COVID-19 during pregnancy could potentially affect placental function.

OBJECTIVE: COVID-19 is an ongoing pandemic and has been extensively studied. However, the effects of COVID-19 during pregnancy, particularly on placental function, have not been verified. In this study, we used blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) to evaluate whether COVID-19 incidence during pregnancy has any lasting effects with respect to placental oxygenation. METHODS: This is a case-control study, in which eight cases of singleton pregnancies before 30 weeks gestation with COVID-19 mothers were included. Placental oxygenation was evaluated using BOLD-MRI after 32 weeks of gestation. BOLD-MRI was consecutively performed under normoxia (21% O2), hyperoxia (100% O2), and normoxia for 4 min each. Individual placental time-activity curves were evaluated to calculate the peak score (peakΔR2*) and the time from the start of maternal oxygen administration to the time of peakΔR2* (time to peakΔR2*). Eighteen COVID-19-free normal pregnancies from a previous study were used as the control group. RESULTS: No significant differences were found between the two groups regarding maternal background, number of days of delivery, birth weight, and placental weight. The parameter peakΔR2* was significantly decreased in the COVID-19 group (8 ± 3 vs. 5 ± 1, p < .001); however, there was no significant difference in time to peakΔR2* (458 ± 74 s vs. 471 ± 33 s, p = .644). CONCLUSIONS: In this study, BOLD-MRI was used to evaluate placental oxygenation during pregnancy in COVID-19-affected patients. COVID-19 during pregnancy decreased placental oxygenation even post-illness, but had no effect on fetal growth; further investigation of the possible effects of COVID-19 on the fetus and mother is warranted.

Comparative study of the usefulness of risk score assessment in the early stages of COVID-19 affected pregnancies: Omicron variant versus previous variants.

AIM: To evaluate the utility of the risk score in assessing the current status and prognosis of COVID-19 in pregnancy. METHODS: Seventy-seven cases affected before the Omicron variant epidemic and 50 pregnant cases affected by the Omicron variant were included. The risk score consists of maternal background, current condition, and examination findings. We determined the risk score in the early stages of disease onset. RESULTS: There were no significant differences in the maternal or gestational ages between the groups. The risk score was significantly lower in the After-Group patients (those affected during the Omicron epoch), while 14.3% of the Before-Group patients (those affected during the pre-Delta and Delta epochs), experienced a worsening of disease after the visit to the center, whereas none of the After-Group patients did. The Before Group's frequency of risk score items was higher among the two groups for "fever for ≥48 h," "mild pneumonia image," and "blood tests," whereas "disease onset 14 days after the second vaccination" was increased in After Group. The blood test parameters for platelet count, C-reactive protein, and D-dimer levels were not significantly different between the groups. CONCLUSIONS: The risk score system appeared superior in detecting deteriorating cases. There were no cases of post-illness deterioration in the After-Group, suggesting that cases of the Omicron variant in pregnancy may have had a less severe course compared to that of previous variants. However, there was no significant difference between the groups in terms of a specific blood test evaluation, suggesting the need for a combined evaluation of cases affected during pregnancy.

Evaluation of the tolerability of monoclonal antibody therapy for pregnant patients with COVID-19.

AIM: To evaluate the tolerability of casirivimab and imdevimab (CAS/IMB) therapy in pregnant women with COVID-19 in Japan and its impact on the neonate and process of delivery. METHODS: Eight cases of pregnancy complicated by COVID-19 and requiring hospitalization during the delta variant epidemic were included. Gestational age, initial symptoms, pregnancy complications and outcome, severity of illness, blood test findings at the time of treatment initiation and on days 3-5 after administration, body temperature at administration, and 8, 24, and 48 h post-administration, delivery outcome, and neonatal findings were recorded. Ten pregnant women who required hospitalization at the same time and did not receive CAS/IMB were used as controls. RESULTS: Of the eight cases, seven were mild, and one case was of moderate severity. Body temperature in the CAS/IMB group was significantly higher at 8 h post-administration than that at the time of administration. However, body temperature significantly reduced at 24 and 48 h post-administration in the CAS/IMB group compared with that in the control group. There were no apparent adverse events after CAS/IMB administration. CONCLUSIONS: Maternal administration of CAS/IMB was safe. Although it was difficult to evaluate the improvement in disease by blood test findings, the fever improved within 24 h, which suggests rapid improvement in patient condition.

