Impacts of Tocolytics on Maternal and Neonatal Glucose Levels in Women With Gestational Diabetes Mellitus.

BACKGROUND: We investigated the impacts of tocolytic agents on maternal and neonatal blood glucose levels in women with gestational diabetes mellitus (GDM) who used tocolytics for preterm labor. METHODS: This multi-center, retrospective cohort study included women with GDM who were admitted for preterm labor from twelve hospitals in South Korea. We excluded women with multiple pregnancies, anomalies, overt DM diagnosed before pregnancy or 23 weeks of gestation, and women who received multiple tocolytics. The patients were divided according to the types of tocolytics; atosiban, ritodrine, and nifedipine group. We collected baseline maternal characteristics, pregnancy outcomes, maternal glucose levels during hospitalization, and neonatal glucose levels. We compared the frequency of maternal hyperglycemia and neonatal hypoglycemia among three groups. A multivariate logistic regression analysis was performed to evaluate the contributing factors to the occurrence of maternal hyperglycemia and neonatal hypoglycemia. RESULTS: A total of 128 women were included: 44 (34.4%), 51 (39.8%), and 33 (25.8%) women received atosiban, ritodrine, and nifedipine, respectively. Mean fasting blood glucose (FBG) (112.3, 109.6, and 89.5 mg/dL, P < 0.001) and 2-hour postprandial glucose (PPG2) levels (145.4, 148.3, and 116.5 mg/dL, P = 0.004) were significantly higher in atosiban and ritodrine group than those in nifedipine group. Even after adjusting for covariates including antenatal steroid use, gestational age at admission, and pre-pregnancy body mass index, there was an increased risk of high maternal mean FBG (≥ 95 mg/dL) and PPG2 (≥ 120 mg/dL) levels in the atosiban and ritodrine group than in nifedipine group. The atosiban and ritodrine groups are also at increased risk of neonatal hypoglycemia (< 47 mg/dL) compared to the nifedipine group with the odds ratio of 4.58 and 4.67, respectively (P < 0.05). CONCLUSION: There is an increased risk of maternal hyperglycemia and neonatal hypoglycemia in women with GDM using atosiban and ritodrine tocolytics for preterm labor compared to those using nifedipine.

Association Between Atopic Dermatitis in Pregnant Women and Preterm Births: The Japan Environment and Children's Study.

OBJECTIVES: This study aimed to evaluate the association between atopic dermatitis in pregnant women and preterm births, accounting for maternal ritodrine hydrochloride administration status. METHODS: Data of 83,796 women with singleton pregnancies at and after 22 weeks of gestation (enrolled between 2011 and 2014) were analyzed. These data were obtained from the Japan Environment and Children's Study. Atopic dermatitis was defined based on self-reported questionnaire responses obtained during the first trimester. The primary outcome measures were preterm births before 37, 32, and 28 weeks of gestation. Using a multivariable logistic regression model, odds ratios for preterm births in pregnant women with atopic dermatitis were calculated, with women without atopic dermatitis included in the reference group. This analysis considered confounding factors and maternal ritodrine hydrochloride administration. RESULTS: Among pregnant women with atopic dermatitis, the adjusted odds ratios (95% confidence intervals) for preterm births before 37, 32, and 28 weeks of gestation were 0.89 (0.81-0.98), 0.98 (0.74-1.30), and 0.88 (0.50-1.55), respectively. This trend remained consistent after excluding participants who received ritodrine hydrochloride. CONCLUSIONS FOR PRACTICE: Atopic dermatitis in pregnant women was significantly associated with a decreased incidence of preterm births before 37 weeks of gestation, even after accounting for the effects of maternal ritodrine hydrochloride administration.

Relationship between maternal mortality and ritodrine hydrochloride as a tocolytic agent in Japan.

