Guideline for gynecological practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2023 edition.

Twelve years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 5th Revised Edition was published in 2023. The 2023 Guidelines includes 5 additional clinical questions (CQs), which brings the total to 103 CQ (12 on infectious disease, 30 on oncology and benign tumors, 29 on endocrinology and infertility and 32 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

Spontaneous echo contrast and decreased umbilical vein blood flow may predict thrombus formation in fetal intra-abdominal umbilical vein varix.

PURPOSE: Fetal intra-abdominal umbilical vein varix (FIUVV) can cause thrombosis, fetal growth restriction (FGR), and intrauterine fetal death (IUFD). However, its management and evaluation to avoid fetal risks have not been elucidated. The aim of this study was to develop a novel method to evaluate fetal risks, including FGR and fetal dysfunction via frequent ultrasound examinations. METHODS: A 28-year-old pregnant woman was diagnosed with FIUVV via ultrasound at 26 weeks of gestation and admitted to our hospital. Ultrasound examinations were performed two to three times weekly to evaluate size and shape of the FIUVV and umbilical vein blood flow at the inflow and outflow sites of the FIUVV. RESULTS: The outflow site of the FIUVV was constricted and collapsed, and the blood flow velocity at the inflow site of the FIUVV was decreased. At 32 weeks of gestation, spontaneous echo contrast (SEC), which indicates increased echogenicity, appeared. At 35 weeks of gestation, the patient noticed decreased fetal movement, and CTG showed non-reassuring fetal status. SEC in the FIUVV was remarkable. Fetal movement could not be confirmed at ultrasound. Cesarean section was performed and a 1,854-g healthy infant was delivered with an umbilical cord arterial pH of 7.266. CONCLUSION: The echographic changes, such as decreased umbilical vein blood flow and SEC, in FIUVV observed in this case could indicate thrombus formation, which can lead to fetal dysfunction. Frequent ultrasound examinations can help determine the timing of delivery and improve the neonatal prognosis.

Diagnostic Utility of Hysteroscopic Biopsy in Cases of Suspected Lobular Endocervical Glandular Hyperplasia and Comparison with Cervical Conization.

BACKGROUND: Cervical cystic lesions encompass a range of benign and malignant pathologies. Magnetic resonance imaging or cytology alone cannot provide a definitive diagnosis, and conventional practice involves performing a cervical biopsy by conization to confirm the histology in cases exhibiting potential signs of lobular endocervical glandular hyperplasia (LEGH) or malignancy. However, as postoperative complications resulting from conization can impact future fertility and pregnancy, alternative diagnostic methods are needed for reproductive-age patients. This study aimed to establish the efficacy of a hysteroscopic biopsy for diagnosing cervical cystic lesions and compare it with conization. METHODS: Thirteen patients with cervical cystic lesions suspected of LEGH or malignancy underwent a hysteroscopic biopsy, while 23 underwent conization. Patient background information, preoperative evaluation, histology, and postoperative outcomes were collected and compared retrospectively. RESULTS: No significant differences were found between the hysteroscopy and conization groups in terms of mean patient age (45 vs. 48 years), operating time (23 vs. 35 min), blood loss (small amount vs. 43 mL), and postoperative hospitalization (1.1 vs. 1.6 days). CONCLUSION: A hysteroscopic biopsy allows for targeted resection of the cervix while maintaining diagnostic accuracy. It may serve as an efficient method for diagnosing cervical cystic lesions.

The Effect of Sexual Intercourse during Pregnancy on Preterm Birth: Prospective Single-Center Cohort Study in Japan.

Several studies in Europe and the United States have shown that sexual intercourse (SI) during pregnancy is not associated with preterm birth. However, it is unclear whether these findings apply to pregnant Japanese women. The aim of this prospective cohort study was to elucidate the influence of SI during pregnancy on preterm birth in Japan. A total of 182 women who underwent antenatal care and delivery were included in this study. The frequency of SI was assessed using a questionnaire, and its association with preterm birth was analyzed. The results showed that SI during pregnancy was associated with a significantly higher cumulative preterm birth rate (p = 0.018), which was more pronounced for SI more than once a week (p < 0.0001). Multivariate analysis showed that SI, bacterial vaginosis in the second trimester, previous preterm birth, and smoking during pregnancy were independent risk factors for preterm birth. The combination of SI and second trimester bacterial vaginosis was associated with a 60% preterm birth rate, whereas either factor alone was associated with a lower rate, suggesting a synergistic effect (p < 0.0001). Future studies are needed to investigate the effect of prohibiting SI in pregnant women with bacterial vaginosis on preterm birth.