Perinatal outcome in case of maternal death for cerebrovascular acute disorders: a nationwide study in Japan.

OBJECTIVE: The goal of this study is to find clues to improve perinatal outcomes in the case of cerebrovascular acute disorders during pregnancy. STUDY DESIGN: We analyzed 35 cases of cerebrovascular diseases related to maternal deaths in Japan those that occurred during pregnancy and reported to the Committee of the Ministry of Health, Labor, and Welfare from 2010 to 2018. RESULTS: Cerebrovascular acute disorders occurred at 34.6 ± 6.6 gestational weeks. There were seven intrauterine fetal deaths (IUFD), and eight cases showed neonatal asphyxia with umbilical arterial pH between 6.7 and 7.0 (asphyxia cases, n = 15). In two of eight newborns, brain hypothermia therapy was given, and all survived without neurological sequelae. Maternal dyspnea was significantly related to severe prolonged decelerations of the fetus (p < .05), and asphyxia cases (p < .005). Median time from maternal onset to delivery (OD time) was significantly longer in asphyxia cases than in the non-asphyxia cases (84 vs 29 min, p < .05). OD time over 30 min was significantly related to the antepartum occurrence, cervical dilatation <5 cm (p < .05), onset outside of the hospital (p < .001), and maternal transfer before delivery (p < .001). CONCLUSION: More than 40% of cases experienced fetal asphyxia, and 20% ended in IUFD in maternal deaths related to cerebrovascular acute disorders. Maternal respiratory support and rapid delivery would be the keys to improve perinatal outcomes in case of cerebrovascular acute disorders during pregnancy.

Analysis of preventability of malignancy-related maternal death from the nationwide registration system of maternal deaths in Japan.

Objective: We reviewed malignancy related maternal deaths in Japan to ascertain if there were avoidable factors.Methods: Malignancy-related maternal death in Japan reported to the Maternal Death Exploratory Committee, from 2010 to 2016 inclusive.Results: There were 12 cases of maternal death caused by malignancy. There were four gastric cancers (two poorly differentiated adenocarcinoma, one signet ring cell carcinoma with adenocarcinoma, one histology not available), 3 leukemia (two acute myeloid leukemia, one aggressive NK cell leukemia), two ureteral cancers (histology not available), one malignant lymphoma (diffuse large B-cell lymphoma with translocation), one brain tumor (gliomatosis cerebri), and one cervical cancer (glassy cell carcinoma). Two gastric cancer patients had chronic gastric pain before conception. In two cases the physicians commented that they had avoided computed tomography and the brain biopsy needed for diagnosis because the patient was pregnant. At diagnosis, the clinical stages were II-IV in 9, and the performance status was 3-5 in 8. Indication for delivery was exacerbated maternal condition in 5, for treatment in 3, spontaneous labor in 3, and one patient declined elective delivery. Median [interquartile rage] (range) gestational weeks of delivery was 29 [24-30] (19-40). One cervical cancer patient had a radical hysterectomy and chemotherapy for 10 months. However, three leukemia and one gastric cancer patients had chemotherapy within 10 d because they deteriorated rapidly. Another seven cases did not have any treatment because of poor general condition or because they remained undiagnosed. In all cases, the Committee considered that there was no evidence of substandard care.Conclusion: In these cases, both the clinical stages and biological degree of malignancy were high. In two-thirds of cases, early termination of the pregnancy was indicated because of deteriorating maternal condition. Chemotherapy was not effective because of short available time for therapy and the advanced stage of the cancers when diagnosed. Encouraging women to have a thorough medical assessment before conception, and early diagnosis and treatment before pregnancy, appears to be the only practical way to reduce deaths from malignancy while a woman is pregnant.

