DOI: https://doi.org/10.21203/rs.3.rs-2208516/v1
Background: Atosiban has shown ameliorative effects in preterm birth (PTB), repeated implantation failure, and breech delivery by suppressing contractions, but its safety profile has not been fully established.
Methods: Published randomized controlled trials and observational studies was electronically searched from inception to September 1, 2022. Our primary outcomes were maternal adverse events and neonatal comorbidities. Random effects model was used for data synthesis, and pooled risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were calculated.
Results: 43 studies comprising 11,772 patients were identified eligible. The incidence of maternal adverse events in atosiban group and controls were 4.0% and 12.4%, respectively. Overall, the risk of maternal adverse events and the discontinuation of treatment due to adverse events were significantly lower with atosiban compared with controls (RR 0.38, 95% CI [0.23, 0.61], P < 0.0001; RR 0.11, 95% CI [0.04, 0.29], P < 0.00001; respectively). The incidence of neonatal comorbidities was similar, and a higher risk of neonatal apnoea was observed in atosiban group compared with controls (RR 1.40, 95% CI [1.04, 1.90], P = 0.03).
Conclusion: Atosiban has comparable efficacy and substantial better safety profile in the management of PTB, in vitro fertilization-embryo transfer (IVF-ET) and external cephalic version (ECV) compared with controls. Additionally, awareness of the presence of neonatal apnoea is required. In clinical practice, the appropriate treatment regimen needs to be selected according to the local circumstances and the individual patient condition.
Preterm birth (PTB),[1] repeated implantation failure (RIF)[2] and breech birth[3] are common disorders in obstetrics that can cause serious consequences. According to a systematic analysis of PTB rates, an estimated 14.9 million babies were born prematurely worldwide, with an average rate of 11.1%.[4] The burden of PTB is substantial,[4] as its comorbidities contribute significantly to child morbidity and are the leading causes of deaths in children under 5 years of age,[5] placing economic and psychological stress on families and increasing significant societal costs.[6] In vitro fertilization-embryo transfer (IVF-ET) is an assisted reproduction technology (ART). The overall implantation rate in ART is approximately 30%,[2, 7] and the incidence of repeated implantation failure (RIF) in patients undergoing IVF is as high as 10%-15%.[7, 8] Breech presentation occurs in 3–5% of all pregnancies at term and account for the largest proportion of non-cephalic presentations.[9] Babies in a breech position are thought to be at higher risk of comorbidities during vaginal delivery.[10] Cesarean section reduces the risk of adverse outcomes in breech newborns, but is also considered the primary contributor to maternal morbidity after delivery.[9, 10]
Atosiban is a nonapeptide, desamino-oxytocin analogue, and a competitive vasopressin/oxytocin receptor antagonist that inhibits uterine contractions,[11, 12] and also boosts endometrial perfusion by suppressing oxytocin-mediated release of prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-α) from the decidua.[12–15] Based on the results of several clinical trials, the effectiveness of atosiban for the treatment of PTB, assisted reproduction, and conversion of breech position by decreasing uterine contractility and improving uterine blood supply has been demonstrated. Despite advances in the treatment of these conditions, the safety of atosiban remains controversial, including maternal adverse events and neonatal comorbidities. In view of the potential usefulness of atosiban in PTB, IVF-ET and external cephalic version (ECV), we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies to comprehensively assess the benefit and risk of atosiban versus conventional therapy in PTB, IVF-ET and ECV.
This systematic review and meta-analysis followed the Preferred Reporting Item for Systematic Reviews and Meta-analyses (PRISMA) statement[16] and was registered with PROSPERO on August 22, 2022 (CRD42022353107).
Pubmed was electronically searched using the keyword “atosiban” from inception to September 1, 2022. In addition, the references of retrieved publications were hand searched to identify any additional studies.
Inclusion criteria: (i) Published randomized controlled trials (RCTs) and observational studies, regardless of language or region; (ii) Eligible participants were women with preterm birth, women undergoing IVF-ET, and women scheduling to receive ECV; (iii) Patients treated with atosiban; (iv) Studies with available data on interested outcomes.
Exclusion criteria: (i) Single-arm studies; (ii) Atosiban was administrated in both treatment and control groups; (iii) Publications without available data on interested outcomes.
Two review authors (YZ, BD) independently searched the literature following selection criteria, screened the titles and abstracts of retrieved publications, and reviewed the full text of potential studies. Any disagreement related to study eligibility was resolved by consultation with a third review author (XF).
Our primary outcomes were maternal adverse events (overall adverse events; adverse events leading to treatment discontinuation; reported adverse events); and neonatal comorbidities (overall comorbidities; fatal/neonatal deaths; reported comorbidities). Each reported maternal adverse event and neonatal comorbidity was classified according to the system organ classes (SOCs) of the medical dictionary for regulatory activities (MedDRA) system.
Our secondary outcomes included maternal outcomes of PTB (not yet delivered at 48 hours; not yet delivered at 7 days; deliver before 28 weeks; deliver before 37 weeks); neonatal outcomes of PTB (birth weight less than 2500 grams; Apgar score less than 7 at 5 minutes; neonatal intensive care unit (NICU) admission); IVF-ET (implantation per embryo transferred; clinical pregnancy; live birth; miscarriage; multiple pregnancy; ectopic pregnancy); maternal outcome of ECV (successful ECV; failed ECV; cephalic presentation at labor; breech presentation at labor; vaginal delivery; cesarean delivery); neonatal outcomes of ECV (Apgar score less than 7 at 5 minutes; NICU admission).
Two review authors independently performed data extraction and subsequently cross-checked the extracted data for accuracy. In order to obtain more comprehensive data, we plan to aggregate data from multiple publications of the same study. Publication with the longest follow-up duration was selected in case of differences in results for the same outcome. Additional data were sought by contacting corresponding authors of publications that did not provide sufficient information.
The following items were extracted: first author; publication year; study design; study region; sample size; therapeutic regimens for treatment and control group; and outcomes of interest.
