing cofactor 1. A splice-site mutation, c.7570-1G>C (p.Glu2524_Lys2525del), cosegregated with the disease in a family with three affected members, whereas in a simplex case a de novo truncating mutation, c.2305delT (p.Ser769GlnfsX8), was detected. Sanger sequencing revealed additional de novo truncating ANKRD11 mutations in three other simplex cases. ANKRD11 is known to interact with nuclear receptor complexes to modify transcriptional activation. We demonstrated that ANKRD11 localizes mainly to the nuclei of neurons and accumulates in discrete inclusions when neurons are depolarized, suggesting that it plays a role in neural plasticity. Our results demonstrate that mutations in ANKRD11 cause KBG syndrome and outline a fundamental role of ANKRD11 in craniofacial, dental, skeletal, and central nervous system development and function.

Inherited mutation of the luteinizing hormone/choriogonadotropin receptor (LHCGR) in empty follicle syndrome.

OBJECTIVE: To test by genomic analysis whether empty follicle syndrome (EFS) in a family with two affected sisters has a genetic basis. DESIGN: Whole-exome sequencing in the context of clinical genetics. SETTING: University hospital. PATIENT(S): Two women (36 and 32 years old at the time of the study) with EFS. INTERVENTION(S): Genetic counseling based on autosomal recessive inheritance. MAIN OUTCOME MEASURE(S): Discovery of a mutation in the LH/choriogonadotropin receptor (LHCGR) as the cause of EFS. RESULT(S): A novel missense mutation in LHCGR, p.N400S, was homozygous in sisters with EFS and/or infertility, but not in their unaffected siblings or parents. The mutation was not present in 500 ancestry-matched control subjects. Asparagine at residue 400 is highly conserved and its substitution by serine predicted to alter critical interactions that stabilize LHCGR. CONCLUSION(S): We describe a genetic basis for EFS and provide strong evidence for the existence of genuine EFS in some patients. A mutation impairing the function of LHCGR explains the lack of response of these patients to repeated administration of ß-hCG.

Risk of peripartum hysterectomy by mode of delivery and prior obstetric history: data from a population-based study.

PURPOSE: To provide an estimate of the incidence of peripartum hysterectomy in the state of New Jersey and calculate the effect of mode of delivery and prior obstetric history. METHODS: A perinatal-linked dataset provided by the Maternal Child Health Epidemiology Program in the New Jersey Department of Health was used to obtain information from birth certificates and hospital discharge records. Using multivariate logistic regression, various demographic and clinical factors were assessed for association with peripartum hysterectomy. RESULTS: A total of 1,004,116 births were identified between 1997 and 2005 and 853 peripartum hysterectomies were performed (0.85/1,000 deliveries). Parity increased the risk of hysterectomy with nulliparous women having approximately half the risk compared to multiparous women. Cesarean delivery with no previous c-section almost doubled the risk (OR 2.20, CI 1.80-26.69) while in the presence of a previous c-section the risk was almost four times higher (OR 4.51, CI 3.76-5.40). Operative vaginal delivery did not result in any increase in the risk. CONCLUSIONS: Mode of delivery and prior obstetric history are major risk factors for peripartum hysterectomy. Patients desiring cesarean delivery need to be counseled on the risk of this serious complication.

MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes.

Distinctive facial features consisting of hypertelorism, telecanthus, blepharophimosis, blepharoptosis, epicanthus inversus, periumbilical defects, and skeletal anomalies are seen in autosomal-recessive Carnevale, Malpuech, Michels, and oculo-skeletal-abdominal (OSA) syndromes. The gene or genes responsible for these syndromes were heretofore unknown. We report on three individuals from two consanguineous Turkish families with findings characteristic of these syndromes, including facial dysmorphism, periumbilical depression, mixed hearing loss, radioulnar synostosis, and coccygeal appendage. Homozygosity mapping yielded an autozygous region on chromosome 3q27 in both families. In one family, whole exome sequencing revealed a missense mutation, MASP1 c.2059G>A (p.G687R), that cosegregated with the phenotype. In the second family, Sanger sequencing of MASP1 revealed a nonsense mutation, MASP1 c.870G>A (p.W290X), that also cosegregated with the phenotype. Neither mutation was found in 192 Turkish controls or 1200 controls of various other ancestries. MASP1 encodes mannan-binding lectin serine protease 1. The two mutations occur in a MASP1 isoform that has been reported to process IGFBP-5, thereby playing a critical role in insulin growth factor availability during craniofacial and muscle development. These results implicate mutations of MASP1 as the cause of a human malformation syndrome and demonstrate the involvement of MASP1 in facial, umbilical, and ear development during the embryonic period.

