Comparison of perinatal outcomes between long-term and short-term use of tocolytic agent: a historical cohort study in a single perinatal hospital

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1 doi: /jog J. Obstet. Gynaecol. Res. Vol. 42, No. 12: , December 2016 Comparison of perinatal outcomes between long-term and short-term use of tocolytic agent: a historical cohort study in a single perinatal hospital Masamitsu Nakamura, Junichi Hasegawa, Tatsuya Arakaki, Shoko Hamada, Hiroko Takita, Tomohiro Oba, Keiko Koide, Ryu Matsuoka and Akihiko Sekizawa Department of Obstetrics and Gynecology, Showa University School of Medicine, Tokyo, Japan Abstract Aim: The aim of this study was to evaluate the effect of long-term use of tocolytic agents to prevent preterm delivery and improve perinatal outcome. Methods: A historical cohort study was performed in a single perinatal center. The maternal characteristics, frequency of preterm labor and prescribed dose of tocolytic agents were compared before and after changing the management protocol for threatened premature delivery. Results: A total of 1548 deliveries were carried out before changing the protocol for the use of tocolytic agents for threatened premature delivery and 1444 deliveries afterwards. There was no significant difference in the maternal characteristics before and after the revision except for maternal age. The total number of ritodrine hydrochloride ampules used was reduced from 4654 to 514, and the total vials of magnesium sulfate used were reduced from 1574 to 193, but perinatal outcomes, such as rate of preterm birth, neonatal weight, and rate of NICU hospitalization were not different between the groups. Conclusion: There was no significant change in the frequency of preterm delivery before and after changing of the protocol for threatened premature delivery. Because a decrease in the given dose of tocolytic agents did not affect the timing of delivery and neonatal outcomes, long-term tocolysis in patients with threatened premature delivery should be restricted to prevent maternal and fetal adverse side-effects. Key words: premature labor, prematurity, prenatal care, risk assessment and prevention. Introduction Tocolytic agents can delay preterm delivery during antenatal corticosteroid therapy to enable maturation of fetal organs, such as the lung, or for maternal transport to a tertiary perinatal care center in Western countries. 1 The use of tocolytic agents in patients with threatened premature delivery was restricted due to side-effects such as maternal lung edema or rhabdomyolysis. 2,3 A preventive effect of long-term tocolysis on premature delivery has not been established; therefore, it is not used in Western countries 4 and the US Food and Drug Administration (FDA) has not recommended the long-term use of tocolytics. Nevertheless, in Japan, it is believed that the long-term use of the tocolytic agent ritodrine hydrochloride and/or magnesium sulfate is useful to prevent preterm birth. This management strategy for prevention of preterm birth may be associated with the fact that the Japanese preterm delivery rate was <6% in 2007: the lowest perinatal mortality in the world. 5 Additionally, it has been reported that the frequency of side-effects of Received: January Revised: May Accepted: June Correspondence: Dr Masamitsu Nakamura, Department of Obstetrics and Gynecology, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo , Japan. mashamitsu1975@gmail.com Japan Society of Obstetrics and Gynecology

2 Perinatal outcome and tocolysis tocolytic agents was lower than the FDA recommendation. 4 Although there are no reports on the frequency of side-effects due to tocolytic agents in Japan, the frequency of side-effects might be lower than in Western countries due to the lower prescribed dosage. Furthermore, it was reported that long-term tocolysis is useful to prolong pregnancy. 