AIM: In Japan, unlike Western countries, tocolytic agents are administered in long-term protocols to treat threatened preterm labor. Evaluating the side effects of this practice is crucial. We examined whether ritodrine hydrochloride had been administered in cases of maternal death, aiming to investigate any relationship between ritodrine administration and maternal death. METHODS: This retrospective cohort study used reports of maternal deaths from multiple institutions in Japan between 2010 and 2020. Data on the reported cases were retrospectively analyzed, and data on the route of administration, administered dose, and clinical findings, including causes of maternal death, were extracted. The amount of tocolytic agents was compared between maternal deaths with ritodrine administration and those without. RESULTS: A total of 390 maternal deaths were reported to the Maternal Death Exploratory Committee in Japan during the study period. Ritodrine hydrochloride was administered in 32 of these cases. The frequencies (n) and median doses (range) of oral or intravenous ritodrine hydrochloride were 34.4% (11) and 945 (5-2100) mg and 84.4% (27) and 4032 (50-18 680) mg, respectively. Frequencies of perinatal cardiomyopathy, cerebral hemorrhage, diabetic ketoacidosis, and pulmonary edema as causes of maternal death were significantly higher with ritodrine administration than without it. CONCLUSIONS: Our results suggest a relationship between long-term administration of ritodrine hydrochloride and an increased risk of maternal death due to perinatal cardiomyopathy, cerebral hemorrhage, diabetic ketoacidosis, and pulmonary edema. In cases where ritodrine should be administered to prevent preterm labor, careful management and monitoring of maternal symptoms are required.

Risks of maternal cardiopulmonary events associated with ritodrine for tocolysis: A national database linkage study in 1 831 564 pregnant women.

OBJECTIVE: Real-world data on cardiopulmonary events among pregnant women receiving ß-agonist therapy are scarce. In the present study, we aimed to examine the absolute and relative risks of maternal cardiopulmonary events associated with the use of ß-agonist ritodrine during pregnancy. METHODS: By linking Taiwan's National Birth Certificate Application Database with National Health Insurance data, 1 831 564 pregnancies at ≥20 weeks' gestation were identified. Age-standardized incidence rates of cardiopulmonary events among pregnant women exposed to ritodrine were estimated. Nested case-control analyses were conducted to evaluate the relative risk of pulmonary edema, heart failure, and arrhythmia associated with prior ritodrine use. Cases and controls were matched using risk set sampling, and adjusted odds ratios were estimated using conditional logistic regression models. RESULTS: A total of 189 cases of pulmonary edema, 126 cases of heart failure, and 162 cases of arrhythmia were identified (corresponding age-standardized incidence rates: 20.90, 8.35, and 16.63 per 100 000 among pregnant women only exposed to oral ritodrine; 91.28, 36.01, and 14.61 per 100 000 among those ever exposed to intravenous ritodrine). Exposure to oral ritodrine was associated with a lower increased risk of pulmonary edema (aOR 1.76; 95% CI: 1.12-2.76) and arrhythmia (2.21; 1.47-3.32) whereas exposure to ritodrine injection was associated with a significantly higher risk of pulmonary edema (10.56; 6.39-17.45), arrhythmia (4.15; 1.99-8.64), and heart failure (5.58; 2.27-13.74). CONCLUSIONS: Pregnant women receiving intravenous ritodrine therapy had higher cardiopulmonary risks and should be intensively monitored. While the relative risk associated with oral ritodrine is not pronounced, it should be used judiciously among pregnant women as well.

A singleton pregnancy with placental chorioangioma and hydrops fetalis complicated with mirror syndrome and ritodrine-induced side effects: a case report.

