Possibilities and predictabilities by atosiban: meta-regressions
1. Introduction
The detailed analysis of a large number of clinical trials [1] concerning the
tocolytic possibility and side-effects of the oxytocin receptor antagonist atosiban in
women with threatened preterm birth will be reviewing systematically within this text.
The aim of this review will reveal important and meaningful determinants of preterm
birth, and subsequent management. These determinants can be used in clinical
practice for not only the management but also the outcome prediction of women
deemed to be in preterm labour. Along, it will offer a broad and detailful basis for
comparing atosiban to any other prospective tocolytic agent up to any particular
feature elicited by history or clinical examination of the women. So, from 13 clinical
trials that were published before March 2005, the findings will be reported: All women
in labour over 18 years of age and beyond 23 completed weeks were requested to
participate. Women were excluded if they had serious maternal diseases (e.g. preeclampsia, maternal hypertension, HELLP syndrome, metabolic or cardiovascular
diseases, ruptured amniotic membranes, previous[12h] tocolytic NSAIDs use, fever,
urinary
infection,
hyperthyroidism,
uncontrolled
diabetes
mellitus,
pheochromocytoma, asthma, terbutaline use contradiction, alcohol or drug abuse,
history of hypersensitivity, renal disease or cervical incompetence) or fetal or
placental abnormalities (intrauterine growth restriction, fetal malformation, high order
multiple pregnancy, major vaginal bleeding, chorioamnionitis, abruptio placentae,
placenta previa, hydramnios, retained intrauterine device, fetal distress or death).
2. Methods
The basic concept of including these clinical trials is to participate all of the known
published trials concerning atosiban in order as maximized as possible sample of
women to be concetrated for a more reliable statistical procedure. That‘ s why not
only all of the single branch atosiban published studies were used, but also an effort
became the atosiban branch trials to be mined by controlled ones, without interest in
what the control groups get.
The first uncontrolled study was performed by Akerlund et al. [2], in order to
show the effects of atosiban on the myometrium. 13 women with 2 hours at least
preterm contractions were given this medication. The results in terms of neonate‘ s
birth weight, alternative tocolysis used or not, pregnancy prolongation or not,
gestional age in delivery, atosiban discontinuation or alteration, preterm delivery
rates, as well as maternal or neonatal adverse events are depicted in tables 1-6.
The second uncontrolled study [3] was performed by the same researcher 2
years later (Andersen et al. 1989), who described the preterm labour outcome of 12
women treated by atosiban. The women received this medication until 2 hours after
the preterm contractions discontinuation. The outcome was monitored as above in
terms of neonate‘ s birth weight, alternative tocolysis used or not, pregnancy
prolongation or not, gestional age in delivery, atosiban discontinuation or alteration,
preterm delivery rates, as well as maternal or neonatal adverse events; and is
depicted in tables 1-6.
The third study was performed by Goodwin et al. [4], who compared the efficacy
and side effects profile of atosiban to placebo. 56 women who were given atosiban
for 2 hours, had a greater decrease in contraction rates (p=0.001) when compared to
placebo. The maternal and neonatal adverse events profile are depicted in tables 16.
The forth study was performed by the same researcher Goodwin et al. [5], who
described the preterm labour outcome of 61 women treated by atosiban. The women
received this medication at 300μg/min for 12 hours, or until 6 hours after the preterm
contractions discontinued. As successful preterm labour outcome was assessed the
contractions discontinuation for 48 hours at least. The detailed outcomes are
depicted in tables 1-6.
The fifth study was performed by Valenzuela et al. [6], who compared the efficacy
and side effects profile of atosiban when used for preterm contractions. All women
began this medication as bolus treatment. The atosiban branch of 252 women
continued this medication as maintenance treatment, while the other control branch
women were given placebo, until 36weeks. The median pregnancy prolongation was
better for atosiban (p=0.02). The maternal and neonatal adverse events and
discontinuation rates were comparable in both groups Detailed numeric data and a
side effects profile of this atosiban branch trial are depicted in tables 1-6.