Two review authors independently assessed the quality of each included RCT using the Cochrane collaboration's tool for assessing risk of bias[17] and evaluated the quality of each eligible observational study using the tool for assessing risk of bias in non-randomised studies of interventions (ROBINS-I).[18]
We used random effects models for data synthesis, and pooled risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method for dichotomous outcomes. For each primary and secondary outcome, subgroup analysis was performed according to different control groups (Placebo/none; beta-agonists; calcium channel blockers (CCBs)). P values ≤ 0.05 were considered statistically significant. The results were performed using Review Manager (RevMan version 5.4).
The details of study selection process were summarized in Fig. 1. Of 468 studies from the literature retrieve, 79 studies were potentially eligible for full-text screening after removing obvious duplicates and screening titles, abstracts and keywords. Finally, 43 studies comprising 11,772 patients were identified eligible.
The details of study characteristics were illustrated in Table 1. The meta-analysis included 28 RCTs and 15 observational studies (12 were cohort studies and 3 were case-control studies). 27 studies were conducted in women with preterm birth, 12 in women undergoing IVF-ET, and 4 in women scheduling to receive ECV. Supplementary Appendix Figure S1 and Table S1 summarized risk of bias for each RCT and observational studies, respectively.
Author (publication year) or NCT number |
Study design |
Participants |
Country /Region |
Treatment group |
Control group |
Outcomes |
Treatment group |
Control group |
---|---|---|---|---|---|---|---|---|
(Sample size) |
(Sample size) |
|||||||
Xu (2016) |
RCT |
Threatened PTB |
China |
Atosiban (35) |
Ritodrine (35) |
Not yet delivered at 48 hours |
30/35 |
22/35 |
Not yet delivered at 7 days |
20/35 |
15/35 |
||||||
Gestational age at delivery (weeks) |
32.43 ± 3.93 |
31.27 ± 3.81 |
||||||
Maternal adverse events |
9/35 |
17/35 |
||||||
Fatal/neonatal deaths |
9/58 |
18/55 |
||||||
Vliet (2016) |
RCT |
Threatened PTB |
Netherlands and Belgium |
Atosiban (256) |
Nifedipine (249) |
Prolongation of delivery (days) |
4 (1–38) |
7 (1–40) |
Not yet delivered at 48 hours |
168/255 |
169/248 |
||||||
Not yet delivered at 7 days |
116/255 |
127/248 |
||||||
Gestational age at delivery (weeks) |
32.4 (30.1–35.8) |
33.1 (30.5–37.0) |
||||||
NICU admission |
182/294 |
155/297 |
||||||
Ventilation support |
53/286 |
42/292 |
||||||
Discontinuation of drug due to adverse events |
7/253 |
15/248 |
||||||
Perinatal adverse events |
45/294 |
42/297 |
||||||
Salim (2012) |
RCT |
PTB |
Israel |
Atosiban (70) |
Nifedipine (75) |
Not yet delivered at 48 hours |
60/70 |
69/75 |
Not yet delivered at 7 days |
55/70 |
67/75 |
||||||
Deliver before 28 weeks |
2/70 |
1/75 |
||||||
Deliver before 37 weeks |
45/70 |
31/75 |
||||||
Gestational age at delivery (weeks) |
35.2 ± 3.0 |
36.4 ± 2.8 |
||||||
Birth weight (g) |
2326 ± 627 (n = 91) |
2408 ± 658 (n = 98) |
||||||
Birth weight < 2500g |
60/91 |
54/98 |
||||||
Apgar score < 7 at 5 minutes |
1/91 |
2/98 |
||||||
NICU admission |
46/91 |
29/98 |
||||||
Ventilation support |
13/91 |
10/98 |
||||||
Neonatal deaths |
0/91 |
0/98 |
||||||
Nonnenmacher (2009) |
RCT |
PTB |
German |
Atosiban (51) |
Fenoterol (54) |
Not yet delivered at 48 hours |
44/51 |
43/54 |
Not yet delivered at 7 days |
40/51 |
36/54 |
||||||
Gestational age at delivery (weeks) |
34.1 ± 4.2 |
34.2 ± 3.4 |
||||||
Birth weight (g) |
2213 ± 889 (n = 60) |
2211 ± 756 (n = 66) |
||||||
Apgar score < 7 at 5 minutes |
8/60 |
7/66 |
||||||
Maternal adverse events |
8/51 |
53/54 |
||||||
Neonatal complications |
4/60 |
15/66 |
||||||
Lin (2009) |
RCT |
Threatened PTB |
Taiwan |
Atosiban (23) |
Ritodrine (22) |
Not yet delivered at 48 hours |
19/23 |
19/22 |
Not yet delivered at 7 days |
18/23 |
19/22 |
||||||
Gestational age at delivery (weeks) |
37.1 ± 2.5 |
37.4 ± 2.4 |
||||||
Birth weight (g) |
2900 ± 500 (n = 23) |
2800 ± 400 (n = 19) |
||||||
Apgar score < 7 at 5 minutes |
17/23 |
15/22 |
||||||
NICU admission |
17/23 |
15/22 |
||||||
Maternal adverse events |
3/23 |
4/22 |
||||||
Cabar (2008) |
RCT |
PTB |
Brasil |
Atosiban (40) |
Terbutaline (40) |
Not yet delivered at 48 hours |
39/40 |
31/40 |