Evaluation of Maternal and Neonatal Outcomes of Assisted Reproduction Technology: A Retrospective Cohort Study.

BACKGROUND: To evaluate maternal and neonatal outcomes of assisted reproductive technology (ART). MATERIALS AND METHODS: Pregnant women registered from 2015 through 2017 (n = 6994) at five perinatal centers that managed high-risk pregnancies in Mie, Japan, retrospectively. Rates of preterm birth (<37 gestational weeks), early onset preeclampsia (<34 gestational weeks), late onset preeclampsia (≥34 gestational weeks), low-lying placenta, placenta previa, placenta accreta, placental abruption, atonic bleeding, uterine rupture, and amniotic fluid embolism after ART were evaluated. ART was defined as in vitro fertilization and micro-fertilization. Fisher's exact test, Mann-Whitney's U test, and logistic regression analysis were used to analyze the data. RESULTS: Rates of obstetrical complications including low-lying placenta, placenta previa, placenta accreta, and atonic bleeding were increased with ART compared to those with the control. Particularly, ART was associated with a significantly increased rate of placenta accreta (adjusted odds ratio: 7.35, 95% confidence interval (CI): 3.20-16.6) and significantly decreased rate of placental abruption (adjusted odds ratio: 0.24, 95% CI: 0.07-0.61). CONCLUSIONS: This study showed that ART may reduce placental abruption and increase placenta previa. There is a possibility that the placenta attaches deeper in the myometrium because of ART.

Safety trial of tadalafil administered for the treatment of preeclampsia.

Purpose: The aim of this study is to evaluate the safety of clinical usage of tadalafil in women with preeclampsia.Materials and methods: Maternal, fetal, and neonatal adverse events were closely examined in eight preeclampsia patients receiving tadalafil treatment.Results: There were no maternal adverse events associated with 10 mg/day of tadalafil. Even at 20 mg/day, only grade 1 headaches in two cases and grade 1 palpitation in one case were observed, which resolved spontaneously within 3 days. At a dose of 40 mg/day, there was only one case of grade 1 headache. All these adverse events were grade 1 and spontaneously resolved within 3 days. There were no fetal adverse events. All observed neonatal adverse events were thought to be caused by prematurity and not related to tadalafil.Conclusion: This study shows that tadalafil treatment for preeclampsia is deemed sufficiently tolerable. Although there was a dose-dependent increase in maternal adverse events, all the adverse events were mild and deemed to be safe for the mother and fetus at all dosages.

Cardiac function and tadalafil used for treating fetal growth restriction in pregnant women without cardiovascular disease.

BACKGROUND: The aim of the present study was to evaluate tadalafil for the treatment of fetal growth restriction (FGR) and the cardiac function in pregnant women without cardiovascular disease who used tadalafil for this reason. MATERIALS AND METHODS: We examined nine pregnant women without cardiovascular disease who were using tadalafil to treat FGR. Maternal heart rate, systolic blood pressure (BP), and echocardiographic findings were assessed before and after tadalafil use. RESULTS: Diastolic BP was lower after compared to that before using tadalafil, but the difference was not significant. Echocardiographic findings were not significantly different before and after tadalafil use. CONCLUSIONS: Tadalafil did not adversely affect pregnant women without cardiovascular disease and was considered acceptable for use since it did not affect the mother's cardiac function.

Placental growth factor as a predictor of the efficacy of tadalafil treatment for fetal growth restriction.