Conservative Management for Retained Products of Conception in Late Pregnancy.

This retrospective study aims to compare the early manual removal of placenta (MROP) and conservative management of retained products of conception (RPOC) after 34 weeks of gestation. Nineteen cases underwent MROP within 24 h of delivery, of which nine patients had no symptoms requiring emergent treatment. These 9 patients (group M) were compared with 22 patients who were treated conservatively (group C). Massive bleeding was observed in 5 (56%) patients in group M and 11 (50%) patients in group C, with no significant difference in frequency. However, the lowest hemoglobin level within 72 h after massive bleeding was lower in group M (median: 6.7 vs. 7.7 g/dL, p = 0.029), suggesting that massive bleeding occurred in a short period of time. On the other hand, a retained placenta was observed in four patients in group M after the MROP; however, the placenta disappeared more quickly than in group C (median; 1.0 vs. 99.0 days, p = 0.009). In group C, all bleeding and infection occurred within 60 days of delivery, including heavy bleeding in six cases during the placental-extraction trial. Human chorionic gonadotropin in group C fell below the measurable threshold at a median of 67 days postpartum. In conclusion, for RPOC without urgent symptoms, early MROP and conservative treatment have their advantages and disadvantages. Randomized controlled trials are needed to determine which of those treatments is superior.

A case of a pregnant woman with locally advanced cervical esophageal cancer treated with definitive chemoradiotherapy.

The information of definitive radiotherapy for a pregnant woman with malignancy was limited; however, it was reported to be potentially feasible with minimal risks. We performed definitive chemoradiotherapy for a pregnant woman with locally advanced cervical esophageal cancer. Feasibility of radiotherapy and safety of fetus were confirmed by the phantom study estimating fetal dose, and monitoring it in each radiotherapy session. The planned chemoradiotherapy completely eradicated esophageal cancer while preserving her laryngopharyngeal function. A female infant was delivered by cesarian section after planned chemoradiotherapy, and she grew without any apparent disorders 2 years after chemoradiotherapy. Chemoradiotherapy might be one of the treatment options for a pregnant woman with cervical esophageal cancer especially wishing the preservation of laryngopharyngeal function.

Fetal macrophages assist in the repair of ruptured amnion through the induction of epithelial-mesenchymal transition.

The premature rupture of the amniotic sac, a condition referred to as a preterm prelabor rupture of membranes (pPROM), is a leading cause of preterm birth. In some cases, these ruptured membranes heal spontaneously. Here, we investigated repair mechanisms of the amnion, a layer of epithelial cells in the amniotic sac closest to the embryo. Macrophages migrated to and resided at rupture sites in both human and mouse amnion. A process called epithelial-mesenchymal transition (EMT), in which epithelial cells acquire a mesenchymal phenotype and which is implicated in tissue repair, was observed at rupture sites. In dams bearing macrophage-depleted fetuses, the repair of amnion ruptures was compromised, and EMT was rarely detected at rupture sites. The migration of cultured amnion epithelial cells in wound healing assays was mediated by EMT through transforming growth factor-ß (TGF-ß)-Smad signaling. These findings suggest that fetal macrophages are crucial in amnion repair because of their ability to induce EMT in amnion epithelial cells.

Plasma Antithrombin Activity during Long-Term Magnesium Sulfate Administration for Preeclampsia without Severe Hypertension.

In preeclampsia, plasma antithrombin activity is decreased, which leads to exacerbation of the disorder. We previously showed that long-term magnesium sulfate (MgSO4) administration prolonged the pregnancy period and may be able to improve pregnancy outcomes for patients with severe preeclampsia. The present study aimed to investigate the changes in plasma antithrombin activity during long-term MgSO4 administration for patients without severe hypertension. This multicenter retrospective study included patients with preeclampsia and superimposed preeclampsia without severe hypertension at diagnosis. The participants were divided into two groups: MgSO4 nontreatment group (three institutions) and MgSO4 treatment group (one institution). Antithrombin activity from time of diagnosis to delivery were compared between the two groups. In the MgSO4 nontreatment group (n = 16), antithrombin activity prior to delivery was significantly lower than at time of diagnosis (p = 0.015). In three cases, antithrombin activity was less than 60%. On the other hand, in the MgSO4 treatment group (n = 34), antithrombin activity did not change until just before delivery (p = 0.74). There were no cases in which antithrombin activity was decreased below 60%. Long-term MgSO4 administration for preeclampsia without severe hypertension may prevent a decrease in antithrombin activity and improve the disease state of preeclampsia.