Not yet delivered at 7 days |
35/40 |
9/40 |
||||||
Birth weight (g) |
2554.6 ± 530.8 |
2448.3 ± 439.0 |
||||||
Apgar score < 7 at 5 minutes |
0/40 |
0/40 |
||||||
Maternal adverse events |
11/40 |
30/40 |
||||||
Neonatal complications |
7/40 |
8/40 |
||||||
Neonatal deaths |
0/40 |
0/40 |
||||||
Heus (2008) |
RCT |
Term birth |
Netherlands |
Atosiban (70) |
Ritodrine (70) |
Gestational age at delivery (weeks) |
39.4 ± 2.5 |
39.5 ± 1.9 |
Birth weight (g) |
3306 ± 708 |
3288 ± 576 |
||||||
Husslein (2007) |
RCT |
PTB |
Europe |
Atosiban (295) |
Conventional treatment (290) |
Not yet delivered at 48 hours |
229/295 |
164/290 |
Gestational age at delivery (weeks) |
35.72 ± 4.02 (n = 282) |
35.44 ± 4.05 (n = 277) |
||||||
Maternal adverse events |
105/223 |
110/270 |
||||||
Fetal adverse events |
14/195 |
20/172 |
||||||
Fetal deaths |
1/195 |
2/172 |
||||||
Neonatal complications |
40/206 |
42/227 |
||||||
Neonatal deaths |
3/206 |
9/227 |
||||||
Shim (2006) |
RCT |
Acute PTB |
South Korea |
Atosiban (63) |
Ritodrine (63) |
Not yet delivered at 48 hours |
58/63 |
59/63 |
Not yet delivered at 7 days |
57/63 |
56/63 |
||||||
Deliver before 28 weeks |
19/63 |
7/63 |
||||||
Gestational age at delivery (weeks) |
37.3 ± 3.5 |
37.3 ± 3.1 |
||||||
Birth weight (g) |
2906 ± 763 |
3017 ± 631 |
||||||
Apgar score < 7 at 5 minutes |
1/53 |
1/48 |
||||||
NICU admission |
14/63 |
10/63 |
||||||
Ventilation support |
6/63 |
2/63 |
||||||
Maternal adverse events |
5/63 |
46/65 |
||||||
Discontinuation of drug due to adverse events |
0/63 |
13/65 |
||||||
Kashanian (2005) |
RCT |
PTB |
Iran |
Atosiban (40) |
Nifedipine (40) |
Prolongation of delivery (days) |
29.03 ± 16.12 |
22.85 ± 13.9 |
Not yet delivered at 48 hours |
33/40 |
30/40 |
||||||
Not yet delivered at 7 days |
30/40 |
26/40 |
||||||
Maternal adverse events |
7/40 |
16/40 |
||||||
Al-Omari (2004) |
RCT |
PTB |
Iraq |
Atosiban (31) |
Nifedipine (32) |
Not yet delivered at 48 hours |
24/31 |
26/31 |
Not yet delivered at 7 days |
23/31 |
22/31 |
||||||
Deliver before 28 weeks |
2/31 |
3/32 |
||||||
Neonatal deaths |
6/31 |
5/32 |
||||||
French/Australian Atosiban Investigators Group (2001) |
RCT |
PTB |
France/ Australia |
Atosiban (119) |
Salbutamol (122) |
Gestational age at delivery (weeks) |
36.5 ± 3.0 |
36.3 ± 3.7 |
Birth weight (g) |
2708 ± 743 |
2619 ± 743 |
||||||
Apgar score < 7 at 5 minutes |
4/129 |
5/143 |
||||||
NICU admission |
26/129 |
25/143 |
||||||
Discontinuation of drug due to adverse events |
1/119 |
13/122 |
||||||
Fatal deaths |
1/129 |
2/143 |
||||||
Neonatal deaths |
0/129 |
2/143 |
||||||
Worldwide Atosiban versus Beta-agonists Study Group (2001) |
RCT |
PTB |
Global |
Atosiban (361) |
Beta-agonists (372) |
Not yet delivered at 48 hours |
317/361 |
330/372 |
Not yet delivered at 7 days |
287/361 |
288/372 |
||||||
Gestational age at delivery (weeks) |
35.8 ± 3.8 |
35.5 ± 4.1 |
||||||
Birth weight (g) |
2941 ± 813 |
2641 ± 831 |
||||||
NICU admission |
127/405 |
128/430 |
||||||
Discontinuation of drug due to adverse events |
4/361 |
56/372 |
||||||
Fatal/neonatal deaths |
6/361 |
12/372 |
||||||
European Atosiban Study Group (2001) |
RCT |
PTB |
Europe |
Atosiban (116) |
Terbutaline (129) |
Not yet delivered at 48 hours |
99/116 |
110/129 |
Not yet delivered at 7 days |
88/116 |
87/129 |
||||||
Deliver before 28 weeks |
24/130 |
43/135 |
||||||
Gestational age at delivery (weeks) |
35.1 ± 4.1 (n = 130) |
34.6 ± 4.4 (n = 135) |
||||||
Birth weight (g) |
2473 ± 819 (n = 130) |
2356 ± 929 (n = 135) |
||||||
Apgar score < 7 at 5 minutes |
2/130 |
8/135 |
||||||
NICU admission |
44/130 |
64/135 |
||||||
Discontinuation of drug due to adverse events |
2/119 |
17/129 |
||||||
Moutquin (2000) |
RCT |
PTB |
Canada /Israel |
Atosiban (126) |
Ritodrine (121) |
Not yet delivered at 48 hours |
107/126 |
105/121 |
Not yet delivered at 7 days |
92/126 |
92/121 |
||||||
Gestational age at delivery (weeks) |
35.1 ± 4.2 (n = 146) |
35.2 ± 4.0 (n = 135) |
||||||
Birth weight (g) |
2314 ± 825 (n = 146) |
2478 ± 759 (n = 135) |
||||||
Birth weight < 2500g |
80/146 |
69/135 |
||||||
Apgar score < 7 at 5 minutes |
5/144 |
4/135 |
||||||
NICU admission |
57/146 |
39/135 |
||||||
Discontinuation of drug due to adverse events |
1/126 |
36/135 |
||||||
Fatal deaths |
0/146 |
0/135 |
||||||
Neonatal deaths |
2/146 |
1/135 |
||||||
Romero (2000) |
RCT |
