This study was approved by the Local Ethical Committee. Written informed consent for publication of their clinical details and clinical images was obtained from our patient.

BackgroundBetamimetics 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 presentationA 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.ConclusionsThis case report serves as a warning regarding the potential risk of neonatal rebound hyperkalemia in association with maternal long-term ritodrine administration.

Pulse wave velocity (PWV) reflects blood pulse pressure. We attempted to determine whether commercially marketed ultrasound machine can accurately measure the PWV of the descending aorta of the human fetus. Thirty-two singleton pregnant women participated. Eight women (tocolysis group) were given ritodrine hydrochloride, and the other 24 women (normal group) were not. The descending aorta of the fetus was depicted in the longitudinal direction. Two distant sample volumes were set, and two Doppler waveforms were simultaneously obtained. The distance between the two sample volumes was divided by the time interval between the start of the two waveforms, and a PWV value was obtained. (1) Scatter diagrams for the gestational week and PWV were made, and a linear regression analysis was determined. (2) The PWV for the normal group was compared with the PWV for a group described in a previous report, one measured using ultrasonic phased-tracking. (3) The PWV values in the tocolysis group were compared with those in the normal group. (1) Significant correlations between PWV and gestational weeks were not found. (2) The mean (SE) of the PWV was 2.1 (0.12) m/s, which was similar to the PWV (2.2 (0.069) m/s) measured with ultrasonic phased-tracking. (3) The mean (SE) of the PWV (2.6 (0.25) m/s) in the tocolysis group was larger than that in the normal group (p = 0.032). The PWV of the descending fetal aorta could be accurately and conveniently measured with a commercially marketed ultrasound machine. In addition, PWV measurement with dual Doppler technique had ability to detect fetal cardio-vascular changes by ritodrine infusion.

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. 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. 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. 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.

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.

Background: Preterm labor is a serious cause of neonatal morbidity and mortality. This study aims to compare the effects of nifedipine, Magnesium sulfate and ritodrine as tocolytic drugs in patients presented with threatened preterm labor. Patients and Methods: The current study was randomized controlled trial conducted in Sohag Teaching Hospital between November 2015 and September 2016. Patients were divided into: Group A: 101 patients received intravenous ritodrine infusion; Group B: 101 patients received intravenous magnesium sulfate; Group C: 101 patients received oral nifedipine. Different maternal and neonatal outcomes were assessed. Results: The baseline criteria were homogenous among the study groups with no statistically significant differences. There is no difference between each other group regarding the need for additional tocolysis or the rate of recurrence of labour pains. Nifedipine was associated with the least length of hospital stay. There is no difference between all groups regarding the rate of preterm delivery before full steroid dose (p > 0.05). However, nifedipine group was the least one in the rate of occurrence of preterm delivery within 7 days from initiation of tocolytic therapy. Similarly, nifedipine group was associated with higher gestational age at delivery and significant prolongation of pregnancy than the other groups. Conclusion: Oral nifedipine use was associated with less recurrence of labor pains, less need for additional tocolysis, less duration of hospital stay, and more patient satisfaction in patients with threatened preterm labour.

