Clarithromycin is a macrolide antibiotic that is widely used, including during pregnancy. However, few studies have examined the safety of clarithromycin alone in early pregnancy. In this two-center retrospective cohort study, we evaluated pregnancy outcomes following first-trimester clarithromycin exposure. Information on medication use and obstetric history was obtained retrospectively. Pregnancy outcomes were collected using patient-completed postal questionnaires. We investigated pregnancy outcomes and the incidence of major anomalies in women who took clarithromycin during the first trimester, and compared them with those in women who took β-lactams or control drugs known to be safe during pregnancy. The primary outcome was the incidence of major anomalies, and the secondary outcome was overall pregnancy outcomes. The numbers of major anomalies in the clarithromycin group (n = 347), β-lactam group (n = 1367), and control group (n = 1313) were 8 (2.31%), 26 (1.90%), and 18 (1.37%), respectively. When restricted to patients with live births only, the numbers of major anomalies in these groups (n = 333, n = 1323, and n = 1261, respectively) were 8 (2.40%), 25 (1.89%), and 18 (1.43%), respectively, with no significant differences between groups. The odds ratio for major anomalies in the clarithromycin group relative to the control group was 1.70 (95% confidence interval [CI], 0.73–3.94), while that relative to the β-lactam group was 1.28 (95% CI, 0.57–2.86). Inverse probability weighting to compensate for small sample sizes also yielded no significant differences. Overall, clarithromycin use during the first trimester was not associated with an increased risk of major anomalies relative to β-lactams or control drugs.
Cleidocranial dysplasia is a congenital malformation syndrome characterized by skeletal and dental abnormalities as well as distinctive craniofacial features. Most previous reports have relied on two-dimensional radiographs, and no comprehensive three-dimensional investigations have been conducted. This study aimed to provide a detailed overview of craniofacial features in patients with cleidocranial dysplasia using computed tomography. Craniofacial characteristics of 11 Japanese patients were assessed using three-dimensional computed tomography reconstructions. Qualitative evaluations were performed across three regions: cranial, nasomaxillary complex, and mandibular. In the cranial region, all patients presented Wormian bones and hypoplastic mastoid processes. In the nasomaxillary complex, hypoplastic nasal bones, atypical piriform aperture contours, and discontinuous or downward-bent zygomatic arches were frequently observed. In the mandibular region, atypical sigmoid notch morphology, nearly parallel-sided ascending rami, and abnormally rounded mandibular angles were identified. Novel findings included aplastic/hypoplastic styloid processes, thin-appearing orbital walls, downward displacement of the temporal process of the maxillary bone, and atypical coronoid process morphology. Bilateral expression of all craniofacial traits was also newly confirmed. To our knowledge, this is the first comprehensive three-dimensional study of craniofacial morphology in cleidocranial dysplasia. These observations provide new insights into the pathophysiology and developmental mechanisms underlying craniofacial anomalies in affected patients.
Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility and frequent fractures. The disorder is caused by pathogenic variants in genes that encode type I collagen. The COL1A1 gene encodes the pro-α1(I) collagen chain, which assembles with another pro-α1(I) chain and one pro-α2(I) chain to form a heterotrimeric triple helix. The C-terminal propeptide (C-propeptide) contributes to molecular recognition and initiation of triple helix formation, thereby promoting correct chain alignment during procollagen biosynthesis. Variants in this region may disrupt chain association and folding, and impair collagen assembly. Here, we present the case of a Japanese male infant who presented with respiratory distress, pulmonary hypoplasia, recurrent fractures, and hearing loss. Radiographic examination revealed slender long bones with multiple acute and healing fractures in the ribs, clavicles, and limbs, as well as Wormian bones. Genetic analysis identified a de novo heterozygous COL1A1 variant, NM_000088.4:c.4223A>G, p.(Tyr1408Cys). Based on the clinical and molecular findings, the patient was diagnosed with OI type III. The patient received bisphosphonate therapy and respiratory support with continuous positive airway pressure. In silico structural modeling suggested that Tyr1408 is located near the C-propeptide interface, where it may contribute to local stability through aromatic and hydrogen-bonding interactions. Substitution by cysteine could alter the local folding environment and inter-chain interactions. Presently, the report provides clinical and structure-based context for how cysteine substitutions in the C-terminal region of COL1A1 may be associated with severe OI phenotypes.