PTB |
United State |
Atosiban (246) |
Placebo (255) |
Not yet delivered at 48 hours |
165/246 |
142/255 |
Not yet delivered at 7 days |
153/246 |
125/254 |
||||||
Deliver before 28 weeks |
12/44 |
4/33 |
||||||
Birth weight (g) |
2336.8 ± 787.26 (n = 286) |
2450.4 ± 741.63 (n = 292) |
||||||
NICU admission |
115/274 |
110/286 |
||||||
Fatal deaths |
3/286 |
3/292 |
||||||
Neonatal deaths |
13/286 |
5/292 |
||||||
Valenzuela (2000) |
RCT |
PTB |
United State |
Atosiban (261) |
Placebo (251) |
Deliver before 28 weeks |
7/45 |
6/29 |
Birth weight (g) |
2746.9 ± 792.14 (n = 289) |
2746.8 ± 796.16 (n = 269) |
||||||
NICU admission |
61/284 |
68/266 |
||||||
Fatal deaths |
0/251 |
1/261 |
||||||
Neonatal deaths |
5/251 |
4/261 |
||||||
Goodwin (1996) |
RCT |
PTB |
United State |
Atosiban (244) |
Placebo (58) |
Not yet delivered at 48 hours |
215/244 |
49/58 |
Birth weight < 2500g |
68/238 |
20/56 |
||||||
Goodwin (1994) |
RCT |
Preterm uterine activity |
United State |
Atosiban (60) |
Placebo (60) |
Gestational age at delivery (weeks) |
37.8 ± 3.5 (n = 57) |
38.3 ± 2.1 (n = 57) |
Birth weight (g) |
2996 ± 750 (n = 57) |
3224 ± 525 (n = 57) |
||||||
Maternal adverse events |
2/56 |
3/56 |
||||||
Neonatal complications |
15/57 |
11/57 |
||||||
Buddhabunyakan (2021) |
RCT |
IVF-ET |
Thailand |
Atosiban (25) |
Placebo (25) |
Implantation per embryo transferred |
12/32 |
9/29 |
Clinical pregnancy |
11/25 |
9/25 |
||||||
Miscarriage |
3/25 |
3/25 |
||||||
Multiple pregnancy |
1/31 |
9/25 |
||||||
Yuan (2019) |
RCT |
IVF-ET |
China |
Atosiban (102) |
Placebo (102) |
Implantation per embryo transferred |
56/215 |
21/217 |
Clinical pregnancy |
46/102 |
16/102 |
||||||
Miscarriage |
6/46 |
4/16 |
||||||
Ectopic pregnancy |
0/46 |
0/46 |
||||||
Multiple pregnancy |
10/46 |
5/16 |
||||||
Maternal adverse events |
0/102 |
0/102 |
||||||
He-a (2016) |
RCT |
IVF-ET |
China |
Atosiban (60) |
Placebo (60) |
Implantation per embryo transferred |
50/122 |
30/128 |
Clinical pregnancy |
35/60 |
23/60 |
||||||
Miscarriage |
3/35 |
2/23 |
||||||
Multiple pregnancy |
11/35 |
6/23 |
||||||
Hebisha (2016) |
RCT |
IVF/ICSI |
Egypt |
Atosiban (91) |
Placebo (91) |
Implantation per embryo transferred |
67/146 |
50/147 |
Clinical pregnancy |
58/91 |
44/91 |
||||||
Ng (2014) |
RCT |
IVF-ET |
Vietnam |
Atosiban (400) |
Placebo (400) |
Clinical pregnancy |
201/400 |
187/400 |
Live birth |
159/400 |
152/400 |
||||||
Miscarriage |
37/217 |
35/198 |
||||||
Ectopic pregnancy |
9/217 |
10/198 |
||||||
Multiple pregnancy |
65/217 |
68/198 |
||||||
Maternal adverse events |
1/400 |
3/400 |
||||||
Song (2013) |
RCT |
IVF-ET |
China |
Atosiban (60) |
None (60) |
Implantation per embryo transferred |
48/60 |
31/60 |
Clinical pregnancy |
36/60 |
25/42 |
||||||
Miscarriage |
2/36 |
4/25 |
||||||
Maternal adverse events |
0/60 |
0/60 |
||||||
Moraloglu (2010) |
RCT |
IVF-ET |
Turkey |
Atosiban (90) |
Placebo (90) |
Implantation per embryo transferred |
57/279 |
34/270 |
Clinical pregnancy |
42/90 |
26/90 |
||||||
Miscarriage |
7/42 |
6/26 |
||||||
Maternal adverse events |
1/279 |
2/270 |
||||||
Ahn (2009) |
RCT |
IVF/ICSI |
South Korea |
Atosiban (20) |
None (20) |
Implantation per embryo transferred |
11/65 |
4/67 |
Clinical pregnancy |
8/20 |
4/20 |
||||||
Velzel (2017) |
RCT |
ECV |
Netherlands |
Atosiban (410) |
Fenoterol (408) |
Successful ECV |
140/416 |
144/414 |
Cephalic presentation at labor |
139/416 |
169/414 |
||||||
Vaginal delivery |
163/416 |
160/414 |
||||||
Cesarean delivery |
240/416 |
218/414 |
||||||
Birth weight |
3356 ± 460 |
3364 ± 523 |
||||||
Apgar < 7 at 5 minutes |
6/410 |
13/418 |
||||||
NICU admission |
16/410 |
17/408 |
||||||
Maternal adverse events |
15/385 |
16/386 |
||||||
Fatal deaths |
0/410 |
0/408 |
||||||
Neonatal deaths |
0/410 |
2/408 |
||||||
Fu (2021) |
Retrospective cohort study |
Threatened PTB |
China |
Atosiban + Ritodrine (30) |
Ritodrine (22) |
Prolongation of delivery (days) |
42.53 ± 31.70 |
93.55 ± 42.29 |
Birth weight (g) |
1950 ± 940 |
2470 ± 980 |
||||||
Apgar score at 1 minute |
8.36 ± 2.08 |
8.70 ± 1.53 |
||||||
Yu (2020) |
Retrospective cohort study |
Threatened PTB |
China |
Atosiban (28) |
Conventional treatment (33) |
Prolongation of delivery (days) |
7.35 ± 5.64 |
7.22 ± 5.53 |
Not yet delivered at 48 hours |
27/28 |
32/33 |
||||||
Deliver before 28 weeks |
4/28 |
5/33 |
||||||