Purpose: We recently demonstrated the efficacy of tadalafil treatment for fetal growth restriction (FGR). This study aimed to evaluate the utility of serum placental growth factor (PlGF) level for predicting the efficacy of tadalafil for the treatment of FGR. Materials and methods: The correlations between serum level of PlGF and fetal growth velocity were retrospectively assessed in nine pregnant women receiving tadalafil for FGR before 30 weeks' gestation. Results: Median gestational age was 26 weeks (range 26-28 weeks), and median deviation of estimated fetal weight from standard weight was -2.1 standard deviations (SD) (-2.2 to -1.9 SD) at the beginning of tadalafil treatment. The median serum PlGF level was 227 pg/ml (40.2-427.0 pg/ml) before tadalafil treatment and 278 pg/ml (66.2-729.5 pg/ml) more than 2 weeks after initiation of tadalafil treatment (median gestational week at measurement of PlGF after treatment, 33 weeks [28-33 weeks]). The median fetal growth velocity from enrollment to birth was 17.5 g/day (12.1-20.3 g/day). Maternal serum PlGF levels were increased after tadalafil treatment in all nine cases (median increase in PlGF, 73.1 pg/ml [26.0-281.5 pg/ml]). Notably, maternal serum PlGF level before tadalafil treatment significantly correlated with fetal growth velocity (R2 = 0.63, p < .01). Conclusions: Tadalafil treatment may increase maternal serum PlGF levels. Our results suggest that maternal serum PlGF levels can be used as a predictor of the efficacy of tadalafil treatment for FGR.

Analysis of preventability of hypertensive disorder in pregnancy-related maternal death using the nationwide registration system of maternal deaths in Japan.

Objective: Hypertensive disorder of pregnancy (HDP) is a major cause of maternal death. The goal of this study was to investigate factors associated with maternal death due to HDP. Study design: HDP-related maternal deaths in Japan reported to the Committee of the Ministry of Health, Labor and Welfare from 2010 to 2015 were examined. Results: Out of 47 cases of HDP, 30 were identified as the major cause of maternal death. The median maternal age was 34 years (range 24-45) and the mortality in women aged ≥40 years was seven times higher that than in women aged <34 years. The etiologies were intracerebral hemorrhage (n = 22), subarachnoid hemorrhage (n = 3), subcapsular hematoma of the liver (n = 2), peripartum cardiomyopathy (n = 2), and eclampsia (n = 1), and 19 cases were deemed preventable. The most frequent antepartum problems were delays in hospitalization, maternal transfer, and termination of pregnancy. In four cases, diagnosis of HELLP syndrome was too late because laboratory data were not checked, despite the patient reporting epigastric pain or showing elevation of blood pressure (BP). Treatment for lowering of BP was improper in 2/3 intrapartum cases, even though BP was elevated during pregnancy (144 versus 188 mmHg, p < .001). There was inadequate lowering of BP and lack of use of magnesium sulfate in 7/11 postpartum cases (64%), despite aspartate aminotransferase (AST) (p < .005), alanine aminotransferase (ALT) (p < .01), lactate dehydrogenase (LDH) (p < .005), and platelet count (PLT) (p < .01) all significantly worsening after delivery. Conclusion: HDP accounts for 11% of maternal deaths in Japan. Mothers aged ≥40 years are most at risk for HDP-related maternal death. Major concerns for preventabilities were late hospitalization, maternal transportation, and termination of pregnancy for term or near-term HDP. Regular vital checks and prompt lowering of BP were lacked during labor in most cases. HELLP syndrome should be managed at a general hospital with sufficient medical resources.

Relationship between reproductive medicine for women with severe complications and maternal death in Japan.

AIM: To investigate the influence of reproductive medicine in maternal death cases in Japan. METHODS: This retrospective study investigated the incidence of maternal deaths related to reproductive medicine in Japan from 2013 to 2015, and the relationship between fertility treatment and maternal death. RESULTS: Fifteen out of 134 women (11.2%) involved in this study who underwent treatment for infertility died. Four experienced pregnancy with severe maternal complications (26.6%). The complications were active systemic lupus erythematosus, exacerbated depression, uncontrolled arrhythmia and uncontrolled type 2 diabetes mellitus. At least three of these four died due to these complications. CONCLUSION: The maternal death rate of women who have undergone fertility treatment is similar to the birth rate due to assisted reproductive technology in Japan. Some maternal death cases involve severe uncontrolled complications. Therefore, medical histories should be evaluated before fertility treatment.