The significance of clinical symptoms of subchorionic hematomas, "bleeding first", to stratify the high-risk subgroup of very early preterm delivery.

OBJECTIVE: To investigate the factors that stratify high-risk cases among subchorionic hematomas (SCHs) patients with persistent vaginal bleeding in early pregnancy. MATERIALS AND METHODS: A total of 56 patients who required hospitalization for SCH with vaginal bleeding in early pregnancy were classified into two groups: 1) no hematoma by ultrasonography when vaginal bleeding occurred, and then hematoma was observed by ultrasonography "bleeding to hematoma (BH group, n = 15)" and 2) no vaginal bleeding when hematoma was observed by routine ultrasonography, and then vaginal bleeding occurred later "hematoma to bleeding (HB group, n = 41)". Retrospective cohort study was performed and maternal and neonatal outcomes were evaluated. RESULTS: The duration of SCHs and/or vaginal bleeding was significantly longer in the BH group than in the HB group (mean: 60.8 days [BH group] vs. 33.3 days [HB group], p = 0.015). BH group patients delivered earlier than HB group patients significantly (mean: 27.3 weeks [BH group] vs. 35.6 weeks [HB group], p = 0.0028). The frequency of chronic abruption and oligohydramnios sequence (CAOS) was significantly higher in the BH group than in the HB group (3/15; 20.0% [BH group] vs. 0/41; 0.0% [HB group], p = 0.016). The frequency of sever fetal distress (Apgar score <4 points) was significantly higher in the BH group than in the HB group (4/15; 26.7% [BH group] vs. 0/41; 0.0% [HB group], p = 0.0037). The levels of factor XIII were relatively lower in the BH group than in the HB group (mean: 54.8% (n = 4) [BH group] vs. 76.1% (n = 7) [HB group], p = 0.077). CONCLUSION: The order of the symptoms, bleeding first, is an important feature that reflects the subsequent prolonged duration of SCHs/vaginal bleeding, resulting in very early preterm delivery. Continuous hemorrhage consumes coagulation factor XIII, which further worsen the hemostasis.

The effect of celecoxib for treatment of preterm labor on fetuses during the second trimester of pregnancy: A pilot case series.

OBJECTIVE: Although cyclooxygenase inhibitors effectively suppress uterine contraction, constriction of the fetal ductus arteriosus (DA) and oligohydramnios are major concerns. Celecoxib, a selective cyclooxygenase 2 inhibitor, is a potential potent tocolytic agent, but there are no studies that have evaluated the beneficial or adverse effects of celecoxib use on fetuses for more than 48 hours in pregnant women. We therefore aimed to evaluate the effect of middle-long-term celecoxib administration on the fetus during the second trimester of pregnancy, particularly in terms of fetal DA and amniotic fluid volume. MATERIALS AND METHODS: We retrospectively extracted and reviewed data from patients with preterm labor who received celecoxib for tocolysis for more than 48 hours between 2016 and 2020. Celecoxib was used for tocolysis only when treatment of patients with conventional tocolytic agents was ineffective. Data on the peak systolic velocity in ductus arteriosus (PSV-DA) and the maximum vertical pocket (MVP) were collected. RESULTS: A total of 15 patients were eligible. The median gestational age at celecoxib introduction was 22.6 weeks, and the median period of administration was 9 days (range 3-40 days). The median gestational age at delivery was 27.1 weeks, and the median duration from initial celecoxib administration to delivery was 40 days. The Z scores of PSV-DA and MVP did not change significantly after celecoxib administration. During administration, PSV-DA exceeded the 95th percentile of the corresponding normal reference range in three cases, but the levels returned to normal after reduction or discontinuation of treatment. There was no oligohydramnios during the treatment. CONCLUSION: Celecoxib administration for more than 48 hours in the second trimester of pregnancy might be safe and tolerable in terms of fetal PSV-DA and amniotic fluid volume as long as careful ultrasound monitoring is performed. Celecoxib could be an alternative for preterm labor when conventional tocolysis is not effective.

Chronic abruption-oligohydramnios sequence (CAOS) revisited: possible implication of premature rupture of membranes.