BACKGROUND: Ritodrine hydrochloride is a widely used beta-adrenergic agonist used to stop preterm labor in Taiwan. Many side effects causing maternal morbidity and mortality have been reported. We report a case complicated with ritodrine-induced side effects and mirror syndrome that was associated with placental chorioangioma. CASE PRESENTATION: A 36-year-old singleton pregnant woman at 25 6/7 weeks of gestation, with an undiagnosed placental chorioangioma, underwent tocolysis due to preterm uterine contractions. Her clinical condition deteriorated, attributed to mirror syndrome and adverse events induced by ritodrine. An emergency cesarean section was performed at 27 1/7 weeks of gestation, delivering an infant with generalized subcutaneous edema. A placental tumor measuring 8.5 cm was discovered during the operation, and pathology confirmed chorioangioma. Gradual improvement in her symptoms and laboratory data was observed during the postpartum period. Identifying mirror syndrome and ritodrine-induced side effects poses challenges. Therefore, this case is educational and warrants discussion. CONCLUSION: Our case demonstrates mirror syndrome induced by chorioangioma, which is rare, and ritodrine-induced side effects. The cessation of intravenous ritodrine and delivery are the best methods to treat maternal critical status due to fluid overload.

Neonatal hyperkalemia associated with maternal ritodrine: A retrospective study.

BACKGROUND: We recently reported on a late preterm infant born at 36 weeks' gestation with serious arrhythmia due to hyperkalemia associated with long-term maternal ritodrine administration. It is unknown whether ritodrine alone increases the risk of neonatal hyperkalemia in infants born at 34-36 weeks' gestation. METHODS: This single-center, retrospective, cohort study enrolled late preterm infants (34-36 gestational weeks) born between 2004 and 2018. Cases with maternal magnesium sulfate use were not sufficient for statistical analysis and so were excluded from the study. Risk factors for the occurrence of hyperkalemia were determined based on clinical relevance and previous reports. RESULTS: In all, 212 late preterm infants with maternal ritodrine use and 400 infants without tocolysis were included in the study. Neonatal hyperkalemia occurred in 5.7% (12/212) in the ritodrine group and 1.8% (7/400) in the control group. The risk of neonatal hyperkalemia was significantly increased by maternal ritodrine administration with a crude odds ratio (OR) of 3.37 (95% confidence interval [CI]: 1.30-8.69; p < 0.01) and an adjusted OR of 3.71 (95% CI: 1.41-9.74; p < 0.01) on multivariable analysis. Long-term tocolysis (≥28 days) with ritodrine increased the risk of neonatal hyperkalemia with 9.3% (11/118) of infants developing hyperkalemia (adjusted OR 4.86; 95% CI: 1.59-14.83; p < 0.01). Neonatal hyperkalemia was not found within 2 weeks of ritodrine administration. CONCLUSION: This research suggests that late preterm infants born after long-term ritodrine administration are at risk of neonatal hyperkalemia and require special attention.

Neonatal rebound hyperkalemia associated with ritodrine alone: a case report.

BACKGROUND: Betamimetics have been used for tocolysis extensively in the past, and one of them, ritodrine is widely used in Japan. Various adverse events have been reported for this agent, including newborn hypoglycemia and hypokalemia, as well as maternal hypokalemia and rebound hyperkalemia; however, cases of neonatal rebound hyperkalemia are not described in the literature. CASE PRESENTATION: A male infant born at 36 weeks of gestation by cesarean section at a local maternity clinic suddenly entered cardiopulmonary arrest with ventricular tachycardia and fibrillation due to hyperkalemia (K+, 8.7 mmol/L). No monitoring, examination of blood electrolyte levels, or infusions had been performed prior to this event. Maternal infusion of ritodrine (maximum dose, 170 µg/min) had been performed for 7 weeks prior to cesarean section. After resuscitation combined with calcium gluconate, the infant died at 4 months old due to serious respiratory failure accompanied by acute lung injury following shock. No cause of hyperkalemia other than rebound hyperkalemia associated with ritodrine was identified. CONCLUSIONS: This case report serves as a warning regarding the potential risk of neonatal rebound hyperkalemia in association with maternal long-term ritodrine administration.

Association between maternal ritodrine hydrochloride administration during pregnancy and childhood wheezing up to three years of age: The Japan environment and children's study.