The most common causative bacteria in maternal sepsis-related deaths in Japan were group A Streptococcus: A nationwide survey.

The present retrospective study provides an in-depth analysis of the maternal sepsis-related deaths reported in Japan, and aims to guide future care regarding maternal sepsis. This is a nationwide, retrospective, descriptive cohort study. Data were retrospectively analyzed on all maternal death cases related to sepsis reported in Japan from 2010 through 2016. A total of 7,347,727 births and 317 maternal deaths were reported during the study period. The cause of maternal death was sepsis in 24 women (7.5%). Causative bacteria were Streptococcus pyogenes (54.2%), Chlamydia psittaci (8.3%), Mycobacterium tuberculosis (8.3%), Escherichia coli (4.2%), Neisseria meningitidis (4.2%), Epstein-Barr virus (4.2%), and unknown (16.6%). In maternal death due to S. pyogenes (13 women), onset periods ware antepartum in 10 women (76.9%) and postpartum in 3 (23.1%); death within 24 h after hospital admission occurred in 7 women (53.8%); and the median time from hospital admission to death was 12 h (6-744 h). The most common causative bacteria in to maternal sepsis-related death were GAS. When encountering severe sepsis during the peripartum period, we recommend considering severe GAS infection and early intervention.

TADAFER II: Tadalafil treatment for fetal growth restriction - a study protocol for a multicenter randomised controlled phase II trial.

INTRODUCTION: There is no proven therapy to reverse or ameliorate fetal growth restriction (FGR). Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, has been reported to potentially play a therapeutic role in FGR, but this has not been established. Tadalafil is also a selective PDE5 inhibitor. We have demonstrated the efficacy of tadalafil against FGR along with short-term outcomes and the feasibility of tadalafil treatment. Based on the hypothesis that tadalafil will safely increase the likelihood of increased fetal growth in FGR, we designed this phase II study to prospectively evaluate the efficacy and safety of tadalafil against FGR. METHODS AND ANALYSIS: This study is a multicentre, randomised controlled phase II trial. A total of 140 fetuses with FGR will be enrolled from medical centres in Japan. Fetuses will be randomised to receive either the conventional management for FGR or a once-daily treatment with 20 mg of tadalafil along with the conventional management until delivery. The primary endpoint is fetal growth velocity from the first day of the protocol-defined treatment to birth (g/day). To minimise bias in terms of fetal baseline conditions and timing of delivery, a fetal indication for delivery was established in this study. The investigator will evaluate fetal baseline conditions at enrolment and will decide the timing of delivery based on this fetal indication. Infants will be followed up for development until 1.5 years of age. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board of Mie University Hospital and each participating institution. Our findings will be widely disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBER: UMIN000023778.

Grafting Neural Stem and Progenitor Cells Into the Hippocampus of Juvenile, Irradiated Mice Normalizes Behavior Deficits.

The pool of neural stem and progenitor cells (NSPCs) in the dentate gyrus of the hippocampus is reduced by ionizing radiation. This explains, at least partly, the learning deficits observed in patients after radiotherapy, particularly in pediatric cases. An 8 Gy single irradiation dose was delivered to the whole brains of postnatal day 9 (P9) C57BL/6 mice, and BrdU-labeled, syngeneic NSPCs (1.0 × 105 cells/injection) were grafted into each hippocampus on P21. Three months later, behavior tests were performed. Irradiation impaired novelty-induced exploration, place learning, reversal learning, and sugar preference, and it altered the movement pattern. Grafting of NSPCs ameliorated or even normalized the observed deficits. Less than 4% of grafted cells survived and were found in the dentate gyrus 5 months later. The irradiation-induced loss of endogenous, undifferentiated NSPCs in the dentate gyrus was completely restored by grafted NSPCs in the dorsal, but not the ventral, blade. The grafted NSPCs did not exert appreciable effects on the endogenous NSPCs; however, more than half of the grafted NSPCs differentiated. These results point to novel strategies aimed at ameliorating the debilitating late effects of cranial radiotherapy, particularly in children.

