Management of pulmonary hemodynamics prior to delivery in a pregnant woman with development of decompensated pulmonary arterial hypertension.

Prompt termination of pregnancy in patients with decompensated pulmonary arterial hypertension (PAH) is imperative for improvement of maternal hemodynamics, but such termination may also result in maternal death due to further deterioration of PAH immediately after delivery. However, there have been limited reports on whether implementation of PAH therapy with continuation of pregnancy improves the maternal outcome, especially in treatment-naïve patients with PAH. A 24-year-old woman was admitted to our hospital with a chief complaint of dyspnea (WHO functional class IV) at 22 weeks and 3 days of gestation. She was diagnosed with PAH accompanied by right heart failure and low cardiac output. Intensive treatment was initiated with inotropic agents, oxygen therapy, and PAH therapy, resulting in improvement of her hemodynamics. A caesarean section was performed at 23 weeks and 3 days. Although her pulmonary arterial pressure transiently increased with oxygenation deteriorating immediately after delivery, worsening PAH improved without mechanical circulatory support. She continued receiving pulmonary vasodilators without relapse of pulmonary hypertension for three years. The improvement of pulmonary hemodynamics prior to delivery with PAH therapy led to a favorable outcome after delivery. Learning objective: Pulmonary hemodynamics in pregnant patients with pulmonary arterial hypertension (PAH) can deteriorate with the continuation of pregnancy, while termination can also cause PAH surge immediately after delivery. In treatment-naïve patients with PAH, who are most likely to benefit from PAH therapy, implementation of PAH therapy with continuation, even with a decompensated status, may improve the hemodynamics prior to delivery, resulting in a favorable outcome after delivery.

RETRACTED ARTICLE: Intrapartum cardiotocogram monitoring between obstetricians and computer analysis.

We, the Editors and Publisher of The Journal of Maternal-Fetal & Neonatal Medicine, have retracted the following article:Shoichi Magawa, Hiroaki Tanaka, Fumi Furuhashi, Shintaro Maki, Masafumi Nii, Kuniaki Toriyabe, Eiji Kondo & Tomoaki Ikeda; Intrapartum cardiotocogram monitoring between obstetricians and computer analysis, The Journal of Maternal-Fetal & Neonatal Medicine (Author Accepted Version), 10.1080/14767058.2019.1615876.The incorrect manuscript was provided by the authors resulting in a duplicate publication.We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions.The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as "Retracted".

Intrapartum cardiotocogram monitoring between obstetricians and computer analysis.

Purpose: To investigate the accuracy of computer analysis and its features to be used as a fu fetal heart rate (FHR) interpretation method in clinical settings.Methods: The Trium CTG Online® was used as the computer analysis software. Twenty-six cases of intrapartum FHR tracings (total time, 6900 min) were randomly selected from third-trimester pregnancies. Three obstetricians blinded to the patients' clinical information traced the decelerations, variability, and baseline cardiotocogram (CTG) data. Three obstetrician observer individually interpreted the data and only the waveforms they interpreted were adopted. The agreement between the deceleration and baseline, variability, and level of five-tier system was estimated. Weighted kappa (κ) statistics were used to assess reliability.Results: Based on the observers and Trium's classification, κ was 0.78 and the strength of agreement level was substantial. The obstetricians and Trium mostly agreed on the variability and baseline data. However, κ of each deceleration was approximately 0.65 (0.63-0.66), with substantial strength of agreement.Conclusion: Based on the obstetricians and Trium's interpretation, the latter was found to be excellent for FHR interpretation. However, it was difficult for Trium to interpret specific waveform patterns. Therefore, clinical staff should understand these characteristics to more sensitively evaluate the fetal well-being.

Phase-1 clinical study of tadalafil administered for selective fetal growth restriction in twin pregnancy.