6 As a result, short-term tocolysis using ritodrine and/or magnesium sulfate is not common in Japan. At Showa University Hospital, long-term tocolysis protocol was used until December 2013, and then a short-term tocolysis protocol was adopted for management of threatened preterm birth in January The aim of this study was therefore to analyze the effects of long-term tocolysis by comparing perinatal outcome and use of tocolytic agents before and after revision of the protocol. Methods A historical cohort study was performed in a single perinatal center between October 2012 and March The management protocol for threatened preterm birth was changed in January 2014 from long-term tocolysis to short-term tocolysis. Gestational age was determined as weeks from accurate date of ovulation obtained from data on artificial insemination by husband (AIH), in vitrofertilization (IVF), or basal body temperature (BBT). Alternatively, crown rump length (CRL) was measured at 9 weeks gestation in order to determine gestational age in women with irregular menstrual cycle or uncertain memory of the first day of the menstrual period and uncertain timing of ovulation. Gestational age was then confirmed using the CRL reference for Japanese fetuses established by the Japan Society of Ultrasonics in Medicine. 7 In the previous long-term tocolysis protocol, threatened preterm delivery was diagnosed when a pregnant woman complained of cyclic uterine contractions, genital bleeding, and/or a shortened cervical length <25 mm or opening cervical os (Fig. 1a). Pregnant women with threatened preterm delivery were admitted for observation to deterioration and causal examination of symptoms or shortened cervical length. If uterine contractions were observed at the time of admission, then ritodrine hydrochloride was initially administered via continuous i.v. infusion. If the uterine contractions were controlled, or genital bleeding and a trend of shortening cervical length were not observed, then tocolytic agents were discontinued at that time. In contrast, when uterine contractions were not controlled, magnesium sulfate was additionally given via continuous i.v. infusion. When uterine contractions were uncontrolled or genital bleeding and a trend of shortening cervical length, including opening cervical os, were observed, then tocolytic agents might be continued until 35 weeks of gestation at maximum. Corticosteroids were used when a water bag was observed during a speculum examination or when combination therapy with tocolytic agents was started. In this study, the majority of patients continued tocolysis until 35 weeks of gestation. In the revised protocol, pregnant women with cyclic uterine contractions, genital bleeding, shortened cervical length <25 mm or opening cervical os were indicated for admission to observe the symptoms or cervical findings (Fig. 1b), similar to the previous protocol. The following points were added in the revised protocol: (i) tocolytic agents were used in pregnant women who had both opening cervical os and cyclic uterine contractions; (ii) when tocolytic agents were administered, corticosteroid therapy was also initiated to decrease fetal complications, such as respiratory distress syndrome or intracranial hemorrhage, when gestational age was < 34 weeks; (iii) tocolytic agents were administered for up to 48 h during corticosteroid therapy or until the uterine contractions were controlled; (iv) if pregnant women with threatened preterm delivery were admitted before 24 weeks of gestation, then tocolytic agents would permitted beyond 24 weeks of gestation; and (v) pregnant women who did not complain of cyclic uterine contractions or whose uterine cervical os was not open were not eligible for tocolytic agents. Preterm labor was diagnosed on regular uterine contraction or observed shortening of uterine cervical length before protocol revision, and on both regular uterine contractions and shortening or opening of uterine cervical os after that. The long-term protocol was used between October 2012 and December 2013, and the short-term protocol was used between January 2014 and March The maternal characteristics, data on bacterial vaginosis and biomarkers for threatened preterm delivery, perinatal outcomes and prescribed dose of tocolytic agents were compared between the two protocols. Bacterial vaginosis was evaluated using Nugent score, 8 and the biomarkers for threatened preterm labor were fetal fibronectin and neutrophil elastase. Statistical analysis The clinical data were obtained from clinical records and entered into SPSS Windows version 22.0 (SPSS, Chicago, 2016 Japan Society of Obstetrics and Gynecology 1681