Carbamylated Erythropoietin Decreased Proliferation and Neurogenesis in the Subventricular Zone, but Not the Dentate Gyrus, After Irradiation to the Developing Rat Brain.

Cranial radiotherapy for pediatric brain tumors causes progressive, debilitating late effects, including cognitive decline. Erythropoietin (EPO) has been shown to be neuroprotective and to promote neuroregeneration. Carbamylated erythropoietin (CEPO) retains the protective properties of EPO but is not erythrogenic. To study the effects of CEPO on the developing brain exposed to radiotherapy, a single irradiation (IR) dose of 6 Gy was administered to the brains of postnatal day 9 (P9) rats, and CEPO (40 µg/kg s.c.) was injected on P8, P9, P11, P13, and P15. To examine proliferation, 5-Bromo-2-deoxyuridine (BrdU) was injected on P15, P16, and P17. CEPO administration did not affect BrdU incorporation in the granule cell layer (GCL) of the hippocampus or in the subventricular zone (SVZ) as quantified 7 days after the last BrdU injection, whereas IR decreased BrdU incorporation in the GCL and SVZ by 63% and 18%, respectively. CEPO did not affect BrdU incorporation in the GCL of irradiated brains, although it was reduced even further (to 31%) in the SVZ. To evaluate the effect of CEPO on neurogenesis, BrdU/doublecortin double-positive cells were quantified. CEPO did not affect neurogenesis in non-irradiated brains, whereas IR decreased neurogenesis by 58% in the dentate gyrus (DG) but did not affect it in the SVZ. In the DG, CEPO did not affect the rate of neurogenesis following IR, whereas in the SVZ, the rate decreased by 30% following IR compared with the rate in vehicle-treated rats. Neither CEPO nor IR changed the number of microglia. In summary, CEPO did not promote neurogenesis in non-irradiated or irradiated rat brains and even aggravated the decreased neurogenesis in the SVZ. This raises concerns regarding the use of EPO-related compounds following radiotherapy.

Practical use of C1 esterase inhibitor concentrate for clinical amniotic fluid embolism.

Amniotic fluid embolism (AFE) causes consumption coagulopathy, which requires a massive transfusion to save the mother's life. The preparation of such a massive transfusion is too time-consuming in extremely emergent clinical settings and occasionally leads to devastating side effects such as transfusion-associated acute lung injury. C1 esterase inhibitor (C1INH) is a protein with the ability to inhibit complement, coagulation and kinin pathways. The C1INH concentration in AFE patients is low, and it has been speculated that the administration of C1INH concentrate could have a striking and beneficial effect on AFE patients in critical condition by ameliorating their perturbed coagulation system. We report the case of a 32-year-old Japanese AFE patient in whom deteriorated vital signs and coagulopathy recovered within minutes after an injection of C1INH concentrate. C1INH concentrate can quickly revive the deteriorated vital signs and the atonic uterus that stem from AFE and may reduce the total amount of transfusion.

Analysis of maternal death autopsies from the nationwide registration system of maternal deaths in Japan.