The seventh study was performed by Romero et al. [7], who compared the
efficacy and side effects profile of atosiban with placebo when used for preterm
contractions. The atosiban branch of 246 women received this medication bolus i.v.
6.75 mg, then 300μg/min for 3 hours, after 100μg/min for 45 hours and finally
30μg/min until the end of 36 weeks. The efficacy in both groups was comparable in
mean pregnancy prolongation, as well as for discontinuation rates. The atosiban
superiority was obvious for stopping uterine contractions in 24, 48 hours and in one
week (p=0.008) particularly in pregnancies younger than 28 weeks . The maternal
and neonatal adverse events and neonatal mortalities older than 24 weeks were
comparable to placebo. Detailed numeric data and a side effects and neonatal
mortality profile of this atosiban branch trial are depicted in tables 1-6.
The eighth study was performed by Moutquin et al. [8], who compared the
efficacy and side effects profile of atosiban with ritodrine when used for preterm
contractions. The atosiban branch of 361 women received this medication bolus i.v.
6.75 mg, then 300μg/min for 3 hours and finally 100μg/min until 18 hours. The
efficacy of both branch medications was similar for stopping uterine contractions in
48 hours (p=0.99), in one week (p=0.85) as well as for mean duration of labour and
neonatal side effects. The atosiban superiority was obvious at significantly (p<0.001)
much fewer maternal mainly cardiovascular adverse events and discontinuation rates
too, than ritodrine. Detailed numeric data and a side effects profile of this atosiban
branch trial are depicted in tables 1-6.
The ninth study was performed by European Atosiban Study Group in 2001 [9],
which compared the efficacy and side effects profile of atosiban with terbutaline when
used for preterm contractions. 115 women received an atosiban bolus i.v. 6.75 mg,
then 300μg/min for 3 hours and finally 100μg/min. The efficacy of both branch
medications was comparable for stopping uterine contractions in 48 hours (p=0.783),
in one week (p=0.067) as well as for discontinuation rates. The atosiban superiority
was obvious at significantly much fewer maternal and neonatal adverse events than
salboutamole. Detailed numeric data and a side effects and neonatal mortality profile
of this atosiban branch trial are depicted in tables 1-6.
The tenth study was performed by French / Australian Atosiban Investigators
Group in 2001 [11], who compared the efficacy and side effects profile of atosiban
with salbutamol when used for preterm contractions. The atosiban branch of 119
women received this medication bolus i.v. 6.75 mg, then 300μg/min for 3 hours and
finally 100μg/min for 45 hours. The efficacy of both branch medications was similar
for stopping uterine contractions in 48 hours (p=0.67), in one week (p=0.93) as well
as for discontinuation rates and neonatal side effects. The atosiban superiority was
obvious at significantly much fewer maternal adverse events than salbutamol.
Detailed numeric data and a side effects profile of this atosiban branch trial is
depicted in tables 1-6.
The eleventh study was performed by Worldwide Atosiban versus Beta-agonists
Study Group in 2001 [12], which compared the efficacy and side effects profile of
atosiban with β-agonists: ritodrine, salbutamol and terbutaline. The atosiban branch
of 361 women received this medication bolus i.v. 6.75 mg, then 300μg/min for 3
hours and finally 100μg/min for 18-48 hours. The efficacy of both branch medications
was similar for stopping uterine contractions in 48 hours (p=0.99), in one week
(p=0.28) and mean duration of labour; as well as for neonatal side effects. The
atosiban superiority was obvious with significantly fewer and milder maternal mainly
cardiovascular adverse events (p<0.001) and lower discontinuation rates (p=0.0001)
than β-agonists. Detailed numeric data and a side effects profile of this atosiban
branch trial are depicted in tables 1-6.