Gestational age at delivery (weeks) |
37.8 ± 3.82 |
36.63 ± 3.53 |
||||||
Birth weight (g) |
2314 ± 825 |
2478 ± 759 |
||||||
Maternal adverse events |
0/28 |
beta-agonists: 5/21 |
||||||
Gómez (2018) |
Retrospective cohort study |
Threatened PTB |
Spain |
Atosiban (100) |
No atosiban (200) |
Gestational age at delivery (weeks) |
39 (38–39) |
39 (39–41) |
Birth weight (g) |
3166 ± 344 |
3294 ± 411 |
||||||
Apgar score < 7 at 5 minutes |
0/100 |
0/200 |
||||||
Heus (2009) |
Prospective cohort study |
Threatened PTB |
Netherlands and Belgium |
Atosiban (575) |
Conventional treatment (753) |
Maternal adverse events |
1/575 |
18/752 |
Fatal deaths |
0/575 |
0/752 |
||||||
Neonatal deaths |
0/575 |
0/752 |
||||||
Locci (2006) |
Retrospective cohort study |
High risk of PTB /ICSI |
Italy |
Atosiban (16) |
Ritodrine (16) |
Gestational age at delivery (weeks) |
35.9 ± 2.05 |
33.5 ± 2.4 |
Birth weight < 2500g |
12/25 |
15/20 |
||||||
Apgar score < 7 at 5 minutes |
7/25 |
10/18 |
||||||
He-b (2016) |
Prospective cohort study |
IVF-ET |
China |
Atosiban (294) |
None (294) |
Implantation per embryo transferred |
194/491 |
196/588 |
Clinical pregnancy |
130/242 |
137/294 |
||||||
Miscarriage |
13/242 |
15/294 |
||||||
Zhang (2014) |
Retrospective cohort study |
IVF-ET |
China |
Atosiban (120) |
None (120) |
Implantation per embryo transferred |
75/278 |
41/250 |
Clinical pregnancy |
61/120 |
35/120 |
||||||
Live birth |
50/120 |
25/120 |
||||||
Miscarriage |
5/61 |
4/35 |
||||||
Ectopic pregnancy |
2/61 |
3/35 |
||||||
Multiple pregnancy |
20/61 |
8/35 |
||||||
Chou (2011) |
Retrospective cohort study |
IVF-ET |
Taiwan |
Atosiban (70) |
None (80) |
Implantation per embryo transferred |
40/165 |
21/178 |
Clinical pregnancy |
21/70 |
10/80 |
||||||
Live birth |
19/70 |
8/80 |
||||||
Miscarriage |
2/21 |
2/10 |
||||||
Multiple pregnancy |
7/21 |
1/10 |
||||||
Naveira (2020) |
Prospective cohort study |
ECV |
Spain |
Atosiban (215) |
Ritodrine (215) |
Successful ECV |
99/215 |
107/215 |
Failed ECV |
116/215 |
108/215 |
||||||
Cephalic presentation at labor |
96/215 |
108/215 |
||||||
Breech presentation at labor |
119/215 |
107/215 |
||||||
Vaginal delivery |
75/215 |
82/215 |
||||||
Cesarean delivery |
140/215 |
133/215 |
||||||
Birth weight |
3201.6 ± 430.2 |
3171.5 ± 421.5 |
||||||
Apgar < 7 at 1 min |
4/215 |
1/215 |
||||||
Apgar < 7 at 5 min |
0/215 |
1/215 |
||||||
NICU admission |
12/215 |
15/215 |
||||||
Burgos (2010) |
Prospective cohort study |
ECV |
Spain |
Atosiban (118) |
Ritodrine (118) |
Successful ECV |
37/118 |
67/118 |
Failed ECV |
81/118 |
51/118 |
||||||
Cephalic presentation at labor |
38/118 |
67/118 |
||||||
Breech presentation at labor |
80/118 |
51/118 |
||||||
Vaginal delivery |
50/118 |
75/118 |
||||||
Cesarean delivery |
68/118 |
43/118 |
||||||
Apgar < 7 at 5 minutes |
2/118 |
2/118 |
||||||
NICU admission |
5/118 |
4/118 |
||||||
Maternal complications |
0/118 |
5/118 |
||||||
Stergiotou (2007) |
Retrospective cohort study |
ECV |
United Kingdom |
Atosiban (21) |
Ritodrine (17) |
Successful ECV |
6/21 |
7/17 |
Maternal complications |
0/21 |
0/17 |
||||||
Cardoso (2018) |
Prospective cohort study |
PTB |
France |
Atosiban (314) |
Nifedipine/ Nicardipine (118) |
Neonatal deaths |
23/121 |
41/214 |
Madkour (2013) |
Prospective case-control study |
PTB |
United Arab Emirates |
Atosiban (50) |
Nifedipine (50) |
Not yet delivered at 7 days |
28/50 |
30/50 |
Atosiban + Nifedipine (50) |
43/50 |
|||||||
Duchateau (2010) |
Retrospective Case-control study |
Threatened PTB |
France |
Atosiban (14) |
Nicardipine (42) |
The aim of this study was to compare the frequency of tocolysis-induced hypotension. |
||
Mishra (2018) |
Prospective Case-control study |
IVF-ET |
India |
Atosiban (160) |
Placebo (160) |
Implantation per embryo transferred |
80/457 |
81/489 |
Clinical pregnancy |
58/160 |
48/160 |
||||||
Miscarriage |
8/66 |
6/56 |
||||||
Ectopic pregnancy |
3/66 |
3/56 |
||||||
Abbreviation: | ||||||||
RCT, randomized controlled trial; PTB, preterm birth; IVF-ET, in vitro fertilization and embryo transfer; ECV, external cephalic version. |
The overall safety outcomes are summarized in Table 2, maternal adverse events according to different systems and control groups are shown in Table 3, and neonatal comorbidities according to different systems and controls are illustrated in Table 4.