OBJECTIVE: To clarify the necessity for and problems related to autopsy for determining the cause of maternal death in Japan. METHODS: Women who died during pregnancy or within a year after delivery were analyzed by the Maternal Death Exploratory Committee between 2012 and 2015 in Japan. Maternal deaths were analyzed to verify the requirement of autopsy in cases in which autopsy was performed and the need for autopsy in cases in which it was not performed. RESULTS: Among the 49 cases performed autopsy, the final diagnosis was compatible with the clinical course in 24 cases, while the autopsy diagnosis was incompatible with the clinical course in 13 cases. In two cases, the final diagnosis was based on the clinical course, but an autopsy could exclude other possible causes. In three cases, no exact cause of maternal death was identified after autopsy. On the other hand, in cases without an autopsy, the final diagnosis was made using ante-mortem operating findings and surgical specimens in twenty-one cases. Though, thirty-one cases were estimated diagnosis based on post-mortem imaging or ante-mortem examinations, the exact original cause of death was not determined in 25 cases, and the cause of death could not be identified in eight cases without autopsy. CONCLUSION: Because in most cases the autopsy provides an exact cause of death, the necessity of autopsies should be more widely accepted in Japan.

Analysis of preventability of stroke-related maternal death from the nationwide registration system of maternal deaths in Japan.

OBJECTIVE: The number of stroke-related maternal deaths is increasing in Japan. We investigated methods to reduce maternal death from stroke. METHODS: We analyzed stroke-related maternal deaths in Japan reported to the Committee of the Ministry of Health, Labor, and Welfare from 2010 to 2014 inclusive. RESULTS: A total of 35 cases were identified. The median maternal age was 35 years (range 22-45) and the incidence of stoke in women ≥40 was seven-fold higher than in <34. Etiologies were pregnancy induced hypertension in 16, subarachnoid hemorrhage in seven, cerebral infarction in three, arteriovenous malformation in two, Moyamoya disease in one, and origin unknown cerebral hemorrhage in six. These cases occurred in antepartum 43%, in postpartum 31%, and in intrapartum 26%. 23 cases were deemed non-preventable and 12 cases preventable. Possible preventable factors occurred antepartum in 23, postpartum in seven, and intrapartum in six. Preventable features included inadequate hypertension control (33%), presenting too late for termination of pregnancy (14%), delayed hospitalization (11%), and delayed maternal transfer (11%). CONCLUSIONS: A total of 90% of strokes were hemorrhagic, and older mothers (≥ 40) were most at risk. Most possible preventable factors occurred antepartum, and improved control of hypertension and earlier termination would help to reduce maternal death from stroke.

Tadalafil Improves L-NG-Nitroarginine Methyl Ester-Induced Preeclampsia With Fetal Growth Restriction-Like Symptoms in Pregnant Mice.

BACKGROUND: We investigated the efficacy and mechanisms of tadalafil, a selective phosphodiesterase 5 inhibitor, in treating preeclampsia (PE) with fetal growth restriction (FGR) using L-NG-nitroarginine methyl ester (L-NAME)-induced PE with FGR in pregnant mice as our experimental model. METHODS: C57BL/6 mice were divided into 2 groups 11 days postcoitum (d.p.c.). A control group of dams (C dam) received 0.5% carboxymethylcellulose (CMC). A L-NAME-treated group received 1 mg/ml L-NAME dissolved in CMC. The L-NAME-treated dams were divided into 2 subgroups 13 d.p.c. One subgroup continued to receive L-NAME (L dams). The other subgroup received L-NAME with 0.08 mg/ml tadalafil suspended in CMC (TL dams). Maternal systolic blood pressure (SBP) and proteinuria were assessed 16 d.p.c. Fetal weight was recorded, and placentas and maternal kidneys were collected 17 d.p.c. RESULTS: Maternal SBP, proteinuria, and fetal weight were improved for TL dams compared to L dams. The placental concentration of placental growth factor (PlGF) was higher for TL dams than for the C and L dams. The placental maternal blood sinuses of L dams were narrower than those of C dams, but those of TL dams improved to a similar width as C dams. Glomerular oxidative stress was ameliorated in TL dams compared to L dams. CONCLUSIONS: Tadalafil dilates the placental maternal blood sinuses, which leads to increase PlGF production, and contributes to facilitate fetal growth and improve maternal SBP. Moreover, tadalafil ameliorates glomerular damage by reducing oxidative stress. These results suggest that tadalafil is a candidate for treatment of PE with FGR.