Maternal Exposure to Stress During Covid-19 and Non-Syndromic Orofacial Clefts: A Cohort Retrospective Study.

OBJECTIVE: The coronavirus (COVID-19) pandemic presents an opportunity to study stress's effect on the development of non-syndromic orofacial clefts (NSOFCs). This study was aimed at assessing maternal stress exposure during the pregestational to first trimester pregnancy periods and the development of NSOFCs during a year of the COVID-19 pandemic. DESIGN: Cohort study of infants with NSOFCs and controls matched based on recruitment site and age. SETTING: Government hospitals in Saudi Arabia between November 2020 and November 2021. MAIN OUTCOME MEASURES: Data collection included NSOFC clinical examination and maternal stress exposure assessment using the Modified Life Events Questionnaire, the Fear of COVID-19 Scale, and a focus on the lack of pregnancy planning and a threatened miscarriage. RESULTS: Of the 557 infants recruited, 191 had NSOFCs. Logistic regression analysis with adjusted odds ratios (AORs) that removed the effects of confounders showed that any of the seven stressful life events (AOR:3.78, P < .001) and the family histories of relatives with NSOFCs (AOR:9.73, P < .001) increased the AOR for NSOFC development. In contrast, maternal folic acid (AOR:0.56, P.010), threatened miscarriage (AOR:0.17, P = .001), fear of COVID-19 (AOR:0.83, P = .038), and suspected COVID-19 infection (AOR:0.43, P = .008) decreased the AOR for NSOFC development. CONCLUSION: Along with an established risk associated with family history of birth defects, stressful life events may be a risk factor for NSOFC development. Beyond folic acid's known benefit, it may be that higher maternal health concerns contribute to increased protective health behaviors during pregnancy. Ongoing research is needed to specify the maternal risk factors for NSOFC.

Incidence of non-syndromic orofacial cleft during the COVID-19 pandemic in Saudi Arabia.

OBJECTIVES: This is the first national study to investigate the incidence of non-syndromic oro-facial clefts (NSOFC) and Pierre-Robin-Sequence in Saudi Arabia over the Covid-19 pandemic period. METHODS: All maternity hospitals (30-hospitals) in the major regions and cities of Saudi from November 2020-to-2021 were included in the study. Patients were evaluated for cleft phenotype using the LASHAL-classification system. The incidence of NSOFC in Saudi Arabia was calculated by comparing the number of NSOFCs cases born out of all live births during the study period at the included hospitals. Clinical examination was performed and information was gathered using a validated data collection form. RESULTS: In one year, 140,380 live-infants were born at the selected hospitals. Of these, 177 were diagnosed with NSOFC giving an incidence of 1.26/1,000 live-births in Saudi Arabia and the highest incidence in Medina city (2.46/1000 live-births). The incidence of cleft lip-and-palate (0.67/1000 live-births) was higher than that of cleft-palate (0.37/1000 live-births) and cleft-lip (0.22/1000 live-births). Pierre-Robin Sequence incidence was (0.04/1000 live-births). There were 21(12.1) or 23(13.2%) of NSOFC's mothers exposed or vaccinated with Covid-19, respectively. CONCLUSION: The national incidence of NSOFC in Saudi Arabia was 1.26/1000 live births with variation between phenotypes and regions in the country. In addition, to reporting Covid-19 infection prevalence and vaccine exposure among NSOFC's mothers, this study represents the first of its type to evaluate NSOFC prevalence in Saudi Arabia on a national level.

A 27-Year-Old Woman Diagnosed with Tuberculous Spondylitis, or Pott Disease, During Pregnancy: A Case Report.

BACKGROUND Tuberculous spondylitis, or Pott disease, includes vertebral body osteomyelitis and intervertebral discitis following infection with Mycobacterium tuberculosis and can present with vertebral collapse and back pain. This report is of a 27-year-old woman diagnosed with tuberculous spondylitis, or Pott disease, during pregnancy. CASE REPORT A 27-year-old female, in her first pregnancy and at 29 weeks of gestation, presented to the Emergency Department with worsening severe neck and back pain for the past 5 months. Post-gadolinium contrast T1-weighted diffusion magnetic resonance imaging demonstrated multiple soft tissue spinal lesions (T2-T4). Computed tomography-guided biopsy showed a central caseous necrosis enclosed by a granuloma containing a wide array of cells comprising epithelioid cells, Langhans giant cells, lymphocytes, and plasma cells. Ziehl-Neelsen staining was positive for acid-fast bacilli. The final diagnosis was consistent with Pott disease. The patient received anti-tuberculosis medications, her symptoms improved over time, and she delivered vaginally at term. At a 16-month follow-up, her symptoms had improved, and she returned to her normal daily activities. There were no complications arising from the use of gadolinium contrast in the mother or toddler. CONCLUSIONS This report has highlighted the importance of imaging of the spine in the diagnosis of causes of severe back pain. This rare presentation of Pott disease in pregnancy has shown the challenges in diagnosis and the importance of a multidisciplinary approach to diagnosis and management so that treatment protects both the mother and fetus.