Outcomes |
Type of control |
No. of studies |
Incidence |
RR [95% CI] |
P value |
Total |
Subgroup differences (P value) |
|||||
T (%) |
C (%) |
Incidence |
RR [95% CI] |
P value |
||||||||
T (%) |
C (%) |
|||||||||||
Preterm birth |
Not yet delivered at 48 hours |
Placebo/none |
2 |
77.6 |
61 |
1.12 [0.96, 1.30] |
0.17 |
79.7 |
75.7 |
1.03 [0.98, 1.08] |
0.25 |
0.15 |
Beta-agonist |
8 |
86.8 |
84.1 |
1.03 [0.97, 1.10] |
0.3 |
|||||||
CCB |
4 |
72 |
74.6 |
0.96 [0.89, 1.04] |
0.3 |
|||||||
Not yet delivered at 7 days |
Placebo/none |
1 |
62.2 |
49.2 |
1.26 [1.08, 1.48] |
0.004 |
69.7 |
65.1 |
1.07 [0.98, 1.18] |
0.12 |
0.02 |
|
Beta-agonist |
7 |
77.1 |
70.6 |
1.13 [0.97, 1.33] |
0.12 |
|||||||
CCB |
6 |
63 |
64.7 |
0.99 [0.90, 1.08] |
0.78 |
|||||||
Deliver before 28 weeks |
Placebo/none |
2 |
21.3 |
16.1 |
1.28 [0.44, 3.78] |
0.65 |
17.2 |
17.4 |
1.19 [0.59, 2.40] |
0.63 |
0.97 |
|
Beta-agonist |
2 |
22.3 |
25.3 |
1.21 [0.27, 5.52] |
0.81 |
|||||||
CCB |
2 |
4 |
3.7 |
1.02 [0.25, 4.10] |
0.98 |
|||||||
Deliver before 37 weeks |
CCB |
1 |
64.3 |
41.3 |
1.56 [1.13, 2.14] |
0.007 |
64.3 |
41.3 |
1.56 [1.13, 2.14] |
0.007 |
NA |
|
Birth weight < 2500g |
Placebo/none |
1 |
28.6 |
35.7 |
0.8 [0.53, 1.20] |
0.28 |
44 |
51.1 |
0.97 [0.76, 1.22] |
0.77 |
0.17 |
|
Beta-agonist |
2 |
53.8 |
54.2 |
0.87 [0.53, 1.43] |
0.57 |
|||||||
CCB |
1 |
65.9 |
55.1 |
1.2 [0.95, 1.51] |
0.13 |
|||||||
Apgar score < 7 at 5 minutes |
Placebo/none |
1 |
0 |
0 |
Not estimable |
NA |
5.7 |
5.7 |
0.91 [0.68, 1.22] |
0.53 |
0.69 |
|
Beta-agonist |
8 |
7.3 |
8.2 |
0.88 [0.62, 1.26] |
0.48 |
|||||||
CCB |
1 |
1.1 |
2 |
0.54 [0.05, 5.84] |
0.61 |
|||||||
NICU admission |
Placebo/none |
2 |
31.5 |
32.2 |
0.98 [0.76, 1.26] |
0.89 |
28 |
26 |
1.08 [0.96, 1.23] |
0.2 |
0.29 |
|
Beta-agonist |
9 |
19.4 |
19 |
1.03 [0.88, 1.20] |
0.72 |
|||||||
CCB |
2 |
59.2 |
46.6 |
1.37 [0.96, 1.95] |
0.08 |
|||||||
IVF-ET |
Implantation per embryo transferred |
Placebo/none |
11 |
30.0 |
21.4 |
1.52 [1.29, 1.79] |
< 0.00001 |
30.0 |
21.4 |
1.52 [1.29, 1.79] |
< 0.00001 |
NA |
Clinical pregnancy |
Placebo/none |
12 |
49.1 |
38.0 |
1.39 [1.18, 1.62] |
< 0.0001 |
49.1 |
38.0 |
1.39 [1.18, 1.62] |
< 0.0001 |
NA |
|
Live birth |
Placebo/none |
3 |
38.6 |
30.8 |
1.66 [0.92, 3.01] |
0.09 |
38.6 |
30.8 |
1.66 [0.92, 3.01] |
0.09 |
NA |
|
Miscarriage |
Placebo/none |
10 |
10.9 |
11.4 |
0.87 [0.66, 1.16] |
0.35 |
10.9 |
11.4 |
0.87 [0.66, 1.16] |
0.35 |
NA |
|
Multiple pregnancy |
Placebo/none |
6 |
27.7 |
31.6 |
0.95 [0.60, 1.51] |
0.82 |
27.7 |
31.6 |
0.95 [0.60, 1.51] |
0.82 |
NA |
|
Ectopic pregnancy |
Placebo/none |
4 |
3.6 |
4.8 |
0.73 [0.36, 1.47] |
0.38 |
3.6 |
4.8 |
0.73 [0.36, 1.47] |
0.38 |
NA |
|
ECV |
Successful ECV |
Beta-agonist |
4 |
36.6 |
42.5 |
0.80 [0.62, 1.05] |
0.10 |
36.6 |
42.5 |
0.80 [0.62, 1.05] |
0.10 |
NA |
Failed ECV |
Beta-agonist |
2 |
59.2 |
47.7 |
1.30 [0.88, 1.90] |
0.19 |
59.2 |
47.7 |
1.30 [0.88, 1.90] |
0.19 |
NA |
|
Cephalic presentation at labor |
Beta-agonist |
3 |
35.2 |
46.1 |
0.75 [0.60, 0.93] |
0.01 |
35.2 |
46.1 |
0.75 [0.60, 0.93] |
0.01 |
NA |
|
Breech presentation at labor |
Beta-agonist |
2 |
35.7 |
47.4 |
1.31 [0.93, 1.83] |
0.12 |
35.7 |
47.4 |
1.31 [0.93, 1.83] |
0.12 |
NA |
|
Vaginal delivery |
Beta-agonist |
3 |
38.5 |
42.4 |
0.86 [0.67, 1.10] |
0.24 |
38.5 |
42.4 |
0.86 [0.67, 1.10] |
0.24 |
NA |
|
Cesarean delivery |
Beta-agonist |
3 |
59.8 |
52.7 |
1.17 [0.98, 1.40] |
0.08 |
59.8 |
52.7 |
1.17 [0.98, 1.40] |
0.08 |
NA |
|
Apgar < 7 at 5 min |
Beta-agonist |
3 |
1.1 |
2.1 |
