Hindawi Publishing Corporation
ISRN Obstetrics and Gynecology
Volume 2013, Article ID 120735, 4 pages
Ritodrine Should Be Carefully Administered during Antenatal
Glucocorticoid Therapy Even in Nondiabetic Pregnancies
Masaki Ogawa,1Yoshio Matsuda,1Aiko Kobayashi,1Etsuko Shimada,1Yoshika Akizawa,1
Minoru Mitani,1Yasuo Makino,1and Hideo Matsui2
1Perinatal Medical Center, Tokyo Women’s Medical University Hospital, Kawadacho 8-1, Shinjuku, Tokyo 162-8666, Japan
2Department of Obstetrics and Gynecology, Tokyo Women’s Medical University, Tokyo, Japan
Correspondence should be addressed to Masaki Ogawa; firstname.lastname@example.org
Received 19 January 2013; Accepted 12 February 2013
Academic Editors: M. Friedrich, N. A. Ginsberg, and K. Yang
Copyright © 2013 Masaki Ogawa et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Aim. Antenatal glucocorticoid therapy (AGT) has been commonly used recently. However, this therapy has severe harmful effects
such as maternal hyperglycemia. In Japan, ritodrine hydrochloride has been used as a tocolytic agent. In this study, we performed
retrospective casecontrol study to clarify whether concomitant use of ritodrine and glucocorticoid was safe to pregnant women
and nondiabetes (푛 = 45) who gave birth at our hospital between 2002 and 2011. Cases and controls received AGT. Blood glucose
40mg/dL was seen after the therapy even in nondiabetic pregnant women. Blood glucose increased significantly in the group that
also received ritodrine, and it was shown that the number of pregnant women who might develop ketoacidosis might increase
11-fold. Conclusions. Ritodrine should be carefully administered during antenatal glucocorticoid therapy. It may be necessary to
adequately monitor blood glucose, when performing the therapy, even in nondiabetic pregnant women.
withoutdiabetesmellitus.Methods.Wereviewedthecomputerizedrecordsofpregnantwomenwithpregestationaldiabetes(푛 = 9)
30 units of insulin were necessary when performing AGT in diabetic pregnant women. And also, an increase in blood glucose of
after the therapy was analyzed, and additional volume of insulin was compared to that before the therapy. Results. From this study,
worldwide debate since an epoch-making report by Liggins
distress syndrome in preterm infants [2–4]. This therapy has
severe harmful effects such as maternal hyperglycemia [5, 6].
Endocrinologists and perinatologists must pay attention to
In some patients with diabetes mellitus, additional insulin
therapy is needed. Unfortunately, there are no guidelines
on additional insulin therapy, and little is known about the
suitable volume of additional insulin.
Many patients requiring AGT present as threatened
preterm labor, with regular uterine contractions and/or pro-
gressive uterine cervical dilatation. Subsequently, they also
need tocolytic agents. Tocolytic therapy in Japan consists of
two main drugs, ritodrine hydrochloride and magnesium
sulfate, unlike many Western countries. Ritodrine, the main
traditional drug in Japan, is a beta-2 stimulant that causes
maternal hyperglycemia. Using both ritodrine and glucocor-
ticoid could cause maternal hyperglycemia. However, there
are no guidelines for cases like this without diabetes mellitus.
Star et al. reported that prophylactic use of insulin was better
, but Schumacher et al. opposed this notion . It is
very difficult to extrapolate from these overseas reports why
substantial tocolytic therapy in Japan is different from that in
those other countries.
We planned this retrospective case-control study to clar-
and to clarify how nondiabetic patients requiring tocolytic
agents after the therapy should be managed.
2ISRN Obstetrics and Gynecology
2. Materials and Methods
This study was approved by our institutional ethics com-
mittee. We reviewed the computerized records of pregnant
women with pregestational diabetes mellitus (n = 9) and
uncomplicated pregnant women (n = 45) with singleton ges-
tations who gave birth at Tokyo Women’s Medical University
Hospital between January 2002 and March 2011. Cases and
controls received AGT after giving full informed consent
based on the guidelines of our institutional review board.