BACKGROUND: The effects of maternal ritodrine hydrochloride administration (MRA) during pregnancy on fetuses and offspring are not entirely clear. The present study aimed to evaluate the association between MRA and childhood wheezing using data from a nationwide Japanese birth cohort study. METHODS: This study analyzed the data of the participants enrolled in the Japan Environment and Children's Study, a nationwide prospective birth cohort study, between 2011 and 2014. Data of women with singleton live births after 22 weeks of gestation were analyzed. The participants were divided according to MRA status. Considering childhood factors affecting the incidence of wheezing, including smoking environment and childhood viral infections, a logistic regression model was used to calculate odds ratios for "wheezing ever," diagnosis of asthma in the last 12 months, and "asthma ever" in women with MRA, with women who did not receive MRA as the reference. Additionally, participants were stratified by term births, and odds ratios for outcomes were calculated using a logistic regression model. RESULTS: A total of 68,123 participants were analyzed. The adjusted odds ratio for wheezing was 1.17 (95% confidence interval, 1.12-1.22). The adjusted odds ratios for the other outcomes did not significantly increase after adjusting for childhood factors. The same tendency was confirmed after excluding women with preterm births. CONCLUSION: MRA was associated with a slightly increased incidence of childhood wheezing up to three years, irrespective of term or preterm birth status. It is important that perinatal physicians consider the potential effects of MRA on the offspring's childhood health.

Acute Pulmonary Edema Induced by a Low Dose of Ritodrine Hydrochloride: A Case Report.

OBJECTIVE: Acute pulmonary edema associated with ritodrine hydrochloride is a rare, life-threatening complication, and dose and duration of ritodrine use are closely associated with this pathology. We report a case of acute pulmonary edema associated with short-duration infusion of ritodrine hydrochloride in a patient with pectus excavatum as an underlying factor. CASE REPORT: A 30-year-old healthy pregnant woman was treated with oral ritodrine for tocolysis between 31 and 35 weeks of pregnancy. At 36 weeks of gestation, she went into preterm labor, with premature rupture of the membrane and breech presentation, and received an infusion of ritodrine hydrochloride for a few hours. Although she was normotensive until labor onset, mild hypertension and proteinuria were recognized. Intraoperatively, a funnel-chest deformity was observed, and she developed postoperative pulmonary edema associated with dyspnea and wet cough and confirmed on chest radiography and arterial gas analysis, and recovered with supportive care. CONCLUSION: Small-dose infusion of ritodrine hydrochloride might cause pulmonary edema in patients with underlying medical problems, including pectus excavatum.

The safety of ritodrine hydrochloride: Adverse effects on fetuses and newborns.

Prematurely born infants face unique risks, and the treatment of imminent preterm birth is thus an important part of perinatal care. Ritodrine hydrochloride (Rito) is widely used as a therapeutic agent to treat imminent preterm birth in Japan. Following assessment of the risks and benefits of short-acting ß-agonists, including Rito, in Europe, however, the use of Rito has begun to be questioned. Thus, in this study we investigated the safety of Rito in the treatment of imminent preterm birth, with a particular focus on the adverse effects (AEs) on fetuses and newborn infants. Using the Pharmaceuticals and Medical Devices Agency of Japan's Japanese Adverse Drug Event Report (JADER) database, the AEs on fetuses and newborns caused by oral and injected Rito were extracted and analyzed. The reported odds ratios for oral Rito were significantly higher for fetal tachycardia, fetal bradycardia, neonatal hypoglycemia, and neonatal heart failure than for other drugs. The reported odds ratios for Rito injection were significantly higher for fetal tachycardia and neonatal hypoglycemia than for other drugs. Oral drugs had more adverse effect reports than injectable drugs.

Noninvasive positive-pressure ventilation in pregnancy to treat acute pulmonary edema induced by tocolytic agents: a case report.