The twelfth one was performed by Afshar P. et al between October 2000 and May
2001 [13], which compared the efficacy and side effects profile of atosiban with
hexoprelaline when used for acute tocolysis and intrauterine resuscitation. 13 women
with singleton pregnancy at term and cephalic presentation were given atosiban in
92% of which tocolysis and resuscitation was achieved or hexoprenaline in 100% of
which these were achieved. Generally the efficacy of both medications was similar for
stopping uterine contractions, although these were resumed more promptly by
atosiban which had significantly fewer and milder maternal adverse events than
hexoprenaline. Outcome monitoring and a side effects profile of this atosiban branch
trial is depicted in tables 1-6.
The last study was a pilot preliminary study performed by Lurie S. et al in 2002
[14], who assessed the ability and side effects profile of atosiban in alleviating uterine
hyperactivity unless was alleviated within 5 minutes with “intrauterine resuscitation”
measures. 15 women with singleton pregnancy at term and cephalic presentation
were given atosiban in 14 of which alleviation was achieved. Atosiban was well
tolerated by all women and no side effects were noted. Outcome monitoring of this
trial is depicted in tables 1-6.
Although some of these trials report about the normal distribution of their numeric
data, the total consideration of a 1651 women sample, practically secures such an
occurrence. So, meta-regression analysis can be used setting each of the variables
of tables 2-6 as the dependant one at a time; and these of table 1, the independent
tested ones in a linear model. Analysis became by STATA programme, and the most
statistically important variables found at the level of 0.000 were kept.
Table 1A. Atosiban clinical trials independant descriptive statistics
Trial Women Pregnancyage+SD(wbd) Contractionrate Dilatation<max(cm) Totaldosage(mg)
Akerlund et al. 1987 13
27-35
>4/20 min
1.5 - 5.4
Akerlund et al. 1989 12
27-33
>4/20 min
1.5 - 5.4
Goodwin et al. 1992 56
32.1+3.6
>6/hour
3
36
Goodwin et al. 1995 61
31.2+3.4
>6/hour
3
216
Val et al. 1995(atosiban) 261 30.6+2.78
>4/30 min
3
1739.07
Val et al. 1995(placebo) 251 31.0+2.62
>4/30 min
3
330.75
Romero et al. 1995 246 30.3+3.07
>4/30 min
3
1138.59
Μοutquin et al. 1995 126 30.0+2.3
>4/30 min
3
168.75
EASG 1996 115
30.0+2.3
>4/30 min
3
168.75
F/AAIG 1997 119
30.2+2.4
>4/30 min
3
330.75
WAvBSG 1997 363
30.1+2.3
>4/30 min
3
168.75 – 348.75
40.6
>5.5/30min
Afschar et al. 2001 13
6.75
Lurie et al 2002 15
37-42
>5/10min
9
Concisely* 1651
30.61+1.4
>8.14+2.23/hour
3.05+0.57
7.65
609.59+588.45
Table 1B. Atosiban clinical trials independant descriptive statistics
Trial