AIM: The pathogenic mechanism of chronic abruption-oligohydramnios sequence (CAOS) remains unknown, and there are no objective standards for diagnosis on imaging or using pathological evidence. We aimed to reconsider and clarify the true pathology of CAOS by integrating clinical, magnetic resonance imaging (MRI) and histopathological findings of the placenta. MATERIAL AND METHODS: This is a case series of patients with CAOS managed at our hospital between 2010 and 2020. The clinical data of the patients, including MRI findings and placental pathology, were reviewed retrospectively. RESULTS: A total of 18 patients were eligible. Preterm birth occurred in 17 (94%) cases; the median gestational age at delivery was 25. Three neonates (17%) died within two years, and 10 neonates (56%) developed chronic lung disease. MRI was performed in 13 cases and clearly showed intrauterine hematoma and hemorrhagic amniotic fluid. Pathologically, in all cases, retroplacental hematoma was not detected, and fetal membranes were extremely fragile and ragged. Shedding and necrosis of the amniotic epithelium was a characteristic finding, which was confirmed in 17 cases (94%). Diffuse chorionic hemosiderosis (DCH) was detected in all cases. CONCLUSIONS: The fundamental cause of CAOS is repeated intrauterine hemorrhage and subsequent subchorionic hematoma, which induces hemorrhagic amniotic fluid and DCH. Consequently, these factors result in the necrosis and weakening of the amnion. Therefore, the true pathology of CAOS is believed to be premature rupture of membranes rather than chronic abruption.

Predictive factors for flares of established stable systemic lupus erythematosus without anti-phospholipid antibodies during pregnancy.

PURPOSE: To identify predictors of systemic lupus erythematosus (SLE) flares during pregnancy in patients previously considered to be at low risk. MATERIALS AND METHODS: The retrospective cohort study included 54 singleton pregnancies, managed between 2005 and 2019, involving maternal diagnosed SLE at a low disease activity (SLE Disease Activity Index ≤4) for ≥12 months before conception and without anti-phospholipid antibodies. Pregnancy outcomes were compared between patients who had SLE exacerbations during pregnancy (flare group, n = 21) and patients that did not have a flare (non-flare group, n = 33). RESULTS: The flare group had shorter gestational durations (p = .01), lower birth weights (p = .02), and a higher risk of emergent cesarean section (p = .002) compared with the non-flare group. The flare group demonstrated higher doses of prednisone (p = .04) at the time of conception as well as an increased rate of low 50% hemolytic complement (CH50) activity (p = .03) in the first trimester compared to the non-flare group. A decision tree drawn using a prednisone dose ≥10.5 mg/day and a low CH50 predicted SLE flares with a net accuracy of 78%. CONCLUSIONS: A prednisone dose ≥10.5 mg daily and CH50 hypocomplementemia in early pregnancy are useful in the early detection of patients at a high risk of SLE exacerbation.

Three-dimensional human placenta-like bud synthesized from induced pluripotent stem cells.

Placental dysfunction is related to the pathogenesis of preeclampsia and fetal growth restriction, but there is no effective treatment for it. Recently, various functional three-dimensional organs have been generated from human induced-pluripotent cells (iPSCs), and the transplantation of these iPSCs-derived organs has alleviated liver failure or diabetes mellitus in mouse models. Here we successfully generated a three-dimensional placental organ bud from human iPSCs. The iPSCs differentiated into various lineages of trophoblasts such as cytotrophoblast-like, syncytiotrophoblast-like, and extravillous trophoblast-like cells, forming organized layers in the bud. Placental buds were transplanted to the murine uterus, where 22% of the buds were successfully engrafted. These iPSC-derived placental organ buds could serve as a new model for the study of placental function and pathology.

Guideline for Gynecological Practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2020 edition.

Nine years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 4th Revised Edition was published in 2020. The 2020 Guidelines includes 4 additional clinical questions (CQ), which brings the total to 99 CQ (12 on infectious disease, 29 on oncology and benign tumors, 29 on endocrinology and infertility and 29 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

Comparison of Cerebral Blood Flow Patterns in Patients with Phantom Bite Syndrome with Their Corresponding Clinical Features.