Household income, fetal size and birth weight: an analysis of eight populations.

BACKGROUND: The age at onset of the association between poverty and poor health is not understood. Our hypothesis was that individuals from highest household income (HI), compared to those with lowest HI, will have increased fetal size in the second and third trimester and birth. METHODS: Second and third trimester fetal ultrasound measurements and birth measurements were obtained from eight cohorts. Results were analysed in cross-sectional two-stage individual patient data (IPD) analyses and also a longitudinal one-stage IPD analysis. RESULTS: The eight cohorts included 21 714 individuals. In the two-stage (cross-sectional) IPD analysis, individuals from the highest HI category compared with those from the lowest HI category had larger head size at birth (mean difference 0.22 z score (0.07, 0.36)), in the third trimester (0.25 (0.16, 0.33)) and second trimester (0.11 (0.02, 0.19)). Weight was higher at birth in the highest HI category. In the one-stage (longitudinal) IPD analysis which included data from six cohorts (n=11 062), head size was larger (mean difference 0.13 (0.03, 0.23)) for individuals in the highest HI compared with lowest category, and this difference became greater between the second trimester and birth. Similarly, in the one-stage IPD, weight was heavier in second highest HI category compared with the lowest (mean difference 0.10 (0 .00, 0.20)) and the difference widened as pregnancy progressed. Length was not linked to HI category in the longitudinal model. CONCLUSIONS: The association between HI, an index of poverty, and fetal size is already present in the second trimester.

Fetal Brain Injury in Rhesus Isoimmunization Fetus.

This report presents a rare fetal and neonatal complication brain injury (encephalomalacia and ventriculomegaly) as a consequence of severe fetal anemia resulting from Rhesus (Rh) isoimmunization. A 28-year-old gravida 4 para 3 woman was referred at 21+4 weeks of gestation to the fetal medicine clinic as a case of Rh isoimmunization. Fetal ultrasound showed a normal anatomy scan with normal brain structure, but with severe fetal anemia. The patient was treated with multiple intrauterine transfusions, but still developed complications post-transfusions. This case shows that severe cerebral developmental anomalies can occur because of severe fetal anemia secondary to Rh isoimmunization, such as in this case - ventriculomegaly and encephalomalacia. It has been concluded that proper antenatal counseling and early intervention for severe fetal anemia are beneficial to prevent such complications from occurring. It is crucial to consider appropriate antenatal and postnatal radiological imaging for such cases.

Fetal Diaphragmatic Eventration: A Case Report.

BACKGROUND: Congenital diaphragmatic eventration (CDE) is a rare congenital malformation that is well described in the pediatric literature. In contrast to congenital diaphragmatic hernia (CDH), there is no physical defect in the diaphragm with CDE. Prenatal differentiation of the two pathologies represents a diagnostic and prognostic challenge. CASE: A 26-year-old nulliparous woman was evaluated for a fetal thoracic mass. At 22 weeks, detailed morphology ultrasound revealed a multi-cystic structure in the left side of the thorax. Differential diagnosis included cystic congenital adenomatoid pulmonary malformation and CDH. Left diaphragmatic eventration was added to the differential diagnosis when serial ultrasound at 36 weeks showed the left hemidiaphragm as a thin membrane bulging into the fetal chest with the left kidney in a higher position underneath. The male infant was delivered vaginally at 373 weeks. CT imaging at 2 days of life showed findings consistent with left diaphragmatic eventration with protrusion of small bowel loops and the left kidney underneath. The infant was successfully extubated 3 days later and remained on nasal cannula until discharge on day 17 of life. At 6 months, the infant required operative repair owing to increasing shortness of breath. CONCLUSION: CDE is a rare and difficult diagnosis to consider prenatally. Probable associated features may aid diagnosis. Additional, larger case series are needed to improve prenatal differentiation of this condition.

Outcomes of Isolated Antenatal Hydronephrosis at First Year of Life.