BACKGROUND: We report a case of pulmonary edema induced by tocolytic agents that was successfully managed with noninvasive positive-pressure ventilation (NPPV) and resulted in extended gestation. CASE PRESENTATION: A 36-year-old Japanese pregnant woman received tocolytic therapy with ritodrine hydrochloride, magnesium sulfate, nifedipine, and betamethasone from 28 weeks of gestation. She developed respiratory failure. and her chest X-ray showed enlarged pulmonary vascular shadows. At 29 weeks and 1 day of gestation, she was diagnosed with pulmonary edema induced by tocolytic agents. Because respiratory failure worsened 2 days after ritodrine hydrochloride and magnesium sulfate were stopped, NPPV was initiated. Her respiratory status improved and she was weaned off of NPPV after 3 days. She underwent cesarean section because of breech presentation at 30 weeks and 0 days of gestation due to initiation of labor pains. CONCLUSIONS: NPPV can be safely administered in cases of tocolytic agent-induced pulmonary edema during pregnancy.

In utero exposure to ritodrine during pregnancy and risk of autism in their offspring until 8 years of age.

Beta-2 adrenergic receptor (B2AR) agonists, used as asthma treatments and tocolytics during pregnancy, have recently been reported to be associated with autism in their offspring. However, the particular link between autism and ritodrine, a common type of B2AR agonist used solely as tocolytics, has never been substantiated with any nationwide database. Thus, we aimed to examine the association between in utero exposure of ritodrine and the risk of autism in their offspring using a national database. This population-based cohort study was conducted by merging the Korea National Health Insurance claims database and National Health Screening Program for Infants and Children database. These databases included all women who had delivered singleton between January 2007 and December 2008 in Korea. Out of the total 770,016 mothers, 30,959 (4.02%) were exposed to ritodrine during pregnancy, and 5583 (0.73%) of their children were identified as having autism, defined until 8 years of age. According to our analysis, the overall cumulative incidence of autism up to 8 years was 1.37% in ritodrine exposure group and 0.70% in ritodrine non-exposure group (p < 0.05, log-rank test). By Cox proportional hazard analysis, use of ritodrine in preterm birth was associated with significantly higher hazard of autism [adjusted hazard ratio: 1.23, 95% CI 1.04-1.47], after adjusting for confounding variables including maternal age, parity, cesarean section, preterm labor, steroid use, birth weight, gender, and preeclampsia. Thus, in utero exposure to ritodrine was associated with an increased risk of autism in their offspring.

Identifying genetic variants associated with ritodrine-induced pulmonary edema.

INTRODUCTION: Ritodrine is one of the most commonly used tocolytics in preterm labor, acting as a ß2-adrenergic agonist that reduces intracellular calcium levels and prevents myometrial activation. Ritodrine infusion can result in serious maternal complications, and pulmonary edema is a particular concern among these. The cause of pulmonary edema following ritodrine treatment is multifactorial; however, the contributing genetic factors remain poorly understood. This study investigates the genetic variants associated with ritodrine-induced pulmonary edema. METHODS: In this case-control study, 16 patients who developed pulmonary edema during ritodrine infusion [case], and 16 pregnant women who were treated with ritodrine and did not develop pulmonary edema [control] were included. The control pregnant women were selected after matching for plurality and gestational age at the time of tocolytic use. Maternal blood was collected during admission for tocolytic treatment, and whole exome sequencing was performed with the stored blood samples. RESULTS: Gene-wise variant burden (GVB) analysis resulted in a total of 71 candidate genes by comparing the cumulative effects of multiple coding variants for 19729 protein-coding genes between the patients with pulmonary edema and the matched controls. Subsequent data analysis selected only the statistically significant and deleterious variants compatible with ritodrine-induced pulmonary edema. Two final candidate variants in CPT2 and ADRA1A were confirmed by Sanger sequencing. CONCLUSIONS: We identified new potential variants in genes that play a role in cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) regulation, which supports their putative involvement in the predisposition to ritodrine-induced pulmonary edema in pregnant women.

Effects of KCNMB2 gene polymorphisms on ritodrine therapy outcomes in women with preterm labor.