Type 1, type 2, and gestational diabetes mellitus in the
previous pregnancy were treated as pregestational diabetes
mellitus. Cases without pregnancy prolongation less than
72 hours after AGT were excluded from this study. Fetal
malformation and fetal abnormal karyotyping were also
Liggins and Howie . In brief, two doses of 12 milligrams
of betamethasone were injected intramuscularly 24 hours
apart. Blood was sampled at four points: before injection of
were fasting blood glucose before the morning meal. In cases
of pregestational diabetes mellitus, insulin was administered
subcutaneously in order to maintain blood glucose at less
than 100mg/dL before meals and/or less than 120mg/dL two
hours after meals. Ritodrine hydrochloride (100휇g/hour IV)
Statistical analyses were performed with a computer
program: Statflex 6.0 (Artech Co., Ltd., Osaka, Japan. URL:
and/or magnesium sulfate (1gram/hour IV) were used as
http://www.statflex.net/). Values were given as means ± SD.
and Scheffe’s test were performed as multiple comparisons.
Spearman’s rank test was performed to clarify the correlation
Mann-Whitney U test, two-factor analysis of variance, and
Friedman test were performed after Bartlett test. Dunn’s test
coefficient. 휒-square test was performed to clarify the odds
ratio with 95% confidence intervals. A P value less than 0.05
was considered to be significant.
Cases were defined as pregestational diabetes mellitus and
gestational diabetes mellitus in the previous pregnancy. The
mean age was 32.8 ± 2.2 years old. Three cases of type 1
no evidence of diabetes mellitus. The mean age of controls
diabetes mellitus, one case of type 2 diabetes mellitus, and
study.ThegestationalweeksofAGTwere29.0 ± 3.0.Delivery
shows the distribution diagram of daily insulin volume
before/after administration. Controls were defined as having
were 29.0 ± 3.6. Delivery weeks were 31.2 ± 3.9. Thirty-seven
of blood glucose in controls, Friedman test and subsequent
weeks were 29.7 ± 2.9. Total daily insulin volume before or
was 32.2 ± 4.6 years old. The gestational weeks of AGT
tocolysis, and 17 were treated with both. As the time course
controls received ritodrine tocolysis, 20 received magnesium
0 1020 3040 5060 70
Type 2 DM
Type 1 DM
푦 = 1.04푥 + 31.2 (푟푠= 0.83, 푃 < 0.01)
Total daily insulin after administration (units/day)
Total daily insulin before administration (units/day)
Figure 1: Distribution diagram of daily insulin volume before/after
antenatal glucocorticoid administration. Closed circle: type 1 dia-
gestational diabetes mellitus. Correlation coefficient by Spearman’s
rank test was 0.83 (P < 0.01). DM: diabetes mellitus, GDM:
Dunn’s test revealed significant increases on Day 1 (143.9 ±
the time course of blood glucose in controls that received
or did not receive ritodrine tocolysis. Two-factor analysis
of variance and subsequent Scheffe’s test revealed significant
± 17.5, 87.8 ± 9.0) relative to Day 0 (102.8 ± 18.0, 85.4 ± 14.6,
ritodrine was significantly higher than that in those that
gestational diabetes mellitus.
26.0, P < 0.01) and Day 2 (132.9 ± 17.9, P < 0.01) but not Day 3
increases on Day 1 (149.4 ± 23.6, 118.4 ± 22.4, P < 0.05) and
resp.) in controls that received or did not receive ritodrine.
(90.9 ± 16.3) relative to Day 0 (99.7 ± 18.6). Figure 2 shows
Day 2 (135.2 ± 16.4, 122.5 ± 21.7, P < 0.05) but not Day 3 (91.6
did not receive ritodrine (P < 0.05). In Table 1, the ratio of
compared with the group that did not use ritodrine (odds
ratio: 11.3, 95% confidence interval: 2.28–56.4).
patients with blood glucose above 120 after AGT increased
significantly on Day 1 in the group that used ritodrine as
AGT is used in Japan because it lowers the incidence of
respiratory distress syndrome and periventricular leukoma-
lacia in premature infants . Its use has increased recently
due to the fact that it is now covered by insurance. On the
other hand, maternal hyperglycemia is sometimes found as
a serious side effect of AGT , and it causes secondary
child . Consequently, endocrinologists and obstetricians
ISRN Obstetrics and Gynecology3
Table 1: Ratios of patients with blood glucose above 120 after antenatal glucocorticoid therapy.