OBJECTIVES: To compare the grade of hydronephrosis between the antenatal and first postnatal ultrasound (US) and their clinical outcomes. METHODS: This retrospective study included all cases of isolated hydronephrosis detected by antenatal US from August 2005 to February 2011. Hydronephrosis was classified based on the standard criteria into mild, moderate, or severe. Cases associated with other major congenital anomalies were excluded. All patients were followed-up postnatally and outcomes available were analyzed at one year of age. RESULTS: A total of 105 cases were included out of which 83 (79.0%) were males and 22 (20.9%) were females with a median gestational age of 38 weeks. First postnatal US of 105 cases showed that 20 (19.0%) were free of hydronephrosis, 39 (37.1%) had mild, 29 (27.6%) moderate, and 17 (16.1%) had severe hydronephrosis. Half (50.4%) of hydronephrosis cases improved in their clinical presentation while 13.3% showed deterioration and 36.3% remained the same. Almost half of all cases (52 cases) were diagnosed by US at the end of first year without any effect on renal function. CONCLUSIONS: Antenatal and postnatal US are sensitive tools for detecting hydronephrosis as well as for postnatal counseling. Fetal anatomy US is usually done at 18 weeks gestation and if this reveals any evidence of hydronephrosis, the patient is followed according to the severity. Postnatal US is not done routinely for cases where hydronephrosis resolves completely during pregnancy. Although newborns with antenatal hydronephrosis due to secondary causes are at greater risk for renal impairment, surgical intervention reserves renal function.

The impact of fetal middle cerebral artery Doppler on the outcome of congenital hydrocephalus.

OBJECTIVES: The objective of this study is to investigate the impact of abnormal middle cerebral artery (MCA) Doppler on the perinatal mortality in fetuses with congenital hydrocephalus (CH). METHODS: A prospective study of all fetuses with CH who delivered at our hospital over a period of 7 years. Data were obtained from the ultrasound, Labor room and intensive neonatal care unit (NICU) database. The Perinatal mortality rates were evaluated in relation to the following measures, associated congenital anomalies, cortical mantle thickness (CMT), and MCA Doppler abnormalities (absent or reversed diastole). The main outcome measure was perinatal mortality rate in relation to MCA Doppler changes. RESULTS: A total of 85 cases of CH were diagnosed and managed. The birth prevalence of CH was 2.44 per 1000 live births. On one hand, the perinatal mortality rate was higher in those fetuses with non-isolated hydrocephalus, (37.25% (19/51) versus (35.29% (12/34, p = 0.854 and in those cases with CMT <10 mm, 38.78% (19/49) versus 33.33% (12/36) in those with CMT >10 mm, p = 0.607. On the other hand, the perinatal mortality rate was significantly higher in those fetuses with abnormal MCA Doppler, (100% (13/13) versus 25% (18/72), OR = 78.0, 95% CI (5.52-44085124.60), p < 0.001. CONCLUSIONS: Abnormal fetal MCA Doppler (absent or reversed diastole) appears to be a poor prognostic indicator with significantly high perinatal mortality in fetuses with CH.

Molecular autopsy in maternal-fetal medicine.

PurposeThe application of genomic sequencing to investigate unexplained death during early human development, a form of lethality likely enriched for severe Mendelian disorders, has been limited.MethodsIn this study, we employed exome sequencing as a molecular autopsy tool in a cohort of 44 families with at least one death or lethal fetal malformation at any stage of in utero development. Where no DNA was available from the fetus, we performed molecular autopsy by proxy, i.e., through parental testing.ResultsPathogenic or likely pathogenic variants were identified in 22 families (50%), and variants of unknown significance were identified in further 15 families (34%). These variants were in genes known to cause embryonic or perinatal lethality (ALPL, GUSB, SLC17A5, MRPS16, THSD1, PIEZO1, and CTSA), genes known to cause Mendelian phenotypes that do not typically include embryonic lethality (INVS, FKTN, MYBPC3, COL11A2, KRIT1, ASCC1, NEB, LZTR1, TTC21B, AGT, KLHL41, GFPT1, and WDR81) and genes with no established links to human disease that we propose as novel candidates supported by embryonic lethality of their orthologs or other lines of evidence (MS4A7, SERPINA11, FCRL4, MYBPHL, PRPF19, VPS13D, KIAA1109, MOCS3, SVOPL, FEN1, HSPB11, KIF19, and EXOC3L2).ConclusionOur results suggest that molecular autopsy in pregnancy losses is a practical and high-yield alternative to traditional autopsy, and an opportunity for bringing precision medicine to the clinical practice of perinatology.

Effectiveness of Prophylactic Cervical Cerclage in Prolonging Higher-Order Multiple Pregnancies.