0.53 [0.23, 1.21] |
0.13 |
1.1 |
2.1 |
0.53 [0.23, 1.21] |
0.13 |
NA |
|
NICU admission |
Beta-agonist |
3 |
4.4 |
4.9 |
0.91 [0.58, 1.45] |
0.70 |
4.4 |
4.9 |
0.91 [0.58, 1.45] |
0.70 |
NA |
|
Safety |
Maternal adverse events |
Placebo/none |
5 |
0.4 |
0.9 |
0.51 [0.15, 1.68] |
0.27 |
4 |
12.4 |
0.38 [0.23, 0.61] |
< 0.0001 |
0.85 |
Beta-agonist |
6 |
8.5 |
27.6 |
0.35 [0.19, 0.68] |
0.002 |
|||||||
CCB |
1 |
17.5 |
40 |
0.44 [0.20, 0.95] |
0.04 |
|||||||
Discontinuation of drug due to adverse events |
Beta-agonist |
5 |
1 |
16.4 |
0.07 [0.04, 0.14] |
< 0.00001 |
1.4 |
14 |
0.11 [0.04, 0.29] |
< 0.00001 |
0.001 |
|
CCB |
1 |
2.8 |
6 |
0.46 [0.19, 1.10] |
0.08 |
|||||||
Neonatal comorbidities |
Placebo/none |
1 |
26.3 |
19.3 |
1.36 [0.69, 2.71] |
0.38 |
16.7 |
16.5 |
0.89 [0.53, 1.50] |
0.67 |
0.34 |
|
Beta-agonist |
2 |
11 |
21.7 |
0.52 [0.18, 1.54] |
0.24 |
|||||||
CCB |
1 |
15.3 |
14.1 |
1.08 [0.73, 1.60] |
0.69 |
|||||||
Fatal/neonatal deaths |
Placebo/none |
2 |
3.9 |
2.4 |
1.65 [0.83, 3.29] |
0.15 |
3.5 |
4.7 |
0.87 [0.58, 1.30] |
0.5 |
0.02 |
|
Beta-agonist |
6 |
1.6 |
3.2 |
0.49 [0.29, 0.83] |
0.009 |
|||||||
CCB |
3 |
11.9 |
13.4 |
1.03 [0.67, 1.57] |
0.9 |
|||||||
Abbreviation: PTB, preterm birth; IVF-ET, in vitro fertilization and embryo transfer; ECV, external cephalic version; T, treatment group; C, control group; RR, risk ratio; CI, confidence interval; CCB, calcium channel blocker; NA, not available; g, gram; NICU, neonatal intensive care unit. Significant differences (P value ≤ 0.05) are shown in bold. |
Primary SOC |
Maternal adverse events |
Type of control |
No. of studies |
Incidence |
RR [95% CI] |
P value |
Total |
Subgroup differences (P value) |
||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
T (%) |
C (%) |
Incidence |
RR [95% CI] |
P value |
|
|
|
|
|
|
|
|
T (%) |
C (%) |
|||||||||||
Cardiac disorders |
Palpitation |
CCB |
4 |
6/191 (3.1) |
20/197 (10.2) |
0.37 [0.10, 1.33] |
< 0.00001 |
43/1398 (3.1) |
476/1418 (33.6) |
0.15 [0.08, 0.28] |
< 0.00001 |
0.1 |
Beta-agonist |
7 |
37/1207 (3.1) |
456/1221 (37.3) |
0.11 [0.05, 0.22] |
0.13 |
|||||||
Chest pain |
Placebo/none |
3 |
8/735 (1.1) |
16/560 (2.9) |
0.22 [0.09, 0.51] |
0.0004 |
20/1534 (1.3) |
56/1374 (4.1) |
0.27 [0.16, 0.45] |
< 0.00001 |
0.28 |
|
CCB |
1 |
1/31 (3.2) |
0/32 (0) |
3.09 [0.13, 73.17] |
0.48 |
|||||||
Beta-agonist |
6 |
11/768 (1.4) |
40/782 (5.1) |
0.27 [0.14, 0.55] |
0.0003 |
|||||||
Tachycardia |
Placebo/none |
3 |
4/755 (0.5) |
24/560 (4.3) |
0.17 [0.01, 2.58] |
0.20 |
52/3139 (1.7) |
708/2518 (28.1) |
0.09 [0.06, 0.15] |
< 0.00001 |
0.36 |
|
CCB |
4 |
2/716 (0.3) |
15/689 (2.2) |
0.19 [0.06, 0.66] |
0.008 |
|||||||
Beta-agonist |
10 |
43/1473 (2.9) |
620/1079 (57.5) |
0.08 [0.05, 0.13] |
< 0.00001 |
|||||||
Myocardial ischaemia |
Beta-agonist |
2 |
0/480 (0) |
2/494 (0.4) |
0.34 [0.04, 3.28] |
0.35 |
0/480 (0) |
2/494 (0.4) |
0.34 [0.04, 3.28] |
0.35 |
NA |
|
Arrhythmia |
Beta-agonist |
1 |
1/126 (0.8) |
0/121 (0) |
2.88 [0.12, 70.06] |
0.52 |
1/126 (0.8) |
0/121 (0) |
2.88 [0.12, 70.06] |
0.52 |
NA |
|
Gastrointestinal disorders |
Nausea |
Placebo/none |
3 |
16/474 (3.4) |
12/298 (4.0) |
0.85 [0.12, 5.99] |
0.87 |
134/2585 (5.2) |
137/2006 (6.8) |
0.96 [0.58, 1.59] |
0.86 |
0.28 |
CCB |
3 |
24/676 (3.6) |
4/649 (0.6) |
3.25 [0.56, 18.92] |
0.19 |
|||||||
Beta-agonist |
8 |
94/1435 (6.6) |
121/1059 (11.4) |
0.77 [0.59, 0.99] |
0.04 |
|||||||
Vomiting |
Placebo/none |
1 |
4/244 (1.6) |
13/58 (22.4) |
0.07 [0.02, 0.22] |
< 0.00001 |
57/1130 (5.0) |
180/974 (18.5) |