The clinical utility of oral glucose tolerance test at term: can it predict fetal macrosomia?

OBJECTIVE: The goal of this study was to assess the correlation between true fetal macrosomia and abnormal oral glucose tolerance test (OGTT) in pregnant women at term gestation who had a negative glucose challenge screen (GCT) at 24-28 weeks. STUDY DESIGN: In this cohort observational study, we enrolled all term pregnant patients who presented to our antenatal unit with estimated fetal weight >90th percentile (or >4,000 g) and negative 50 g GCT. The women underwent a 3-h (100 g) OGTT test. Patient's demographics, GCT and OGTT test results, mode of delivery and pregnancy outcomes were recorded and analyzed. RESULTS: One hundred and seventy women (mean age 30.2+4.6 years, range 19-44) were recruited over 15-month period. Ten patients (5.9%) were identified as having impaired glucose metabolism at term. In this sub-group, we found no correlation between GCT values at 24-28 weeks, family history of diabetes mellitus, the patient's BMI or weight at term, and the diagnosis of impaired glucose metabolism. There was no statistically significant difference in the mean fetal weight in patients with normal and abnormal OGTT. No shoulder dystocia or third and fourth degree vaginal tears were reported among the women with suspected fetal macrosomia and impaired glucose metabolism. CONCLUSIONS: There was no correlation between true fetal macrosomia and an abnormal 3-h (100 g) OGTT at term. A larger-scale study is needed to determine the clinical significance of performing an OGTT at term for all patients with macrosomia and negative gestational diabetes screen.

Insulin resistance: the possible link between gestational diabetes mellitus and hypertensive disorders of pregnancy.

Gestational hypertension, preeclampsia, and diabetes are all associated with increased risks of poor maternal and perinatal outcomes. Pregnant women with gestational diabetes have been shown in population studies to have increased risk of pregnancy-associated hypertension compared with nondiabetic women. Moreover, pregnant patients with hypertension are at increased risk for developing gestational diabetes mellitus. It has been hypothesized that this association could be due, at least in part, to insulin resistance. Although insulin resistance is a physiologic phenomenon in normal pregnancy, in predisposed individuals this could lead to hyperinsulinemia with the development of gestational hypertension, gestational diabetes mellitus, or both.

Amniotic fluid embolism-risk factors, maternal and neonatal outcomes.

OBJECTIVE: To investigate demographic characteristics, risk factors, maternal and neonatal outcomes of all cases of amniotic fluid embolism that occurred in New Jersey during 1997-2005. METHODS: Information was derived from a perinatal linked dataset provided by the MCH-Epidemiology Program in the New Jersey Department of Health. Bivariate analysis for dichotomous variables used the Chi-square test. Stepwise logistic regression models were created to assess the influence of potential risk factors and p value < 0.05 considered statistically significant. RESULTS: Forty-five cases of amniotic fluid embolism were identified among 1,004,116 deliveries, for a prevalence rate of 1 in 22,313 pregnancies. Statistically, significant association was found with multifetal pregnancy, caesarean section, placenta previa, placental abruption, eclampsia and cervical laceration. The rate of maternal complications such as coagulopathy, seizures, neurological damage, shock and cardiac arrest were significantly greater in the cases as compared with the overall study population. Neonatal morbidity was significant as demonstrated by higher NICU admissions and neonatal intubation rates and lower 5-min Apgar scores. CONCLUSIONS: Significant correlation was identified between historically reported risk factors and amniotic fluid embolism. The fetal and maternal mortality rates were lower compared with previous studies, attributed both to improvements in perinatal healthcare and reporting of 'milder' cases.

Vulvar and breast Paget's disease with synchronous underlying cancer: a unique association.

BACKGROUND: We report a unique case of Paget's disease of vulva and breast. Sequentially the patient had invasive ductal carcinoma of the breast, 5 years later was diagnosed with vulvar Paget's with underlying adenocarcinoma and after another 2 years was diagnosed with Paget's disease of the breast. CASE: A 58-year-old woman with invasive ductal cancer of the left breast was treated with lumpectomy, lymph node dissection, radiation therapy and tamoxifen. Five years later and after complaints of longstanding vulvar pruritus, the patient was diagnosed with vulvar Paget's disease and treated with simple vulvectomy, which revealed a concurrent underlying adenocarcinoma. Subsequently there was recurrence of vulvar malignancy and wide local excision was performed. Seven years after the initial diagnosis of the breast cancer, a biopsy of a left areolar red, ulcerated lesion revealed Paget's disease of the breast. CONCLUSION: Physicians need to be cognizant of the rare occurrence of mammary and extramammary Paget's disease with underlying malignancies in both locations. A thorough physical examination including biopsy is essential for early detection and appropriate management.