Contraction(sec)
Akerlund et al. 1987
Twin/Multiple(%)
0(0)-
Age(years+SD)
ParityI(%)
White race
Effacement>(%)
Akerlund et al. 1989
Goodwin et al. 1992
2(16.66)>30
0(0)
24.6+6.1
26(46.42)
12(21.42)
Goodwin et al. 1995
2(3.27)
23.5+5.7
32(52.45)
12(19.67)
Val et al. 1995(atosiban) >40
20(7.66)
24.2+6.06
139(53.25)
75
Val et al. 1995(placebo) >40
25(9.96)
23.9+5.82
134(53.38)
75
Romero et al. 1995
>40
36(14.63)
Moutquin et al. 1995
>30
19(15.07)
26.4+5.6
65(51.58)
109(86.5)
50
EASG 1996
>30
15(13.04)
27.3+5.8
57(49.56)
103(89.56)
50
F/AAIG 1997
>30
10(8.4)
26.2+5.0
66(55.46)
108(90.75)
50
WAvBSG 1997
>30
44(12.12)
26.8+5.5
190(52.34)
320(88.15)
50
50
Afschar et al 2001
>180
0(0)
28.4
Lurie et al. 2002
>180
0(0)
20-38
Concisely* >37.52+19.86
173[10.47+3.93]
50
25.59+1.37
7(46.66)
443[52.37+1.92]
937[79.04+23.59]
58.32+11.78
Table 2. Atosiban clinical trials dependant descriptive statistics
Trial Birth weight (gr+SD) Altern.tocolys (%) Prolongation (weeks) gestional age (wbd+SD) Discontin (%) Preterm (%)
Akerlund et al. 1987
4(30.76)
Akerlund et al. 1989
3(25)
>37
0(0)
3(23.07)
0(0)
6(50)
Goodwin et al. 1992
2996+750
11(19.64)
5.7
37.8+3.5
1(1.78)
5(8.92)
Goodwin et al. 1995
2827+744
14(22.95)
6
37.2+0.34
0(0)
21(34.42)
Val et al. 1995(atosiban) 2746.9+792.14 61(23.37)
4.65
35.25
35(13.4)
90(34.48)
Val et al. 1995(place
2746.8+796.16 77(30.67)
3.94
34.94
23(9.16)
92(35.85)
Romero et al. 1995
2336.8+787.26 103(41.86)
2.6
32.9+3.07
39(15.85)
144(58.53)
Moutquin et al. 1995
2314+825
26(20.63)
5.1
35.1+4.2
1(0.79)
EASG 1996
2472+299
39(33.91)
5.4
35.4+1.01
2(1.73)
F/AAIG 1997
2708+743
69(57.98)
6.3
36.5+3.0
22(18.48)
21(18.26)
WAvBSG 1997
2491+813
Afschar et al. 2001
3322
2775-3855
Lurie et al. 2002
Concisely* 2593.2+216.48
134(36.91)
5.7
35.8+3.9
0(0)
8 minutes
40.6
0(0)
0(0)
0(0)
15.53 minutes
37-42
0(0)
0(0)
541[33.32+9.95]
4.68+1.3
4(1.1)
35.31+1.31
127[8.25+6.58]
382[37.43+14.23]
*Sum up or after meta-analysis [10]
Table 3. Maternal adverse events by atosiban
Akerlund Akerlund Goodwin Goodwin Valen(atos.) Valen(plac.) Romero Moutquin EASG F/AAIG WAvBSG Afschar Lu Total
Pulmon. Edema -
-
-
-
-
-
-
-
-
1
1
-
-
2
Chest pain
-
-
-
1
1
1
2
2
1
1
4
-
-
13
Palpitation
-
-
-
-
-
-
-
2
-
6
8
-
-
16
Tachycardia
-
-
-
-
1
-
2
1
5
14
20
1
-
44
Hypotension
-
-
-
-
-
-
-
3
5
4
12
-
-
24
Dyspnea
-
-
-
-
-
-
-
2
-
-
1
-
-
3
Syncope
-
-
-
-
-
-
-
2
-
-
2
-
-
4
Νausea
-
-
-
1
-
-
-
16
16
11
43
-
-
87
Vomiting
-
-
1
1
-
-
-
10
3
12
25
-
-
52
Headache
-
-
-
2
-
-
-
13
5
17
35
-
-
72
Anxiety
-
-
-
-
-
-
-
-
1
3
4
-
-
8
Tremor
-
-
-
-
-
-
-
1
1
3
5
-
-
10
Hyperglycemia -
-
-
-
-
-
-
7
1
15
23
-
-
46
Hypokalemia -
-
-
-
-
-
-
1
-
2
3
-
-
6
Arrhythmia
-
-
-
-
-
-
-
1
-
-
-
-
-
1
Fetal distress -
-
-
-