BACKGROUND: Selective fetal growth restriction (sFGR) is a condition of twin pregnancy in which the development of one fetus is restricted, despite normal growth of the other fetus. A method of intrauterine therapy for sFGR does not currently exist. The only treatment for sFGR is to terminate the pregnancy before the FGR worsens. In twin pregnancies, maternal and intrauterine environments are common in both fetuses, thus a placental factor is considered the cause of FGR in fetuses. Tadalafil is a phosphodiesterase (PDE)-5 inhibitor that induces an increase in uterine blood flow by dilatation of blood vessels in cases of FGR with placental dysfunction, which improves FGR. PURPOSE: The aim of this study was to investigate the safety and maximum tolerated dose (MTD) of tadalafil administered for twin pregnancy (diamniotic-monochorionic twin or diamniotic-dichorionic twin). METHODS: In this phase I, open-label, dose-escalation trial, sequential patient cohorts (3 + 3 dose-escalation design) for twin pregnancy received tadalafil (20 or 40 mg/d) as a single dose by oral administration from the day they were diagnosed with sFGR, defined as estimated fetal weight (EFW) < 3% tiles, that is, -1.8 SD the mean EFW for gestational age (GA) to unacceptable toxicity or the day of delivery. This study evaluated the safety of maternally administered tadalafil for sFGR, examining maternal, fetal, and neonatal adverse events. Maternal adverse events were graded on the basis of the Common Terminology Criteria for Adverse Events v4.0. RESULTS: Six women with sFGR who were pregnant with twins were treated with tadalafil. There were no severe adverse events in either cohort, although the most common (≥3 patients) drug-related adverse events were headache and heart failure. The MTD of tadalafil among Japanese patients was 40 mg. CONCLUSIONS: Tadalafil has a manageable safety profile up to an MTD of 40 mg/d.

Tadalafil treatment for preeclampsia (medication in preeclampsia; MIE): a multicenter phase II clinical trial.

PURPOSE: To evaluate the effectiveness and safety of tadalafil treatment for hypertensive disorder of pregnancy (HDP). MATERIALS AND METHODS: In an open-label, randomized clinical trial, singleton pregnancies with HDP between 20 and 33 weeks of gestation were randomized to take 20 mg oral tadalafil every day (tadalafil treatment group) or no drug (conventional treatment group). The primary outcome was prolongation of pregnancy from randomization to delivery. However, this article primarily focuses on the safety assessments performed in the tadalafil treatment for HDP population, because the safety of using PDE5 inhibitors as therapeutic agents for fetal growth restriction (FGR) has been a problem worldwide. RESULTS: From October 2016 to March 2018, 28 patients were randomized to each group and two cases were excluded (tadalafil treatment group: 12 cases; conventional treatment group: 14 cases). The significant adverse events related to tadalafil did not occur in the tadalafil treatment group. Among maternal adverse events, specifically with regard to headaches, there were significant differences between the two groups (0% in tadalafil group versus 43% in conventional treatment group; p = .02). There was no difference in the prolongation period of pregnancy that served as primary outcomes in both the groups (17.5 d in tadalafil group versus 16.5 d in conventional group, p = .96). The significant adverse events occurred at the same frequency as between the conventional treatment group and the tadalafil treatment group. And, maternal headache decreased significantly in the tadalafil treatment group. CONCLUSIONS: Tadalafil treatment is safe for pregnant women with HDP. Moreover, tadalafil did not prolong the gestational period in pregnant women with HDP.

A literature review of herpes simplex virus hepatitis in pregnancy.

Purpose: Hepatitis due to herpes simplex virus (HSV) during pregnancy is rare, it is often not included in the differential disease. However, hepatitis leads to maternal death; hence, early diagnosis is necessary. Hepatic enzyme elevation in late pregnancy is often associated with obstetric-related diseases, such as acute gestational fatty liver and HELLP syndrome (hemolytic anemia, elevated liver enzymes, low platelet count). These pregnancy-related diseases often improve maternal condition after completion of pregnancy, but in patients with HSV hepatitis, invasive treatment, such as cesarean section, may lead to deterioration of maternal condition after completion of pregnancy. A systematic review was conducted to extract necessary factors to avoid maternal death caused by herpetic hepatitis.Methods: In 24 cases reported since 1991, age, onset gestational weeks, initial symptoms, days from onset of symptoms to consultation, diagnosis method, treatment method, maximum liver escape enzyme value during hospitalization, bilirubin value, international normalized ratio value, and fetal/neonatal prognosis were extracted, and the relationship between maternal death group (n = 6) and maternal alive group (n = 18) was statistically analyzed.Results: Fever as an initial symptom was observed in all cases. Maternal death did not occur in patients administered with acyclovir (ACV) as empiric therapy. No difference was found between the two groups in other factors.Conclusion: Early diagnosis and treatment of herpetic hepatitis during pregnancy are important, as well as administration of empiric ACV concurrently with noninvasive diagnosis when a pregnant woman has elevated liver enzyme accompanied by fever in late pregnancy.

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.

Antenatal Indomethacin Treatment for Congenital Myotonic Dystrophy.