Day 1Day 2Day 3
Blood glucose (mg/dL)
statisticalsignificance (P <0.05) versus Day0.Asterisk(‡)indicates
or did not receive ritodrine tocolysis. Asterisk (∗, †) indicates
statistical significance (P < 0.05).
are very sensitive to glycemic control after AGT in preg-
nant women with diabetes mellitus. However, there are no
guidelines that give an idea of the amount of insulin needed.
Moreover, how to manage nondiabetic pregnant women
during AGT is unclear. Cases that require AGT are those
with threatened premature labor or pregnancy induced-
hypertension, and delivery must be prolonged for 48 hours,
the time it takes for the effects of AGT to appear. To this end,
attempts are often made to forcibly suppress labor after AGT.
In Japan, there is a tendency to use ritodrine hydrochloride,
a beta-2 stimulant that readily changes blood glucose, to
suppress labor in such cases. However, there have been no
previous reports in the literature concerning management
of blood glucose while using ritodrine hydrochloride dur-
ing AGT. Overseas, magnesium sulfate is used to suppress
labor, not ritodrine hydrochloride. Therefore, extrapolating
overseas management of blood glucose during AGT directly
to Japan would carry a large risk. Investigations unique to
circumstances in Japan are necessary. The present study was
conceived and planned based on these circumstances.
The results of the present study showed that 30units/day
of insulin were necessary in pregnant women with diabetes
mellitus receiving AGT. This includes pregnant women who
did not use insulin before AGT. We could not evaluate the
amount of insulin necessary by type of diabetes mellitus due
to the small sample size. However, the results suggested that
to the fact that the slope of the regression line was steeper. In
easily caused hyperglycemia. In the present investigation, the
additional insulin was administered by subcutaneous bolus
injection, but administration by continuous subcutaneous
insulin infusion (CSII) should also be investigated in the
future. However, as pointed out by Bouhanick et al. , CSII
in pregnant women with type 1 diabetes mellitus can cause
neous blood flow, easily putting them at risk for ketoacidosis.
widespread clinical application.
In nondiabetic pregnant women, as well, early morning
fasting blood glucose after AGT increased at least 40mg/dL
on average. Furthermore, it was found that this hyper-
glycemia continued for 2 days. This hyperglycemia increased
tion of pregnant women in the ritodrine group whose early
The risk of developing hyperglycemia ≥120mg/dL early in
Fisher et al. reported that pregnant women were more prone
to developing glucose intolerance during concomitant use of
the beta stimulant oral terbutaline and AGT . Bernstein
and Catalano reported a case of diabetic ketoacidosis during
concomitant use of terbutaline and AGT in a pregnant
woman with normal glucose tolerance . Based on the
previous findings, concomitant use of AGT and a beta
stimulant might increase the risk of glucose intolerance and
diabetic ketoacidosis even in nondiabetic pregnant women.
In particular, the fact that diabetic ketoacidosis occurred in
4/11 (36%) diabetic pregnant women with a blood glucose
the morning while fasting on Day 1 after AGT was 11 times
greater with use of ritodrine than without use of ritodrine.
level <200mg/dL shows that adequate attention should be
were necessary when performing AGT in pregnant women
with diabetes mellitus. In addition, an increase in blood
glucose of 40mg/dL was seen after AGT even in nondiabetic
group that also received ritodrine, and it was shown that the
number of pregnant women who might develop ketoacidosis
might increase 11-fold. Therefore, it may be necessary to
adequately monitor blood glucose, when performing AGT,
even in nondiabetic pregnant women.
paid when performing AGT .
In conclusion, this study showed that 30 units of insulin
4 ISRN Obstetrics and Gynecology Download full-text
Conflict of Interests
The authors report no conflict of interests. The authors alone
are responsible for the content and writing the paper.
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