Fetal Biometric Assessment and Infant Developmental Prognosis of the Tadalafil Treatment for Fetal Growth Restriction.

Background and Objectives: Tadalafil is expected to treat fetal growth restriction (FGR), a risk factor for stillbirth and neonatal morbidity. This study aimed to evaluate the fetal biometric growth pattern of fetuses with FGR treated with tadalafil by ultrasonographic assessment. Materials and Methods: This was a retrospective study. Fifty fetuses diagnosed with FGR and treated by maternal administration of tadalafil and ten controls who received conventional treatment at Mie University Hospital from 2015 to 2019 were assessed. Fetal biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW) at the start of treatment and at two weeks and four weeks of treatment were mainly assessed by ultrasound examination. The Wilcoxon signed-rank test was used to assess the measures. The Kyoto Scale of Psychological Development (KSPD) was used to assess the developmental prognosis on tadalafil-treated children at 1.5 years of corrected age (CA) and 3 years old. Results: The median gestational age at the start of treatment was 30 and 31 weeks in the tadalafil and control groups, respectively, and the median gestational age at delivery was 37 weeks in both groups. The Z-score of HC was significantly increased at 4 weeks of treatment (p = 0.005), and the umbilical artery resistance index was significantly decreased (p = 0.049), while no significant difference was observed in the control group. The number of cases with an abnormal score of less than 70 on the KSPD test was 19% for P-M, 8% for C-A, 19% for L-S, and 11% for total area at 1.5 years CA. At 3 years old, the respective scores were 16%, 21%, 16%, and 16%. Conclusions: Tadalafil treatment for FGR may maintain fetal HC growth and infants' neuro-developmental prognosis.

Cost effectiveness of buprenorphine vs. methadone for pregnant people with opioid use disorder.

OBJECTIVE: To assess the cost effectiveness of buprenorphine versus methadone in the management of opioid use disorder (OUD) during pregnancy. METHODS: We designed a decision-analytic model to evaluate the costs and outcomes associated with buprenorphine compared to methadone for pregnant people with OUD. We used a theoretical cohort of 22,400 pregnant people, which is an estimation of pregnancies affected by OUD per year in the United States. Outcomes included maternal retention in maintenance treatment, neonatal opioid withdrawal syndrome, preterm birth, fetal growth restriction, cerebral palsy, and maternal overdose in addition to cost and quality-adjusted life-years (QALYs). We used a willingness-to-pay threshold of $100,000/QALY. All model inputs were derived from the literature and varied in sensitivity analyses to assess the robustness of our baseline inputs. RESULTS: In our theoretical cohort, treatment of OUD with buprenorphine during pregnancy resulted in 2413 fewer cases of neonatal opioid withdrawal syndrome, 1089 fewer preterm births, 299 fewer cases of fetal growth restriction, 32 fewer stillbirths, and 13 fewer cases of cerebral palsy compared to methadone treatment. Despite lower rates of retention, buprenorphine treatment saved nearly 123 million healthcare dollars and resulted in 558 additional QALYs, making it the dominant strategy compared to methadone treatment. Our findings were robust over a wide range of assumptions. CONCLUSION: Our data suggest that buprenorphine should be considered a cost effective treatment option for OUD in pregnancy, as it is associated with improved neonatal outcomes compared to methadone despite the risk of treatment discontinuation.

Assessment of the value of measuring soluble fms-like tyrosine kinase-1 and placental growth factor levels following administration of tadalafil to treat fetal growth restriction.

PURPOSE: The aim of this study was to measure the blood levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) before and after tadalafil treatment in patients with fetal growth restriction. MATERIALS AND METHODS: Maternal blood was collected from 13 women before and 2 weeks after tadalafil administration in the TADAFER II trial. The tadalafil treatment was conducted in addition to the conventional FGR treatment. As a control, maternal blood was also collected from 11 women before and 2 weeks after conventional treatment for fetal growth restriction. Blood sFlt-1 and PlGF were measured and the sFlt-1/PlGF ratio was calculated. Student's t-test was used to statistically analyze differences in the sFlt-1 and PlGF levels, and in the sFlt-1/PlGF ratios. RESULTS: In both treatment groups, the levels of sFlt-1 and PlGF before and after treatment were not significantly different from each other. The sFlt-1/PlGF ratio was 2.0 ± 1.0 before and 17.6 ± 11.3 after treatment in the control group (p=.04). The sFlt-1/PlGF ratio was 2.2 ± 1.1 before and 22.2 ± 10.6 after tadalafil treatment in the tadalafil group (p=.06). The sFlt-1/PlGF ratios before and after tadalafil treatment were significantly increased in the control group. In both treatment groups, the sFlt-1/PlGF ratios before and after treatment were less than 38. CONCLUSIONS: We conclude that the levels of sFlt-1 and PlGF were not significantly different as a result of tadalafil treatment. Further studies are needed to understand the mechanism of action of tadalafil in the treatment of fetal growth restriction.