Background: Spontaneous preterm labor (SPTL) and preterm birth (PTB), is the single most important cause of perinatal mortality and morbidity in high-income countries despite the enormous efforts over the past several decades. Preterm labor is defined as regular, painful, frequent uterine contractions causing a progressive effacement and dilatation of the cervix occurring before 37 completed weeks of gestation. Many drug therapies were used as tocolytics in cases of preterm labor, however none of them proved to be the best. The present study was performed to compare three of the used drugs for tocolysis to assess their efficacy and side effects on the mother and fetus. Aim: The aim of this study is to compare the effect of oral nifedipine, intravenous ritodrine infusion and magnesium sulfate infusion used as tocolytics in cases of preterm labour on Doppler parameters of fetal umbilical and middle cerebral artery and to evaluate their effects on the mother and the fetus in order to choose the safest and the most effective drug. Methodology: This study was held in the period from December 2014 to october 2015 on 90 patients attended and admitted from the Casualty Unit of the Obstetric Department In Elsayed Glal University Hospital with preterm labor pains , intact membranes, singleton pregnancy between 28 and completed 34 weeks gestation. All patients had been dated accurately with a gestational age based on the last menstrual period and if available a corresponding second trimester ultrasound report performed before 20 weeks gestation. Treatment continued until contractions stopped for 24 hours, maximum doses were attained without response; unacceptable side effects occurred or labor proceeded. Successful treatment was defined as cessation of contractions observed for 24 hours and no further cervical changes. Patients with successful treatment were put under observation for another 24 hours without additional treatment then discharged on no maintenance therapy. Results: Maternal tachycardia, palpitation and dyspnea were more common in the ritodrine group with (p-value = 0.000). The present study showed increase in umbilical artery PI after treatment in the magnesium sulfate group only which was statistically significant (P value = 0.016). The study showed statistically significant increase in middle cerebral artery PI after treatment in magnesium sulfate group with a P value=0.000 and statistically significant decrease in middle cerebral artery with nifedipine group with P value=0.027. When comparing the cerebroplacental ratio before and after treatment in the three groups; the study showed significant increase in cerebroplacental ratio after treatment in the magnesium sulfate group with P value = 0.000, which is statistically significant. This suggests that nifedipine could be used as a safer alternative to ritodrine and magnesium sulfate. Conclusion: In our study, nifedipine therapy was not associated with a significant change in maternal systolic and diastolic blood pressure after 24h, with minor insignificant effect on maternal heart rate. Fetal heart rate was not affected after therapy. Fetal Doppler study found no clinically significant effect on the pulsatility index (PI) of umbilical and middle cerebral artery, while with magnesium sulfate therapy there was increase in cerebro- placental ratio 24hr after treatment, these findings ensure safety of the drugs on the maternal and fetal aspects.

In this case report, we report the anesthetic management of an emergency cesarean section of a parturient who presented with preterm labor and had inadvertently received rapid intravenous administration of ritodrine.

A 36-year-old parturient with a suspicion of placenta accreta under tocolytic therapy with ritodrine infusion underwent emergency cesarean section under general anesthesia with propofol, ketamine, and remifentanil because massive bleeding was anticipated. The ritodrine infusion was discontinued 1 h before cesarean section. The baby was delivered 6 min after induction of anesthesia. However, after the manual removal of the placenta from the uterus, the bleeding was massive and uncontrollable. We rapidly transfused crystalloid, colloid, and red blood cells through potassium removal filter. Hyperkalemia (5.8 mmol/L) was detected just before blood transfusion. One hour later, hemostasis was still difficult, and hyperkalemia was promoted (6.1 mmol/L). Thus, glucose insulin therapy started with intravenous furosemide to treat hyperkalemia. Gynecologists decided to induce the Bakri balloon tamponade for the treatment of postpartum hemorrhage. At the end of surgery, plasma potassium level also reduced to 5.5 mmol/L. In the ICU, the bleeding still continued, and then radiologists performed bilateral internal iliac artery embolization for full hemostasis. Postoperative plasma potassium level was stable and 3.3 mmol/L in the next morning. Although one of the common adverse reactions of ritodrine is hypokalemia, we should also beware of a rebound hyperkalemia after its cessation.

Successful treatment with granulocyte-colony stimulating factor for ritodrine-induced neutropenia in a twin pregnancy