OBJECTIVE: The present prospective follow-up study aimed to evaluate the effects of KCNMB2 gene polymorphisms on ritodrine efficacy and adverse drug events (ADEs) in patients with preterm labor. METHODS: A total of 163 preterm labor patients were included in this single-center study. Nine single nucleotide polymorphisms (SNPs) in the KCNMB2 gene (rs10936979, rs7624046, rs7429015, rs7625907, rs6443559, rs9839376, rs9637454, rs11918114, and rs1382045) were assessed. The primary endpoint was time to delivery, and the secondary endpoint was ritodrine-induced ADEs. RESULTS: Patients with variant homozygotes of two SNPs (rs7624046 and rs9839376), which were in linkage disequilibrium, showed 2.06 [95% confidence interval (CI), 1.14-3.73] and 2.68 (95% CI, 1.16-6.20) times the hazard of time to delivery compared to wild-type allele carriers, respectively. Among demographic characteristics, gestational age at start of drug therapy and modified Bishop score were significant factors for time to delivery. Regarding safety outcomes, patients with variant homozygotes of rs7625907 had fewer ADEs compared to those with other genotypes (odds ratio, 0.32; 95% CI, 0.13-0.83). CONCLUSION: This pharmacogenomic study suggests that ritodrine efficacy and ADEs are associated with KCNMB2 gene polymorphisms in patients with preterm labor.

Synergic interaction between ritodrine and magnesium sulfate on the occurrence of critical neonatal hyperkalemia: A Japanese nationwide retrospective cohort study.

Our aim was to evaluate the association between ritodrine and magnesium sulfate (MgSO4) and the occurrence of neonatal hyperkalemia or hypoglycemia among late preterm infants in a retrospective cohort study. We used a nationwide obstetrical database from 2014. A total of 4,622 live preterm infants born at 32-36 gestational weeks participated. Fourteen risk factors based on both clinical relevance and univariate analysis were adjusted in multivariable logistic regression analyses. Neonatal hyperkalemia and hypoglycemia occurred in 7.6% (284/3,732) and 32.4% (1,458/4,501), respectively. Occurrence of hyperkalemia was associated with concomitant usage of ritodrine and MgSO4 compared with no usage (adjusted odds ratio [aOR] 1.53, 95% confidence interval [CI] 1.09-2.15). Occurrence of hypoglycemia was associated with ritodrine alone (aOR 2.58 [CI 2.21-3.01]) and with concomitant usage of ritodrine and MgSO4 (aOR 2.59 [CI 2.13-3.15]), compared with no usage, and was associated with long-term usage (≥ 48 hours) of ritodrine and cessation directly before delivery. In conclusion, in late preterm infants, usage of ritodrine together with MgSO4 was associated with occurrence of critical neonatal hyperkalemia, and long-term usage of ritodrine and cessation directly before delivery were associated with neonatal hypoglycemia.

Influence of GRK5 gene polymorphisms on ritodrine efficacy and adverse drug events in preterm labor treatment.

The present prospective follow-up study aimed to evaluate the effects of GRK5 polymorphisms on ritodrine efficacy and adverse drug events (ADEs) in pregnant women undergoing preterm labor. A total of 162 women undergoing preterm labor were included in the study. Seven single nucleotide polymorphisms (SNPs) in the GRK5 gene (rs915120, rs2230345, rs2230349, rs7923896, rs1020672, rs4752308, and rs4752292) were assessed. Homozygous variant carriers of rs4752292 and rs1020672 had 0.6 times the hazard of delivery compared to wild-type allele carriers (95% confidence interval [CI], 0.41~0.99 and 0.38~0.99, respectively). In addition, homozygous variant carriers of rs4752292 and rs1020672 had 2.4-fold more (95% CI, 1.10~4.98) and 2.3-fold more (95% CI, 1.04~5.06) ADEs compared to those with the wild-type homozygotes, respectively. Among demographic variables, gestational age and modified Bishop score were significant factors associated with time to delivery, while body weight and maximum ritodrine infusion rate were significant factors associated with ADEs. In silico analysis showed that both rs4752292 and rs1020672 had the potential to affect mRNA splicing by alteration of splicing motifs. The present study shows that ritodrine efficacy and ADEs are associated with GRK5 gene polymorphisms in pregnant women undergoing preterm labor.