3 M. Nakamura et al. Figure 1 (a) Previous protocol for using tocolytic agents (long-term protocol); (b) new protocol for using tocolytic agents (shortterm protocol). IL, USA). Categorical variables are reported as percentages and compared using chi-squared test or Fisher s exact test, whereas continuous variables were analyzed using the standard t-test or Mann Whitney U-test. Statistical significance was set at P < This study was approved by the Hospital Ethics Committee on 3 December Results There were 1548 deliveries managed with the long-term protocol and 1444 deliveries with the revised short-term protocol during the study period. Background patient characteristics are listed in Table 1. There were no significant differences between any of the characteristics except for maternal age. The total number of pregnant women given tocolytic agents and the total amount of tocolytic agents used before and after the protocol revision are given in Table 2. The overall use rate of ritodrine hydrochloride administered to pregnant women under the long-term protocol was 4.1% (64/1548), among which a total of 4658 ampules were used in 64 pregnant women with threatened preterm delivery. In the revised protocol, the overall use of ritodrine hydrochloride was 1.0% (15/1444), among which a total of 514 ampules were used in 15 pregnant women. The monthly amount of ritodrine hydrochloride Japan Society of Obstetrics and Gynecology

4 Perinatal outcome and tocolysis Table 1 Maternal subject characteristics Management protocol for preterm labor Old protocol (n = 1548) n(%)ormean±sd New protocol (n = 1444) n (%) or mean ± SD P -value Maternal age at delivery (years) 34.1 ± ± Primipara 906 (58.5) 799 (55.3) Maternal height (cm) ± ± Uterine cervical cerclage 24 (1.6) 21 (1.5) Multiple pregnancy 52 (3.4) 55 (3.8) Twin 51 (3.3) 53 (3.7) Triplet 1 (0.1) 2 (0.1) Admission due to preterm labor 65 (4.2) 42 (2.9) Placenta previa 24 (1.6) 20 (1.4) Fetal fibronectin positive 27.7% (18/65) 19.4% (8/42) Neutrophil elastase (mm) 2.6 ± ± Nugent score 2 ± 1 2 ± Cervix length in preterm labor (mm) 28.5 ± ± Table 2 Tocolytics use Management protocol for preterm labor Old protocol (n = 1548) n (%) or median (range) New protocol (n = 1444) n(%)ormedian(range) P-value Ritodrine hydrochloride No. patients 64 (4.1) 15 (1.0) <0.001 No. ampules <0.001 Duration of treatment (days) 15 (1 116) 2 (1 14) <0.001 Magnesium sulfate No. patients 15 (1.0) 6 (0.4) No. vials <0.001 Duration of treatment (days) 10 (1 31) 2 (1 10) <0.001 was reduced from 310 ampules to 34 ampules due to protocol revision. Furthermore, the overall proportion of pregnant women given magnesium sulfate on the previous protocol was 1.0% (15/1548), with a total of 1574 vials used in cases of preterm labor. Under the revised protocol, the overall proportion was 0.4% (6/1444), with a total of 193 vials used in cases of preterm labor. Therefore, protocol revision led to a reduction from 105 vials of magnesium sulfate to 13 vials per month. Subject outcome is given in Table 3. Gestational age (week) at delivery, neonatal bodyweight, and Apgar score (1/5 min) between the two groups were 38 ± 3 and 38 ± 3 weeks of gestation, 2855 ± 575 and 2868 ± 585 g, and 8(0 10)/9 (0 10) and 8 (0 10)/9 (0 10), respectively. The frequency of preterm delivery before 37 weeks of gestation and before 28 weeks of gestation were 11.8% (n = 182) and 10.6% (n = 153), and 1.3% (n = 20) and 1.2% (n = 17) for the two groups, respectively. No significant differences were observed between the two groups for any of the parameters in this study. Discussion Long-term tocolytic therapy has been considered to be essential to prevent preterm delivery for more than three decades in Japan. The present historical cohort study shows, however, that long-term use of tocolytic agents, including ritodrine hydrochloride and/or magnesium sulfate, did not confer benefit in reducing preterm delivery. The use of ritodrine hydrochloride and magnesium sulfate decreased to 11.0% and 12.3%, respectively, after revision of the management protocol. This protocol revision for threatened preterm birth did not lead to an increase in the frequency of admission to the neonatal care unit (NICU) or prolonged stay in the NICU. Accordingly, we reconfirmed that long-term tocolysis does not improve perinatal outcome. Preterm delivery due to spontaneous preterm labor before 34 weeks of gestation is considered to be caused by chorioamnionitis, which disturbs the immune system in the uterine cave. 5 Such preterm labor, particularly due 2016 Japan Society of Obstetrics and Gynecology 1683