Myotonic dystrophy is an autosomal-dominant disorder. Its congenital type is the most severe form, with respiratory failure that can be a life-threatening event after birth. There are no antenatal treatments that can improve neonatal outcomes of myotonic dystrophy. We treated a fetus with congenital myotonic dystrophy by administering indomethacin to the 31-year-old Japanese mother affected by myotonic dystrophy and polyhydramnios. We observed increased fetal breathing movement and a reduction of the amniotic fluid volume. The baby was born at 37 weeks and discharged from the neonatal intensive care unit with a favorable outcome. Indomethacin treatment is likely to improve fetal lung function and to control the amniotic fluid volume. This report emphasizes the importance of further investigations regarding the optimal management of congenital myotonic dystrophy.

Management of fetal growth restriction using the contraction stress test: a case-control study.

Purpose: Fetal growth restriction (FGR) is a concerning health issue. However, studies on FGR management are limited due to its rarity. We aimed to evaluate the efficacy of the contraction stress test (CST) for FGR management. Materials and methods: A case-control retrospective study design. Our institute innovated CST in FGR management in 2017. We included women in their 33rd-40th week of pregnancy with a diagnosis of FGR and retrospectively divided them into groups: the CST group (FGR management with CST) and no CST group (FGR management without CST) before and after CST development. Neonatal outcome, pH, and pO2 of umbilical artery (UA) were compared between the two groups. Results: No significant differences in the rate of birth weight, Apgar score <7 (5 minutes), neonatal death, hospitalization to newborn childhood intensive care unit (NICU), and UA pH were found between groups. Average UA pH was 7.29 ± 0.05 and 7.29 ± 0.04 in the CST and no CST groups, respectively (p = .864). Average UA pO2 values were 21.1 ± 8.6 and 15.7 ± 5.0 mmHg in the CST and no CST groups, respectively (p = .016), showing significant differences. Conclusions: Neonatal outcomes and UA pH were slightly different between the groups managed with and without CST. However, UA pO2 values significantly differed between the groups. For FGR management, the use of a CST may allow for early intervention before fetal acidemia and acidosis. For establishing the effects of a CST for FGR management, analysis including several cases and investigation of long-term outcomes of newborn infants is necessary.

Safety Evaluation of Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER): Results from the Phase II Trial.

Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor with a long half-life, high selectivity, and rapid onset of action. Because the safety of using PDE5 inhibitors as therapeutic agents for fetal growth restriction (FGR) has been a problem worldwide, this paper primarily focuses on the safety assessments performed in the Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER) II population. Neonatal and maternal adverse events were analyzed, in addition to fetal, neonatal, and infant death cases, six months after stopping the trial. Eighty-nine pregnant women with FGR were studied between September 2016 and March 2018 (45 and 44 in the tadalafil and conventional treatment groups, respectively). Seven (16%) deaths (four fetal, one neonatal, and two infant) in the control group, whereas only one neonatal death occurred in the tadalafil group. Although headache, facial flushing, and nasal hemorrhage occurred more frequently in the tadalafil group, these symptoms were Grade 1 and transient. In conclusion, this trial showed that tadalafil decreased the fetal and infant deaths associated with FGR. This is thought to be primarily due to pregnancy prolongation. Further studies are warranted to evaluate the efficacy of tadalafil in treating early-onset FGR.

Tadalafil treatment in mice for preeclampsia with fetal growth restriction has neuro-benefic effects in offspring through modulating prenatal hypoxic conditions.

We have demonstrated that tadalafil facilitates fetal growth in mice with L-NG-nitroarginine methyl ester (L-NAME)-induced preeclampsia (PE) with fetal growth restriction (FGR). Tadalafil is a selective phosphodiesterase 5 inhibitor that dilates the maternal blood sinuses in the placenta, thereby facilitating the growth of the fetus. The purpose of this study was to investigate the effects of tadalafil treatment for PE and FGR on the developing brain in FGR offspring using an L-NAME-induced mouse model of PE with FGR. A control group of dams received carboxymethylcellulose (CMC). L-NAME-treated groups received L-NAME dissolved in CMC from 11 days post coitum (d.p.c.). The L-NAME-treated dams were divided into two subgroups 14 d.p.c. One subgroup continued to receive L-NAME. The other subgroup received L-NAME with tadalafil suspended in CMC. Tadalafil treatment for PE with FGR reduced the expression of hypoxia-inducible factor-2α in the placenta and in the brain of the FGR fetus. Moreover, tadalafil treatment in utero shows improved synaptogenesis and myelination in FGR offspring on postnatal day 15 (P15) and P30. These results suggest that tadalafil treatment for PE with FGR not only facilitates fetal growth, but also has neuroprotective effects on the developing brain of FGR offspring through modulating prenatal hypoxic conditions.