BACKGROUND: Phantom bite syndrome (PBS) is characterized by an uncomfortable sensation during occlusion without any evident abnormality. A recent case-control study with single-photon emission computed tomography (SPECT) using 99mTc-ethyl cysteinate dimer could not find the specific features of regional cerebral blood flow (rCBF), which might be due to the heterogeneity of PBS. We analyzed the brain images of PBS corresponding to the clinical features by studying PBS subgroups. METHODS: This study contributes to elucidating the pathophysiology of PBS by evaluating regional brain perfusion on SPECT and its clinical features. We performed SPECT using 99mTc-ethyl cysteinate dimer in 44 patients with PBS. The SPECT images were analyzed qualitatively and quantitatively. RESULTS: Asymmetrical rCBF patterns were detected, corresponding to symptom laterality. Patients with PBS with right-side symptoms showed right-side-predominant rCBF asymmetry in the parietal region and left-side-predominant rCBF asymmetry in the thalamus, and vice versa. Moreover, the analysis of the association between rCBF and patient behaviors revealed that patients who blamed their dentists for their symptoms tended to have a symmetrical rCBF pattern. CONCLUSION: Patients with PBS showed blood flow imbalance in the thalamus and parietal region corresponding to symptom laterality. There are two types of symmetrical and asymmetrical rCBF patterns in the pathophysiology of PBS despite similar clinical manifestations.

Conservative management for retained products of conception after less than 22 weeks of gestation.

AIM: The aim of the study was to investigate the efficacy of conservative treatment in cases of retained products of conception (RPOC) with a preceding pregnancy of less than 22 weeks and to assess whether serum beta-human chorionic gonadotropin (hCG) levels could be a useful index to monitor the progress of treatment. METHODS: This is a case series of patients with RPOC developed after less than 22 weeks of gestation and managed expectantly with serial serum hCG measurement between 2011 and 2017. The clinical data of subjects were reviewed retrospectively. Cases that did not require invasive treatment such as surgery were designated as conservative management success. RESULTS: A total of 19 cases were eligible: 14 miscarriages and 5 induced abortions. Eleven patients underwent dilatation and curettage. The diagnosis of RPOC was made 35 (8-80) days after abortion. All patients were successfully treated with conservative management. Serum hCG levels at diagnosis were 29.6 (3.2-1585) mIU/mL. Serial measurement of serum hCG was continued until the levels became lower than the cutoff value, and the mean duration to hCG disappearance was 67.5 (6-183) days. In all cases, RPOC vanished spontaneously 77 (27-184) days after diagnosis. The disappearance of RPOC in the uterine cavity was subsequent to a significant decrease in serum hCG. Once serum hCG levels reached the cutoff value, no bleeding episodes were observed. CONCLUSION: Conservative management for RPOC might be acceptable and effective. Furthermore, serial serum hCG levels reflect the activity of RPOC, and hCG may be a reliable index to monitor the progress of treatment.

New era of trophoblast research: integrating morphological and molecular approaches.

Many pregnancy complications are the result of dysfunction in the placenta. The pathogenic mechanisms of placenta-mediated pregnancy complications, however, are unclear. Abnormal placental development in these conditions begins in the first trimester, but no symptoms are observed during this period. To elucidate effective preventative treatments, understanding the differentiation and development of human placenta is crucial. This review elucidates the uniqueness of the human placenta in early development from the aspect of structural characteristics and molecular markers. We summarise the morphogenesis of human placenta based on human specimens and then compile molecular markers that have been clarified by immunostaining and RNA-sequencing data across species. Relevant studies were identified using the PubMed database and Google Scholar search engines up to March 2020. All articles were independently screened for eligibility by the authors based on titles and abstracts. In particular, the authors carefully examined literature on human placentation. This review integrates the development of human placentation from morphological approaches in comparison with other species and provides new insights into trophoblast molecular markers. The morphological features of human early placentation are described in Carnegie stages (CS), from CS3 (floating blastocyst) to CS9 (emerging point of tertiary villi). Molecular markers are described for each type of trophoblast involved in human placental development. We summarise the character of human trophoblast cell lines and explain how long-term culture system of human cytotrophoblast, both monolayer and spheroid, established in recent studies allows for the generation of human trophoblast cell lines. Due to differences in developmental features among species, it is desirable to understand early placentation in humans. In addition, reliable molecular markers that reflect normal human trophoblast are needed to advance trophoblast research. In the clinical setting, these markers can be valuable means for morphologically and functionally assessing placenta-mediated pregnancy complications and provide early prediction and management of these diseases.

Differences in the Clinical Characteristics of Persistent Idiopathic Facial Pain (Atypical Odontalgia) Patients with or Without Neurovascular Compression of the Trigeminal Nerve.