5 M. Nakamura et al. Table 3 Outcomes Management protocol for preterm labor Old protocol (n = 1548) Mean ± SD, n (%) or median (range) New protocol (n = 1444) Mean ± SD, n (%) or median (range) P-value Delivery (weeks of gestation 38 ± 3 38 ± Gestational age at diagnosis of preterm labor (weeks) 26 ± 5 28 ± Admission due to preterm labor 65 (4.2) 42 (2.9) Duration of hospitalization due to preterm labor (days) 44 ± ± Preterm birth (<37 weeks) 182 (11.8) 153 (10.6) Preterm birth (<28 weeks) 20 (1.3) 17 (1.2) pprom 57 (3.7 %) 41 (2.8 %) Preterm delivery due to preterm labor 29 (1.9) 20 (1.4) Prolonged gestational days from admission 54 ± ± Male 815 (52.6) 726 (50.3) Neonatal bodyweight (g) 2855 ± ± Apgar score 1 min 8 (0 10) 8 (0 10) min 9 (0 10) 9 (0 10) Admission to NICU 137 (8.4) 129 (8.5) Duration of hospitalization in NICU (days) 59 ± NICU, neonatal intensive care unit; pprom, Preterm premature rupture of membranes. to inflammation, is primarily caused by increased concentrations of prostaglandins and cyclooxygenase (COX)2. 9,10 Accordingly, given this mechanism of preterm labor before 34 weeks of gestation, oxytocin or tocolytic agents (including beta-agonists such as ritodrine or neuromuscular relaxants such as magnesium sulfate) cannot be used as symptomatic therapy for preterm labor. In many countries, tocolytic agents such as ritodrine hydrochloride have been used, for the previous four decades, in high-risk women with threatened preterm birth to avoid preterm delivery and delay delivery. 11 Similarly, ritodrine hydrochloride has been used for threatened preterm birth to extend pregnancy until near term in Japan. The use of tocolytic agents not only reduces perinatal mortality, 1 but also prevents exposure to unnecessary risk in women and their babies, 12 ensures asufficient amount of time for maternal transfer to a tertiary facility, and potentiates the effects of corticosteroids. Japan currently has the lowest perinatal mortality worldwide. 13 The rate of preterm delivery in Japan would be half of in the Western countries. 14,15 Japanese obstetricians believe that long-term tocolysis makes a definite contribution to the low preterm delivery and perinatal mortality rates. Although the rates of singleton preterm delivery in Estonia, Finland, Ireland, Lithuania and Sweden were <5%, 14,15 long-term (>48 h) continuous tocolytic agent treatment might not be used for pregnant women in preterm labor, as it is in Japan, due to insufficient evidence for improvement of perinatal outcome 1 and maternal side-effects The background of preterm delivery among nations may differ because the frequency of preterm delivery is related to social class, for example, occupation, education, ethnicity, migration status, housing, access to medical care and illegal residency. 23 The low frequency of preterm delivery in Japan, however, is not considered to be dependent on long-term tocolytic treatment for spontaneous preterm labor. The low frequency of preterm delivery observed in Estonia, Finland, Ireland, Lithuania, Sweden and Japan may be associated with dietary habits, because the diet in these countries predominantly consists of seafood. Long-chain polyunsaturated fatty acid supplementation during pregnancy has been reported to decrease the risk of early preterm delivery. 24 Such ethnicity, education and environmental factors might be related to perinatal outcome, including preterm delivery due to spontaneous preterm labor. There are some limitations associated with the present study. The major limitation was that the data were collected from a single institution. To generalize the present results and obtain consensus in the management of threatened preterm birth in Japan, a multicenter study to evaluate the effectiveness of tocolytic agents is needed. Because women with preterm delivery due to preterm labor comprised % of the present subject group, in order to demonstrate the preventive effect of tocolytic agents in preterm delivery, a comparison Japan Society of Obstetrics and Gynecology