Background: Ritodrine is a drug used for threatened premature labor. The severe adverse drug reactions associated with ritodrine are known to be pneumonedema, leukopenia, and rhabdomyolysis, but there have been few investigations on the risk factors. We performed a case-control study and selected case reports as a case group and healthy pregnant women in clinical practice as a control group. Methods: We extracted the onsets of pneumonedema, leukopenia, and rhabdomyolysis associated with ritodrine from case reports in Japan as a case group. We selected healthy pregnant women with ritodrine administration in clinical practice as a control group. We investigated their age, medical history; Pregnancy Induced Hypertension (PIH), multiple pregnancies, concomitant drugs administered, and maximum rate of ritodrine infusion, and examined the association with those factors with the onset of adverse drug reactions by logistic regression analysis. Results: The results of the case group showed: pneumonedema (28 cases); leukopenia (25 cases); rhabdomyolysis (21 cases). The risk factors significantly associated with pneumonedema are a medical history of the cardiovascular system, PIH, multiple pregnancy, and concomitant treatment with steroids, which all match with the precautions in ritodrine’s package insert. The factors associated with leukopenia are its administration longer than 7 days and the concomitant treatment with Mg. The factors associated with rhabdomyolysis are multiple pregnancies and a concomitant treatment with Mg. Conclusion: Risk factors for the onset of pneumonedema match the descriptions in the ritodrine package insert, and can be explained by pharmacological actions. Thus, this study could elucidate the risk factors for rare adverse drug reactions limited to pregnant women. The onsets of leukopenia and rhabdomyolysis were caused by physiological changes by pregnancy and its progression of disease state and ritodrine’s pharmacological action, and were suggested the possibility of risk factors.

Strip of the Month: January 2014

Objective: To evaluate the effects of ritodrine on the maternal and fetal blood flow. Material and Methods: Eighty-six women in the 28-35 week of pregnancy were included in the study. Doppler wave forms were recorded from maternal uterine and fetal umblical and middle cerebral artery before and after the treatment with ritodrine. Results and Conclusion: Ritodrine infusion caused a decrease in S/D ratio of uterine and umblical artery Doppler. There was no effect on the middle cerebral artery.

Pulmonary Edema Complicating Ritodrine Infusion in a Patient with Premature Labor

Objectives. We evaluated the efficacy of magnesium sulfate as a second-line tocolysis for 48 hours. Materials and Methods. A multi-institutional, simple 2-arm randomized controlled trial was performed. Forty-five women at 22 to 34 weeks of gestation were eligible, whose ritodrine did not sufficiently inhibit uterine contractions. After excluding 12 women, 33 were randomly assigned to either magnesium alone or combination (ritodrine and magnesium). The treatment was determined as effective if the frequency of uterine contraction was reduced by 30% at 48 hours of the treatment. Results. After magnesium sulfate infusion, 90% prolonged their pregnancy for >48 hours. Combination therapy was effective in 95% (18/19), which was significantly higher than 50% (7/14) for magnesium alone. Conclusion. This randomized trial revealed that combination therapy significantly reduced uterine contractions, suggesting that adjuvant magnesium with ritodrine is recommended, rather than changing into magnesium alone, when uterine contractions are intractable with ritodrine infusion.

A 27-year-old nulligravida woman without a history of dermatosis was hospitalized for threatened preterm labor at 29 weeks' gestation; therefore, continuous infusion of ritodrine hydrochloride was started. At 31 weeks' gestation, erythematous plaques appeared and spread over the body surface; therefore, a topical steroid preparation was applied. At 32 weeks' gestation, the eruptions developed into irregular annular areas of erythema with multiple pustules accompanied by severe itching, and oral prednisolone treatment was started. Bacterial cultures of the pustules were negative, and a crural cutaneous biopsy revealed Kogoj's spongiform pustules. Based on the clinicopathological findings, the most likely diagnosis was impetigo herpetiformis, which causes cutaneous symptoms closely resembling pustular psoriasis in pregnant females without a history of psoriasis. To rule out ritodrine-induced pustular eruptions, the ritodrine infusion was stopped and treatment with an MgSO(4) preparation was started at 33 weeks' 3 days' gestation; however, the uterine contractions could not be suppressed. Because of the patient's highly edematous, severely painful feet, a cesarean section was performed the same day. Within several days of delivery, the eruptions began to resolve, and no recurrence was observed after treatment with oral prednisolone was stopped 31 days after delivery. On the basis of a positive patch test for ritodrine, we diagnosed pustular drug eruptions caused by ritodrine hydrochloride. Although ritodrine-induced pathognomonic cutaneous eruptions are rare, we would like to emphasize that ritodrine can cause drug-induced pustular eruptions distinctly resembling life-threatening impetigo herpetiformis.