Antenatal glucocorticoid treatment of the growth-restricted fetus: benefit or cost?

Women at risk of preterm labor are commonly treated with antenatal glucocorticoids to reduce neonatal complications, including respiratory distress syndrome. Despite the benefits of antenatal glucocorticoid for neonatal lung function, they are associated with negative cardiovascular outcomes. Among this population, there is a group of intrauterine growth-restricted fetuses in which substrate supply is reduced and these fetuses must undergo a range of cardiovascular adaptations to survive. Interestingly, the cardiovascular changes caused by antenatal glucocorticoid in normally grown fetuses are contrary to the cardiovascular adaptations that the intrauterine growth-restricted fetus must make to survive. Hence, the possibility exists that antenatal glucocorticoid in intrauterine growth-restricted infants may compromise cardiovascular development. This review first provides an overview of general antenatal glucocorticoid effects, before outlining the effects on cardiorespiratory development in normally grown fetuses, the cardiovascular adaptations that occur in the intrauterine growth-restricted fetus and finally integrating this with the very limited evidence for the effect of antenatal glucocorticoid in intrauterine growth-restricted infants.

Growth hormone therapy.

Growth hormone (GH) therapy has revolutionized treatment of children with growth hormone deficiency (GHD). Improved height outcome with final height in the target height range has been achieved in these children. Identification of Creutzfeldt-Jakob disease, a deadly prion mediated disorder, in recipients of pituitary GH accelerated the transition from pituitary derived GH to recombinant GH. Once daily subcutaneous administration of the freeze-dried preparation at evening is the recommended mode of GH therapy. Studies have led to use of higher dose of GH for improving height outcome (0.33 mg/kg/week or 0.14 IU/kg/day) albeit at a significantly high cost. Growth velocity increases from 3-4 cm/year before therapy to 10-12 cm/year during the first two years of therapy and is maintained at 7-8 cm/year after a period of two years. Close follow-up with regular clinical and laboratory monitoring is essential for achieving a desirable height outcome. A theoretical unlimited supply has led to wide spread use of GH in a variety of disorders other than GHD. Initially started in children with Turner syndrome, GH has now been used in chronic renal failure, idiopathic short stature and intrauterine growth restriction besides a wide array of newly emerging indications.

Labor induction by vaginal misoprostol in grand multiparous women.

BACKGROUND: Grand multiparous women in poor and under-privileged settings run a high risk of uterine rupture at labor induction. The purpose was to elucidate whether vaginal misoprostol medication is a safe and cost-effective alternative induction method in grand multiparous women, in whom, under prevailing circumstances, induction by oxytocin is associated with high risk of adverse maternal outcome of pregnancy. METHOD: One hundred and sixty-five grand multiparous parturient women with five or more previous deliveries were divided into two groups. The first group (n=134) had the fetus alive and the second (n=31) had late intrauterine fetal death. Both groups were subject to induction of labor by use of vaginal misoprostol in a dose of 50 microg (live fetus) and 100 microg (intrauterine fetal death). No additional oxytocin was utilised. RESULTS: Labor induction by vaginal misoprostol was successful in grand multiparous women. The proportion of women requiring a Cesarean section was 6.0%, which is less than one third of the average Cesarean section rate in the setting studied. Women with fetus alive had significantly shorter application-to-expulsion interval (AEI) than women with fetal death (10.1 versus 15.4 hours; p=0.039). Significantly shorter AEI was recorded in women with prelabor rupture of membranes (9.1 hours) than in women with intact membranes (12.9 hours) (p=0.01). With Bishop's score > or = 5 and < 5 AEI was 8.7 hours and 14.4 hours, respectively (p=0.001). No significantly adverse neonatal or maternal outcomes of pregnancy were registered and it was specifically noted that no uterine rupture occurred among the 165 grand multiparous women induced. CONCLUSIONS: Induction of under-privileged grand multiparous women with live fetus or with fetal death can be performed safely and cost-effectively by vaginal misoprostol.