6 Perinatal outcome and tocolysis between short-term and long-term tocolysis (additionally non-tocolysis) for the same stage of threatened preterm delivery is needed. In conclusion, there was no significant change in the frequency of preterm delivery and neonatal outcome between the long-term and short-term management protocols for threatened preterm birth. Because tocolytic agents can lead to definite maternal side-effects, the use of tocolytic agents should be minimized. The present study indicates that the management of perinatal care in threatened preterm birth in Japan should be reconsidered. Disclosure The authors declare no conflicts of interest. References 1. Haas DM, Caldwell DM, Kirkpatrick P, McIntosh JJ, Welton NJ. Tocolytic therapy for preterm delivery: Systematic review and network meta-analysis. BMJ 2012; 345: e Lamont RF. The pathophysiology of pulmonary oedema with the use of beta-agonists. BJOG 2000; 107: Levy DL. Morbidity caused by terbutaline infusion pump therapy. Am J Obstet Gynecol 1994; 170: Price PH. Review of betamimetic drugs for tocolysis. Report to Special FDA public meeting on re-evaluation of ritodrine labelling. Data held on file by Solvay Duphar BV, Weesp, The Netherlands, Beck S, Wojdyla D, Say L et al. The worldwide incidence of preterm birth: A systematic review of maternal mortality and morbidity. Bull World Health Organ 2010; 88: Takagi K, Satoh T, Multicentre Premature Labour Study Group. Is long-term tocolysis effective for threatened premature labour? JIntMedRes2009; 37: Nakamura M, Hasegawa J, Arakaki T et al. Repeated measurement of crown-rump length at 9 and weeks gestation: association with adverse pregnancy outcome. Fetal Diagn Ther 2015; 38: Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol 1991; 29: Gibb W. The role of prostaglandins in human parturition. Ann Med 1998; 30: Mitchell BF, Olson DM. Prostaglandin endoperoxide H synthase inhibitors and other tocolytics in preterm labour. Prostaglandins Leukot Essent Fatty Acids 2004; 70: Chan J, Cabrol D, Ingemarsson I, Marsal K, Moutquin JM, Fisk NM. Pragmatic comparison of beta2-agonist side effects within the Worldwide Atosiban versus Beta Agonists study. Eur J Obstet Gynecol Reprod Biol 2006; 128: Vogel JP, Souza JP, Gulmezoglu AM et al. Use of antenatal corticosteroids and tocolytic drugs in preterm births in 29 countries: An analysis of the WHO Multicountry Survey on Maternal and Newborn Health. Lancet 2014; 384: World Health Organization. Neonatal and Perinatal Mortality: Country, Regional and Global Estimates. Geneva: World Health Organization, Zeitlin J, Szamotulska K, Drewniak N et al. Preterm birth time trends in Europe: A study of 19 countries. BJOG 2013; 120: Statistics and Information Department, Minister s Secretariat, Ministry of Health. Labour and Welfare, Vital Statistics of Japan 2010, Vol. 1. Tokyo: Health, Labour and Welfare Statistics Association, 2012 (in Japanese). 16. Lamont RF. The prevention of preterm birth with the use of antibiotics. Eur J Pediatr 1999; 158 (Suppl 1): S2 S Braden GL, von Oeyen PT, Germain MJ, Watson DJ, Haag BL. Ritodrine- and terbutaline-induced hypokalemia in preterm labor: Mechanisms and consequences. Kidney Int 1997; 51: Katz VL, Seeds JW. Fetal and neonatal cardiovascular complications from beta-sympathomimetic therapy for tocolysis. Am J Obstet Gynecol 1989; 161: Shen O, Lavie O, Grisaru S, Aboulafia Y, Diamant YZ. Elevated serum liver enzyme concentrations during ritodrine therapy. Acta Obstet Gynecol Scand 1996; 75: Groome LJ, Goldenberg RL, Cliver SP, Davis RO, Copper RL. Neonatal periventricular-intraventricular hemorrhage after maternal beta-sympathomimetic tocolysis. The March of Dimes Multicenter Study Group. Am J Obstet Gynecol 1992; 167: Lu JF, Nightingale CH. Magnesium sulfate in eclampsia and pre-eclampsia: Pharmacokinetic principles. Clin Pharmacokinet 2000; 38: McCubbin JM, Sibai BM, Ardella TN, Anderson GD. Cardiopulmonary arrest due to acute maternal hypermagnesaemia. Lancet 1981; 1: Euro peristat project in collaboration with SCPE, EUROCAT and EURONEOSTAT. European Health Report Imhoff-Kunsch B, Briggs V, Goldenberg T, Ramakrishnan U. Effect of n-3 long-chain polyunsaturated fatty acid intake during pregnancy on maternal, infant, and child health outcomes: A systematic review. Paediatr Perinat Epidemiol 2012; 26 (Suppl 1): Japan Society of Obstetrics and Gynecology 1685