BACKGROUND: Persistent idiopathic facial pain (PIFP) is the unexplained pain along the territory of the trigeminal nerve, including nonorganic tooth pain called atypical odontalgia (AO). Though PIFP is debilitating to patients' livelihood and well-being, its pathophysiology remains poorly understood. Although neurovascular compression (NVC) of the trigeminal nerve is known to be associated with trigeminal neuralgia (TN), the relationship between NVC and other orofacial pains has not been fully elucidated. METHODS: In this study, we investigated the differences in the characteristics of PIFP (primarily AO) patients in the presence or absence of NVC. A retrospective analysis was performed on data from 121 consecutive patients who had been diagnosed with unilateral PIFP according to the criteria of the International Classification of Headache Disorders (ICHD)-3 and underwent magnetic resonance imaging scans of the head. RESULTS: In the group without NVC, characteristic findings were significant for psychiatric morbidity, somatization, and pain disability, when compared with the group with NVC. Furthermore, the group without NVC exhibited significant headache, noncardiac chest pain, shortness of breath, and pain catastrophizing. CONCLUSIONS: These results suggest that PIFP patients can be divided into two groups: one consistent with a neuropathic pain phenotype when NVC is present and a functional somatic symptom phenotype when presenting without NVC. Our findings may enable a more precise understanding of pathophysiology of PIFP and lead to better treatment strategies.

Comorbid depressive disorders and left-side dominant occlusal discomfort in patients with phantom bite syndrome.

BACKGROUND: Phantom bite syndrome (PBS) is characterised by occlusal discomfort without corresponding dental abnormalities. Despite repeated, failed dental treatments, patients with PBS persist in seeking bite correction. PBS has been regarded as a mental disorder. However, we have reported that PBS patients with a dental trigger tend to have less psychiatric history than those without. Hence, the symptoms of PBS cannot be explained by a mental disorder alone, and it is unclear if mental disorders affect occlusal sensation. OBJECTIVE: To elucidate the pathophysiology of PBS, we analysed the dental history, PBS symptom laterality and psychiatric history of patients. METHODS: In this retrospective study, we reviewed outpatients with PBS who presented at our clinic between April 2012 and March 2017. Their medical records were reviewed for demographic data, medical history and laterality of occlusal discomfort. RESULTS: Approximately half of the 199 enrolled patients had bilateral occlusal discomfort. In the others, the side with occlusal discomfort generally tended to be the one that had received dental treatment. There was no significant relationship between the side chiefly affected by occlusal discomfort and whether dental treatment had been received; however, the affected side differed depending on whether the patient had comorbid psychiatric disorders (P = .041). CONCLUSIONS: The distributions of the side with symptoms of PBS were different between those with and without comorbid psychiatric disorders, suggesting that psychiatric disorders might affect occlusal sensation due to a subtle dysfunction in brain areas central to sensory integration. Central dysfunction might play an important role in PBS.

Placental Sonic Hedgehog Pathway Regulates Fetal Growth via the IGF Axis in Preeclampsia.

CONTEXT: Placental dysfunction is the underlying cause of common major disorders of pregnancy, such as fetal growth restriction and preeclampsia. However, the mechanisms of placental dysfunction are not entirely elucidated. We previously reported 10 reliable preeclampsia pathways based on multiple microarray data sets, among which was the sonic hedgehog (SHH) pathway. In this study, we describe the significant role of SHH signaling involved in placental development and fetal growth. DESIGN: The placental expression levels of surrogate markers of the SHH pathway, patched homolog 1 (PTCH1) and glioma-associated oncogene homolog (GLI) 2, were evaluated using quantitative real-time PCR, western blot analysis, and immunohistochemistry. We investigated the underlying mechanisms of the SHH pathway in trophoblast syncytialization, a critical process for placental development and maturation, using primary cytotrophoblasts. Moreover, the potential roles of placental SHH signaling in the regulation of the IGF axis were explored by pathway analysis of microarray data. Finally, the influence of SHH signaling on fetal growth was examined by placental administration of cyclopamine, an SHH pathway inhibitor, to pregnant mice. RESULTS: The SHH pathway was downregulated in preeclampsia placentas, and its activation was highly correlated with birth weight. Trophoblast syncytialization was modulated by noncanonical SHH-adenylate cyclase (ADCY) signaling rather than canonical SHH-GLI signaling. The IGF1 receptor pathway was regulated by both noncanonical SHH-ADCY signaling and canonical SHH-GLI signaling. Inhibition of placental SHH signaling significantly reduced fetal weight in mice. CONCLUSION: Placental development and fetal growth were regulated through the SHH pathway via the IGF axis.