OBJECTIVES: This study aimed to assess the value of prophylactic cervical cerclage in prolonging higher-order multiple pregnancies. METHODS: This retrospective study included all women with higher-order multiple pregnancies beyond 24 gestational weeks treated at the King Abdullah University Hospital in Irbid, Jordan, and King Fahad Medical City in Riyadh, Saudi Arabia, between February 2014 and January 2015. Selected maternal characteristics and obstetric outcomes were compared between women who received prophylactic cervical cerclage and those who did not. RESULTS: A total of 146 women with higher-order multiple pregnancies were included in the study; of these, 94 (64.4%) underwent a prophylactic cervical cerclage insertion procedure and 52 (35.6%) women did not. No significant difference was found between the two groups with regards to maternal age, parity or number of fetuses. However, the mean gestational age at delivery was significantly higher for women without compared to those with prophylactic cervical cerclage (32.9 weeks versus 31.7 weeks) according to both univariate and multivariate analyses (P = 0.013 and 0.046, respectively). Additionally, 40.4% of women without and 14.9% of women with prophylactic cervical cerclage gave birth after 34 gestational weeks (P = 0.003). CONCLUSION: Overall, prophylactic cervical cerclage was not associated with prolongation of the pregnancy among women with higher-order multiple pregnancies in the current study.

The genetic landscape of familial congenital hydrocephalus.

OBJECTIVE: Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only 4 genes are known to cause Mendelian diseases in which congenital hydrocephalus is the main or sole clinical feature, 2 X-linked (L1CAM and AP1S2) and 2 autosomal recessive (CCDC88C and MPDZ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease. METHODS: Exome sequencing combined, where applicable, with positional mapping. RESULTS: We identified a likely causal mutation in the majority of these families (21 of 27, 78%), spanning 16 genes, none of which is X-linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In 1 family with 4 affected members, we identified a homozygous truncating variant in EML1, which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with 5 recessive alleles. INTERPRETATION: Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition. Ann Neurol 2017;81:890-897.

Prevalence of major congenital anomalies at King Fahad Medical City in Saudi Arabia: a tertiary care centre-based study.

BACKGROUND AND OBJECTIVES: The prevalence of major congenital anomalies in Saudi Arabia is a largely understudied area. Knowing the prevalence of birth defects and their trends is important in identifying potential factors that are either causative or preventative. Early antenatal diagnosis of major congenital anomalies is important for possible termination of pregnancy, fetal or neonatal. We determined the prevalence of major congenital anomalies in our hospital population since implementation of an improved screening system. PATIENTS AND METHODS: This single-centre prospective cross-sectional study was conducted in a tertiary care hospital in Riyadh. A total of 63452 obstetrical ultrasound examinations were performed for 30632 female Saudi obstetric patients from the period of January 2007 to December 2012. RESULTS: A total of 1598 fetuses were diagnosed with major congenital anomalies, including 1064 (66.6 %) fetuses with isolated major anomalies and 534 (33.4%) fetuses with non-isolated major anomalies. The antenatal prevalence of congenital anomalies was 52.1 per 1000 pregnancies. The median maternal age at diagnosis was 29 years. The median gestational age at diagnosis was 30 weeks of gestation. Two hundred and eighty five cases (17.85%) had a previous family history of similar anomalies. The most commonly diagnosed anomalies involved the genitourinary system (652 cases). The birth prevalence of major congenital anomalies was 46.5 per 1000 live births. CONCLUSION: The prevalence of major congenital anomalies in our hospital population appears to be higher than international prevalences, with a high recurrence rate. Environmental, nutritional and social factors may be contributing to this phenomenon.

Birth prevalence of non-syndromic orofacial clefts in Saudi Arabia and the effects of parental consanguinity.

OBJECTIVES: To describe the characteristics and prevalence of non-syndromic orofacial clefting (NSOFC) and assess the effects of parental consanguinity on NSOFC phenotypes in the 3 main cities of Saudi Arabia. METHODS: All infants (114,035) born at 3 referral centers in Riyadh, and 6 hospitals in Jeddah and Madinah between January 2010 and December 2011 were screened. The NSOFC cases (n=133) were identified and data was collected through clinical examination and records, and information on consanguinity through parent interviews. The diagnosis was confirmed by reviewing medical records and contacting the infants' pediatricians. Control infants (n=233) matched for gender and born in the same hospitals during the same period, were selected. RESULTS: The prevalence of NSOFC was 1.07/1000 births in Riyadh, and 1.17/1000 births overall; cleft lip (CL) was 0.47/1000 births, cleft lip and palate (CLP) was 0.42/1000 births, and cleft palate (CP) was 0.28/1000 births. Cleft palate was significantly associated with consanguinity (p=0.047, odds ratio: 2.5, 95% confidence interval: 1 to 6.46), particularly for first cousin marriages. CONCLUSION: The birth prevalence of NSOFC in Riyadh alone, and in the 3 main cities of Saudi Arabia were marginally lower than the mean global prevalence. While birth prevalence for CLP was comparable to global figures, the CL:CLP ratio was high, and only CP was significantly associated with consanguinity.