The Burden of urogenital congenital anomalies (UCAs) among children and adolescence aged under 24 years in the world has not been comprehensively studied regarding the Global Burden of Disease Study (GBD) database 2021. This study aims to characterize the burden of UCAs in this population from 1990 through 2021. We extracted data from GBD 2021 to collect information on the prevalence, deaths, and disability-adjusted life years (DALYs) linked to UCAs from 1990 to 2021. Furthermore, we calculated the estimated annual percentage change (EAPC) for each metric to assess temporal trends. In 2021, there were 6343.41 thousand prevalent cases of UCAs worldwide, with UCAs accounting for 7.50 thousand deaths and 882.19 thousand DALYs. UCAs prevalence increased by 3.97% between 1990 and 2021, with the global age-standardized rate (ASR) of prevalence increasing to 89.76 per 100 000. Global deaths decreased by 23.48% over the same interval, with an ASR of 0.12 cases per 100 000. The worldwide DALYs burden decreased by 1.40%, corresponding to an ASR of 13.56 DALYs per 100 000 population. The prevalence of UCAs in the 0–9 age group has been increasing annually, reaching a peak in the 5–9 years age range. Over the past 32 years, mortality and DALYs attributable to UCAs have steadily declined, despite persistent regional disparities. These findings offer vital guidance for developing targeted prevention and management strategies for UCAs.
Bloom syndrome (BS) is an autosomal recessive disorder characterized by prenatal and postnatal growth deficiency, photosensitive skin changes, immune deficiency, insulin resistance, greatly increased risk of early-onset cancer, and the development of multiple malignancies. Few cases of BS diagnosed during the prenatal period have been reported. Here, I present the comprehensive clinical and genetic characterization of two unrelated fetuses diagnosed with BS. Two pregnant women with abnormal ultrasound findings underwent amniocentesis for karyotype analysis, copy number variation sequencing (CNV-seq), and trio-whole exome sequencing (Trio-WES). Both fetuses exhibited severe fetal growth restriction. One fetus had a pericardial effusion. The karyotype analysis and CNV-seq revealed no apparent abnormalities. Trio-WES revealed biallelically likely pathogenic or pathogenic BLM variants in the fetuses. All parents were BLM variant carriers. These cases indicate that affected fetuses are more likely to have severe fetal growth restriction and do not display significant chromosomal abnormalities before birth. Clarification of the molecular diagnosis had important implications for these parents because they carried a 25% risk of recurrence. They were recommended to plan future pregnancies with preimplantation genetic testing for monogenic disorders to avoid future offspring with BS.
Non-syndromic cleft lip with or without palate (NSCL/P) ranks among the most prevalent congenital craniofacial anomalies globally. In Japan, reported rates of cleft lip and/or palate range from 1 in 500 to 1 in 700 live births. This study aims to explore potential sex-specific interactions of NOG rs227731 across NSCL/P subtypes in a Japanese population. This case–control study included 420 participants recruited from the Cleft Lip and Palate Centre at Aichi Gakuin Dental Hospital in Nagoya, Japan. The study population was divided into three groups: 110 individuals with non-syndromic cleft lip and palate (NSCLP), 110 with non-syndromic cleft lip only (NSCLO), and a control group of 200 unaffected individuals. A balanced 1:1 male-to-female ratio was maintained within each group to enhance the statistical power of sex-stratified analyses. There was no evidence about the association of rs227731 with NSCL/P and the NSCLP group in both gender clusters. In the NSCLO subgroup, a significant difference emerged in the allelic model among males (OR = 1.66, 95% CI: 1.03–2.69, p = 0.0385). Conversely, no significant associations were detected in females across any of the models. In conclusion, this study's findings suggest a possible association between the NOG rs227731 variant in males of NSCLO as an increasing risk factor.
Twin Reversed Arterial Perfusion (TRAP) sequence is a rare complication of monochorionic twin pregnancies characterized by reversed blood flow from the pump twin to a nonviable acardiac twin. This study aims to share the clinical outcomes and procedural details of TRAP sequence cases managed at our tertiary fetal therapy center, with emphasis on various intrauterine treatment modalities. We conducted a retrospective review of 20 pregnancies diagnosed with TRAP sequence and managed at a tertiary fetal therapy unit between January 2018 and July 2025. Diagnosis was confirmed via prenatal ultrasonography and Doppler imaging. Patients underwent intrauterine intervention—radiofrequency ablation (RFA), microwave ablation (MWA), intrafetal laser (IFL), or bipolar cord coagulation—based on gestational age, acardiac twin size, and hemodynamic status of the pump twin. Twenty pregnancies diagnosed with TRAP sequence were included. The median maternal age was 32 years (range: 22–47). Both diagnosis and intervention occurred at a median gestational age of 20 weeks (range: 12–29). Invasive treatment was performed in 19 cases: RFA (n = 10), IFL (n = 4), cord coagulation (n = 3), and MWA (n = 2). The median time from procedure to delivery was 98 days (range: 1–135). Overall live birth rate was 80% (16/20), and neonatal survival rate was 75% (15/20). Fetal interventions can significantly enhance survival in TRAP pregnancies, including those referred at advanced gestational ages. Early identification of risk indicators and tailored procedural planning are critical for improving outcomes. Our findings underscore the efficacy of minimally invasive therapies in optimizing prognosis for the pump twin.
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