Effects of PDE4 gene polymorphisms on efficacy and adverse drug events of ritodrine therapy in preterm labor patients: a prospective observational study.

PURPOSE: Phosphodiesterase (PDE) terminates the signaling pathway of myometrial relaxation by degradating cAMP to the inactive 5'-AMP. The PDE4 family is one of the most predominant PDE families that display high affinity to cAMP. The objective of this study was to evaluate the effects of PDE4 gene polymorphisms on tocolytic effects and adverse drug events (ADEs) of ritodrine therapy in patients with preterm labor. METHODS: A total of 170 preterm labor patients were included in this study. To elucidate the effects of genetic polymorphisms on the inter-individual variability of ritodrine efficacy and ADEs, 8 single nucleotide polymorphisms (SNPs) were genotyped: PDE4D (rs1544791, rs983280, rs1504982, rs10940648, rs829259) and PDE4B2 (rs598961, rs2180335, and rs17128809). Additionally, rs1042719 of the ADRB2 gene was included for multivariate analysis. The primary endpoint of this prospective study was the time to delivery (hr). The secondary endpoint was ritodrine-induced ADEs. RESULTS: The mutant-type homozygote carriers of PDE4B2 rs598961 polymorphism showed shorter median time to delivery than those with other genotypes (adjusted hazard ratio 1.6, 95% confidence interval 1.0 to 2.4, P = 0.035). On the other hand, patients with wild-type homozygotes of PDE4B2 rs17128809 showed 2.6~2.9 times higher ADEs compared to those with other genotypes. Among demographic characteristics, gestational age at start of drug therapy and modified Bishop score were significant factors for time to delivery, whereas height, weight, and BSA were significant factors for ritodrine-induced ADEs after adjusting other factors. CONCLUSIONS: This pharmacogenomic study suggested that PDE4 genetic polymorphisms impact individual susceptibility to ß2-adrenergic receptor targeted therapy in patients with preterm labor.

Inappropriate use of ritodrine hydrochloride for threatened preterm birth in Japan: a retrospective cohort study using a national inpatient database.

BACKGROUND: No study has revealed the effectiveness of long-term tocolysis for patients diagnosed with threatened preterm birth, and the use of betamimetics in these patients has not been recommended in the United States or Europe because of the potential for severe maternal adverse effects. However, long-term tocolysis with intravenous infusion of ritodrine hydrochloride, a betamimetic, can be selected as the first-line tocolytic treatment in Japan. This study was performed to (i) examine the current status of long-term tocolytic treatment, particularly with intravenous infusion of betamimetics, for threatened preterm birth in Japan and (ii) clarify the association between long-term tocolytic treatment and maternal adverse effects. METHODS: This retrospective cohort study was conducted using a national inpatient database for acute-care inpatients in Japan. Among all pregnant women who were diagnosed with threatened preterm birth and admitted to the hospital from July 2010 to March 2016, we identified 134,959 eligible patients. The primary outcome was maternal serious adverse effects during hospitalization. A multivariable logistic regression analysis was performed to evaluate factors associated with maternal adverse effects. RESULTS: Among all patients, 17.2% received intravenous infusion of ritodrine hydrochloride for ≤48 h and 28.7% received this treatment for ≥28 days. The proportion of maternal adverse effects was significantly higher among patients treated for ≥28 days than ≤48 h. A longer duration of tocolysis was significantly associated with increased maternal adverse effects. CONCLUSIONS: Long-term tocolysis was associated with an increased incidence of maternal adverse effects in the current study using real-world data. Japanese clinicians should adjust their tocolytic treatment practices in accordance with the latest scientific evidence or make efforts to verify the effectiveness and safety of long-term tocolysis.