Mutation of HES7 in a large extended family with spondylocostal dysostosis and dextrocardia with situs inversus.

Spondylocostal dysotosis (SCD) is a rare developmental congenital abnormality of the axial skeleton. Mutation of genes in the Notch signaling pathway cause SCD types 1-5. Dextrocardia with situs inversus is a rare congenital malformation in which the thoracic and abdominal organs are mirror images of normal. Such laterality defects are associated with gene mutations in the Nodal signaling pathway or cilia assembly or function. We investigated two distantly related individuals with a rare combination of severe segmental defects of the vertebrae (SDV) and dextrocardia with situs inversus. We found that both individuals were homozygous for the same mutation in HES7, and that this mutation caused a significant reduction of HES7 protein function; HES7 mutation causes SCD4. Two other individuals with SDV from two unrelated families were found to be homozygous for the same mutation. Interestingly, although the penetrance of the vertebral defects was complete, only 3/7 had dextrocardia with situs inversus, suggesting randomization of left-right patterning. Two of the affected individuals presented with neural tube malformations including myelomeningocele, spina bifida occulta and/or Chiari II malformation. Such neural tube phenotypes are shared with the originally identified SCD4 patient, but have not been reported in the other forms of SCD. In conclusion, it appears that mutation of HES7 is uniquely associated with defects in vertebral, heart and neural tube formation, and this observation will help provide a discriminatory diagnostic guide in patients with SCD, as well as inform molecular genetic testing.

Antenatal diagnosis, prevalence and outcome of major congenital anomalies in Saudi Arabia: a hospital-based study.

BACKGROUND AND OBJECTIVES: The exact antenatal prevalence of congenital anomalies in Saudi society is unknown. Early antenatal diagnosis of congenital anomalies is crucial for early counselling, intervention and possible fetal therapy. The objective of this study was to evaluate the antenatal frequency of major congenital anomalies and malformation patterns in our hospital population and to evaluate the outcome and perinatal mortality rates for major congenital anomalies. PATIENTS AND METHODS: This was a prospective study of the antenatal diagnosis of major fetal congenital anomalies conducted in the Ultrasound Department of the Women's Specialized Hospital at King Fahad Medical City from March 2005 to February 2007. During this period, 16 639 obstetrical ultrasound examinations were performed for 7762 patients and 5379 babies delivered in our institution. RESULTS: We diagnosed 217 cases of fetal anomalies. The antenatal prevalence of congenital anomalies was 27.96 per 1000. The median maternal age at diagnosis was 27.5 years. The median gestational age at diagnosis was 31 weeks. Genitourinary and cranial anomalies were the commonest; for 186 patients delivered in our institution, the birth prevalence was 34.57 per 1000 births. The median gestational age at delivery was 38 weeks. The perinatal mortality rate was 34.9% (65/186), including all cases of intrauterine fetal and neonatal deaths. CONCLUSION: The prevalence of major congenital anomalies in our population appears to be similar to international figures. Major congenital anomalies are a major cause of perinatal mortality.

The effect of fetal behavioral states on middle cerebral artery peak systolic velocity.

OBJECTIVE: This study was undertaken to determine whether is there a difference in the middle cerebral artery peak systolic velocity (MCA PSV) between active and resting behavioral states in healthy fetuses aged 30 to 32 weeks. METHODS: MCA blood flow was measured by pulsed Doppler sonography 3 times during each fetal behavioral state (active and resting). The average during active state was compared during the resting state. Statistical analysis was performed by paired t test. RESULTS: During the fetal active state, there was a significant increase in the mean PSV (51.59 cm/s vs 46.95 cm/s, P < .0001) and mean end-diastolic velocity (9.59 cm/s vs 7.98 cm/s, P=.0015), and a significant decrease in the mean pulsatility index (PI) (2.07 vs 2.19, P=.0226) and the mean resistance index (0.83 vs 0.85, P=.0481). CONCLUSION: Healthy preterm fetuses have a significantly higher MCA PSV during the active state. Activity state should be considered when interpreting MCA Doppler indices.