1
1
4
-
-
-
-
-
-
6
Subcut. Site -
-
-
-
117
189
44
-
-
-
-
-
-
350
Dysgeusia
-
-
1
-
-
-
-
-
-
-
-
-
1
-
Total
Deths
-
-
Women No 13
(%)
0
-
1
6
120
-
-
-
-
12
56
61
261
0
1.78
191
-
251
9.83 45.97
76.09
52
61
48
79
186
1
-
745
-
-
-
-
-
-
-
-
246
126
115
119
361
13
-
1636
21.13
48.41
41.73
66.38
51.52 7.69
0 45.53
Table 4. Neonatal adverse events by atosiban
Akerlund Akerlund Goodwin Goodwin Valen(atos.) Valen(plac.) Romero Moutquin EASG F/AAIG WAvBSG Afschar Lu Total
RDS
-
-
3
6
33
29
64
32
27
20
79
-
-
293
Apnoea
-
-
-
2
-
-
-
22
4
10
36
-
-
74
Bradycardia
-
-
-
1
-
-
-
11
7
5
23
-
-
47
Arrhythmia
-
-
-
-
-
-
-
-
2
-
2
-
-
4
Patent duct arter -
-
2
2
10
8
18
13
8
1
22
-
-
84
Hypotension
-
-
-
-
-
-
-
3
6
1
10
-
-
20
Sepsis
-
-
-
1
-
-
-
11
13
1
25
-
-
51
Cerebral haemor-
-
-
1
15
9
16
6
7
5
18
-
-
77
Hypoxia/asphyxia-
-
-
-
-
-
-
3
1
2
6
-
-
12
Retinopathy
-
-
-
-
-
-
-
10
5
-
7
-
-
22
Anaemia
-
-
-
-
-
-
-
16
6
9
31
-
-
62
Thrombocytopen.-
-
-
1
-
-
-
2
-
-
2
-
-
5
Hypoglycaemia -
-
3
-
-
-
-
10
8
8
26
-
-
55
Acidosis
-
-
-
-
-
-
2
2
-
-
-
-
4
Necrot. enterocol.-
-
-
-
5
2
1
-
-
-
-
-
-
8
Hyperbilirubinem -
-
6
9
-
-
-
-
-
-
-
-
-
15
Pneumonia
-
-
2
-
-
-
-
-
-
-
-
-
2
-
-
IUGR
-
-
-
3
-
-
-
-
-
-
-
-
-
3
Other
-
-
1
15
-
20
16
-
-
-
-
-
-
52
Total
-
-
15
43
63
68
115
141
96
Deths
-
-
-
-
5
5
3
2
3
Neonates No 13
14
57
62
291
272
274
146
(%)
0
26.31
26.83
43.06
97.94
0
69.35 23.36
62
287
-
-
890
1
6
-
-
25
131
129
406
75.57
48.83 72.16
13
15 1823
0
0 50.19
Table 5. Numbers of undelivered women per endpoint
Trial
Women
28wbd
32wbd
34wbd
36wbd
37wbd
Akerlund et al. 1987
13
10
Akerlund et al. 1989
12
6
Goodwin et al. 1992
56
40
Goodwin et al. 1995
9
Goodwin et al. 1995
29
Goodwin et al. 1995
61
Val et al. 1995(atos)
45
Val et al. 1995(atos)
158
Val et al. 1995(atos)
267
Val et al. 1995(plac)
29
Val et al. 1995(plac)
127
Val et al. 1995(plac)
243
Romero et al. 1995
246
Moutquin et al. 1995
126
7
21
43
43
200
177
174
151
38
139
23
109
102
94
78
60
EASG 1996
48
Afschar et al. 2001
13
12
Lurie et al. 2002
15
14
Concisely per total
7
75/131
363/440
Table 6. Numbers of undelivered women per endpoint
78/126
477/697
555/926
Trial
Women
Goodwin et al. 1995
58
Romero et al. 1995
246
Moutquin et al. 1995
EASG 1996
24hours
48hours
Week
48
45
165
153
126
107
92
115
99
88
179
F/AAIG 1997
119
111
WAvBSG 1997
363
317
Concicely per total
179/246
2 weeks
107
287
847/1027 772/1027
3. Results
The resulted relations (a-n) deduced and statistically important at the level of
0.0000 are depicted in table 7. Please, note that the symbol * stands for
multiplication. The measurement units of any variable are omitted in the interest of
space gaining and is supposed to be the same as in tables 1 & 2.
