Masafumi Nii

Retrospective study of tadalafil for fetal growth restriction: Impact on maternal and perinatal outcomes

The aim of this retrospective study was to assess tadalafil treatment in pregnant women with fetal growth restriction (FGR) in terms of maternal and perinatal outcomes.

Safety and dose-finding trial of tadalafil administered for fetal growth restriction: A phase-1 clinical study

We designed a safety and dose‐finding trial of tadalafil administered for fetal growth restriction (FGR).

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.

Treatment using tadalafil for severe pre-eclampsia with fetal growth restriction

For severe pre‐eclampsia (PE) with fetal growth restriction (FGR), the only effective treatment is early delivery of the placenta. Clinicians are often forced to end the pregnancy because of maternal indications. We report a case of severe PE with FGR in which the PE was temporarily improved and pregnancy successfully prolonged with tadalafil, a phosphodiesterase 5 inhibitor. A 35‐year‐old primigravid woman presented at 27 3/7 weeks of gestation with severe PE and FGR. After commencing tadalafil administration, biochemical and angiogenic markers improved. Thereafter, hypertension and proteinuria temporarily improved. Importantly, the pregnancy was prolonged by 14 days after the initiation of tadalafil administration. Tadalafil may be a novel treatment for severe PE with FGR to prolong pregnancy.

Response to “Letter on ‘Management of pregnancy complicated with intracranial arteriovenous malformation’”

We appreciate the interest and comments of Dr. Kumari and Dr. Bhatia on our article regarding the management of pregnancies complicated by intracranial arteriovenous malformation (iAVM). In the 36 cases we reported, 15 cases had no residual iAVM at conception, so these cases were not at risk for rebleeding. Regarding the angioarchitecture for the iAVM in the other 21 cases, the location of the iAVM was superficial in 13 and deep in 8 cases. The size of the iAVMs was small (<3 cm) in 15, medium (3~6 cm) in 4 and large (>6 cm) in 2 cases. One case had an associated arteriovenous fistula, and no cases had venous stenosis. In our case series, we did not perform endovascular embolism for the treatment of ruptured iAVM. If the nidus was in an operable position, and hemorrhage occurred in the first or second trimester, the nidus was removed, and the pregnancy continued. We decided on this mode of management after multidisciplinary team review because our surgical results for iAVMs are good. Our hospital is a specialized center for cerebrovascular diseases, and we operate a 24/7 service for cerebrovascular surgery. Surgical treatment made vaginal delivery possible in the index pregnancy in nearly all cases without fear of a rebleed. In one case, the nidus was located in the brain stem and was initially inoperable, and the patient had a hemorrhage in the second trimester. To reduce the risk of further bleeding during pregnancy, which could have been fatal for the mother, delivery was induced at 17 weeks, and subsequently, gamma knife radiosurgery was performed. We agree with Dr. Kumari et al. that endovascular embolism has a promising role in palliative as well as primary treatment in the management of iAVMs, including those diagnosed in association with pregnancy. We do use this technique if there are specific indications. As mentioned before, there are no consensus guidelines for the management of iAVMs in pregnancy, and therefore, the best management is likely to be that with which the center has the most expertise. As a result, such management will vary from center to center.

Management of pregnancy complicated with intracranial arteriovenous malformation

To clarify the perinatal outcomes in pregnancy complicated with intracranial arteriovenous malformation (i‐AVM).

In utero spontaneous bladder rupture in a fetus with posterior urethral valve: A case report of prenatal diagnosis and management

Posterior urethral valve (PUV) rarely causes bladder rupture. We experienced hydronephrosis due to ureteral obstruction after the natural repair of a ruptured bladder in a fetus with PUV. Fetal ascites and oligohydramnios were diagnosed at 26 weeks’ gestational age. While we followed up with ultrasonography, we regularly removed the fetal ascites via abdominal puncture, injecting warm saline instead of amniotic fluid. At 35 weeks’ gestational age, the infant was diagnosed with severe bilateral hydronephrosis, absent of ascites and oligohydramnios. Therefore, a Caesarean section was performed. After birth, the infant was diagnosed with hydronephrosis due to ureteral obstruction after the natural repair of a ruptured bladder associated with PUV. Thus, a ruptured bladder in a fetus with PUV that has naturally repaired should be closely monitored via ultrasonography for hydronephrosis due to ureteral obstruction.

Long‐term survival of a patient with malignant transformation of extragonadal endometriosis treated solely with chemotherapy: A case report

A 52‐year‐old woman presented to our hospital complaining of genital bleeding and was found to have a 50‐mm vaginal tumor that involved the bladder, rectum, and small bowel and extended to the left pelvic side wall. Her history included a bilateral salpingo‐oophorectomy and a total abdominal hysterectomy for fibroids and endometriosis. She had been prescribed estrogen replacement therapy (1.25 mg/day) following the second surgery and continued it for 8 years. The pathology of the vaginal biopsy showed endometrioid adenocarcinoma. Total pelvic exenteration was recommended for complete resection, but she chose chemotherapy (paclitaxel 175 mg/m2 and carboplatin AUC:6). Clinical complete remission was obtained for 11 years. She had a recurrence 11 years later. She was again found to have a 5‐cm vaginal tumor. Surgical excision with upper vaginectomy was performed. The tumor was resected without invasion of the bladder, rectum and small bowel. Histologic examination of the specimen confirmed clear cell carcinoma with endometriosis. Chemotherapy may be the first‐line treatment that can preclude aggressive surgery for malignant transformation of extragonadal endometriosis. However, combined chemotherapy and surgery is necessary for this disease.

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

Abstract 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.

Safety and dose-finding trial of tadalafil administered for the treatment of preeclampsia

Abstract 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.