The effects of ritodrine hydrochloride on maternal and fetal arterial blood pH and pCO2, plasma electrolytes and maternal plasma glucose and free fatty acid levels were investigated in the third-trimester pregnant sheep. Ritodrine produced a slight fall in the maternal and fetal arterial pH without changes in the arterial pC02. The pH values were, however, within a normal range. Increases in the maternal plasma glucose and free fatty acid levels were also observed. Although maternal and fetal plasma sodium and chloride concentrations did not change, the potassium decreased in a dose-dependent manner both in the ewe and in the fetus following sequential ritodrine infusion. Constant infusion of ritodrine (3 mcg/kg/min), which is a sufficient dose to inhibit uterine contractions, also resulted in a significant decrease in the maternal plasma potassium concentration. It appears to be necessary to give attention to the metabolic effects of ritodrine in long-term therapy of premature labor.

IntroductionRespiratory failure may develop during the later stages of pregnancy and is usually associated with tocolysis or other co-existing conditions such as pneumonia, sepsis, pre-eclampsia or amniotic fluid embolism syndrome.Case presentationWe present the case of a 34-year-old healthy woman with a twin pregnancy at 31 weeks and 6 days who experienced acute respiratory failure, a few hours after administration of tocolysis (ritodrine), due to preterm premature rupture of the membranes. Her chest discomfort was significantly ameliorated after the ritodrine infusion was stopped and a Cesarean section was performed 48 hours later under spinal anesthesia; however, 2 hours after surgery she developed severe hypoxemia, hypotension, fever and mild coagulopathy. The patient was intubated and transferred to the intensive care unit where she made a quick and uneventful recovery within 3 days. As there was no evidence for drug- or infection-related thromboembolic or myocardial causes of respiratory failure, we conclude that our patient experienced a rare type of non-fatal amniotic fluid embolism.ConclusionIn spite of the lack of solid scientific support for our diagnosis, we conclude that our patient suffered an uncommon type of amniotic fluid embolism syndrome and we believe that this report highlights the need for extreme vigilance and a high index of suspicion for such a diagnosis in any pregnant individual.

We report on three pregnant women with ritodrine-induced neutropenia who were successfully treated with granulocyte-colony stimulating factor (G-CSF). The neutropenia occurred after continuous intravenous infusion of ritodrine for preterm labor. Ritodrine was discontinued and G-CSF was administered. Neutrophil counts returned to normal an average of 4.3 days after the administration. No infectious morbidity or adverse side-effects occurred in the mothers or infants. G-CSF is one possible treatment in women with ritodrine-induced neutropenia.

The efficacy of maternal administration of ritodrine in cases of congenital atrioventricular block (CAVB), especially with fetal heart failure, is not yet determined. At 21 2/7 weeks of gestation, isolated CAVB with a ventricular/atrial rate of 55-70/130-140 bpm was found in a fetus from a 30-year-old Japanese nulliparous woman with anti-SSA antibody. Cardiothoracic area ratio (CTAR) was 40% and no fetal hydrops was observed. At 30 2/7 weeks, the ventricular rate decreased to 49 bpm with an atrial rate of 125 bpm. CTAR increased to 53.8% and ascites appeared. Maternal continuous ritodrine infusion was started with rapid improvement of fetal cardiac function; increment in the ventricular rate to 57 bpm and atrial rate to 137 bpm, with a decrement in CTAR to 44.6%. Ascites also gradually decreased and by the fourth day, it had completely disappeared with CTAR of 40.2%. On the 12th day after ritodrine treatment (32 1/7), amniotic fluid volume decreased and fetal weight gain stopped, which led us to assume a worsening intrauterine environment, and cesarean section was performed. A 1,178 g male infant was born with a 5-min Apgar score of 8. Continuous isoproterenol infusion was started, increasing the ventricular rate from 71 to 80 bpm. Pacemaker implantation is under consideration to treat this infant. Maternal administration of ritodrine not only increased the fetal heart rate but also ameliorated the signs of fetal heart failure, and thus is considered one treatment of choice in CAVB.