Table 7. Deduced relations
Birth weight(gr)=2242.572-58.38653*Twin+28.68704*Age+2.197627*Race (a)
Alternative tocolysis(%) = -4.927181+0.0014321*Dosage-4.840039*Twin+0.0054911*Parity+1.13262*Race (b)
Pregnancy prolongation (weeks) =6.198678+0.0029573*Dosage-0.1112494*Twin-0.0185648*Parity+0.0119813*Race (c)
Labour age (wbd)=38.44467+0.0014497*Dosage-0.1908591*Twin-0.0172341*Parity+0.0017965*Race (d)
Discontinuation rate (%) = -206.9412-0.1232461*Dosage-2.602492*Twin+4.407731*Parity+0.4727928*Race (e)
Preterm rate (%) = -56.41364+14.98134*Contraction+0.008592*Dosage-0.4972738*Effacement (f)
Maternal side effects (%) = -221.9657-0.0613285*Dosage-1.22272*Twin+4.478928*Parity+0.7829587*Race (g)
Neonatal side effects = -91.98702-0.0309198*Dosage+7.937417*Twin+3.030563*Parity-0.9289574*Race (h)
28 wbd undelivery rate (%)=55.74+0.0175895*Dosage (i)
32 wbd undelivery rate (%)=52.39701+0.0015266*Dosage+0.4389074*Effacement (j)
36 wbd undelivery rate (%)= -438.1751+0.0012628*Dosage-1.213703*Twin+9.768563*Parity (k)
37 wbd undelivery rate (%)= -532.5517+19.91643*Pregnancy age+1.466606*Contraction rate+0.0105139**Dosage1.116831*Contraction duration (l)
48 hours undelivery rate (%)= 55.04662-0.8398894*Twin+0.5119471*Parity+0.1818333*Race (m)
1 week undelivery rate (%) = -56.97979+0.0867009*Dosage-1.024729*Twin+4.837143*Age (n)
4. Discussion
Other dependant or independent variables participating to these relations cannot
be excluded. It is up to the inventness of any author to search for them. The
existence of a unique total model incorporating all of the above variables and
probably more, in case of a greater sample, cannot also be excluded. It is being
considered that equations [a-n] are able to suggest the most probable outcomes of a
preterm labour. Some variables are repeated more frequently than other. Their
appearance frequency in equations is up to their importance in regression analysis.
The above equations have double utility. The first is that they can be applied in
tocolytic agents comparison. This is very easily performed by the modified dependant
variables comparison after equalising the mean independent variable values by the
above equations. The outcome will be the minimizing of meta-comparison
heterogenity, and affording more reliable outcomes. The second is that they can be
applied as well as for a unique woman too. As example whether an primary center
obstetrician finds that the possibility of a woman is over >50% by using the equation
(m), rather he has the time to carry this woman in a tertiary center with neonatal
intensive care unit available. In that last case, some variables as parity I rate are
dummy and receive the value either 1 or 0 according to existence or not of what they
mean. Setting the findings (or variables) from history and clinical examination as well
as the amount of scheduled atosiban dosage, a reliable probability of preterm labour
outcome estimation is received. Due to the fact that these equations depict only
correlation and not causation, may direct researchers to investigate any causal
relationship existed. Of course, equations utility is unusual for the mean obstetrician
and awkward in clinical practice, but combined with history and physical examination
data, they reward also in prediction ability.
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