0.28 [0.17, 0.46] |
< 0.00001 |
0.006 |
|
CCB |
2 |
3/101 (3.0) |
2/107 (1.9) |
1.55 [0.28, 8.64] |
0.62 |
|||||||
Beta-agonist |
5 |
50/785 (6.4) |
165/809 (20.4) |
0.32 [0.24, 0.43] |
< 0.00001 |
|||||||
Constipation |
Beta-agonist |
1 |
2/35 (5.7) |
1/35 (2.9) |
2.00 [0.19, 21.06] |
0.56 |
2/35 (5.7) |
1/35 (2.9) |
2.00 [0.19, 21.06] |
0.56 |
NA |
|
Nervous system disorders |
Headache |
Placebo/none |
1 |
12/244 (4.9) |
8/58 (13.8) |
0.36 [0.15, 0.83] |
0.02 |
97/1870 (5.2) |
181/1314 (13.8) |
0.51 [0.40, 0.64] |
< 0.00001 |
0.67 |
CCB |
4 |
11/191 (5.8) |
26/197 (13.2) |
0.47 [0.22, 0.99] |
0.05 |
|||||||
Beta-agonist |
8 |
74/1435 (5.2) |
147/1059 (13.9) |
0.53 [0.41, 0.69] |
< 0.00001 |
|||||||
Tremor |
CCB |
1 |
0/50 (0) |
0/50 (0) |
Not estimable |
NA |
10/870 (1.1) |
118/894 (13.2) |
0.10 [0.06, 0.19] |
< 0.00001 |
NA |
|
Beta-agonist |
6 |
10/820 (1.2) |
118/844 (14.0) |
0.10 [0.06, 0.19] |
< 0.00001 |
|||||||
Syncope |
CCB |
1 |
0/31 (0) |
2/32 (6.3) |
0.21 [0.01, 4.13] |
0.30 |
4/634 (0.6) |
6/654 (0.9) |
0.79 [0.23, 2.75] |
0.71 |
0.33 |
|
Beta-agonist |
3 |
4/603 (0.7) |
4/622 (0.6) |
1.05 [0.27, 4.11] |
0.95 |
|||||||
Dizziness |
Beta-agonist |
3 |
28/549 (5.1) |
56/549 (10.2) |
0.73 [0.16, 3.26] |
0.68 |
28/549 (5.1) |
56/549 (10.2) |
0.73 [0.16, 3.26] |
0.68 |
NA |
|
Vascular disorders |
Hypotension |
Beta-agonist |
6 |
24/820 (2.9) |
44/844 (5.2) |
0.60 [0.36, 0.98] |
0.04 |
34/1866 (1.8) |
87/1866 (4.7) |
0.49 [0.29, 0.82] |
0.007 |
0.33 |
CCB |
7 |
10/1046 (1) |
43/1022 (4.2) |
0.35 [0.13, 0.92] |
0.03 |
|||||||
Flushing |
CCB |
2 |
6/81 (7.4) |
20/82 (24.4) |
0.36 [0.05, 2.80] |
0.33 |
27/471 (5.7) |
121/482 (25.1) |
0.31 [0.12, 0.83] |
0.02 |
0.83 |
|
Beta-agonist |
3 |
18/390 (4.6) |
101/400 (25.3) |
0.28 [0.07, 1.09] |
0.07 |
|||||||
Hypertension |
CCB |
1 |
8/255 (3.1) |
8/248 (3.2) |
0.97 [0.37, 2.55] |
0.95 |
8/255 (3.1) |
8/248 (3.2) |
0.97 [0.37, 2.55] |
0.95 |
NA |
|
General disorders and administration site conditions |
Injection site reactions |
CCB |
1 |
0/75 (0) |
0/75 (0) |
Not estimable |
NA |
236/762 (31.0) |
145/753 (19.3) |
1.57 [1.15, 2.14] |
0.005 |
0.07 |
Placebo/none |
3 |
234/671 (34.9) |
140/662 (21.1) |
1.59 [1.37, 1.83] |
< 0.00001 |
|||||||
Beta-agonist |
1 |
2/16 (12.5) |
5/16 (31.3) |
0.40 [0.09, 1.77] |
0.23 |
|||||||
Chest tightness |
Beta-agonist |
1 |
3/63 (4.8) |
17/65 (26.2) |
0.18 [0.06, 0.59] |
0.005 |
3/63 (4.8) |
17/65 (26.2) |
0.18 [0.06, 0.59] |
0.005 |
NA |
|
Respiratory, thoracic and mediastinal disorders |
Dysponea |
CCB |
2 |
1/606 (0.2) |
2/574 (0.3) |
0.63 [0.08, 4.98] |
0.66 |
5/2159 (0.2) |
87/1751 (5.0) |
0.11 [0.05, 0.23] |
< 0.00001 |
0.08 |
Beta-agonist |
9 |
4/1553 (0.3) |
85/1177 (7.2) |
0.09 [0.04, 0.19] |
< 0.00001 |
|||||||
Pulmonary oedema |
Beta-agonist |
4 |
2/724 (0.3) |
5/733 (0.7) |
0.52 [0.13, 2.12] |
0.36 |
2/724 (0.3) |
5/733 (0.7) |
0.52 [0.13, 2.12] |
0.36 |
NA |
|
Shortness of breath |
Beta-agonist |
1 |
1/126 (0.8) |
1/121 (0.8) |
0.96 [0.06, 15.18] |
0.98 |
1/126 (0.8) |
1/121 (0.8) |
0.96 [0.06, 15.18] |
0.98 |
NA |
|
Metabolism and nutrition disorders |
Hyperglycaemia |
CCB |
1 |
3/255 (1.2) |
1/248 (0.4) |
2.92 [0.31, 27.86] |
0.35 |
59/1040 (5.7) |
105/1057 (9.9) |
0.62 [0.39, 1.00] |
0.05 |
0.17 |
Beta-agonist |
5 |
56/785 (7.1) |
104/809 (12.9) |
0.58 [0.37, 0.90] |
0.02 |
|||||||
Hypokalaemia |
Beta-agonist |
5 |
6/785 (0.8) |
55/809 (6.8) |
0.14 [0.06, 0.30] |
< 0.00001 |
6/785 (0.8) |
55/809 (6.8) |
0.14 [0.06, 0.30] |
< 0.00001 |
NA |
|
Psychiatric disorders |
Anxiety/ nervousness |
Beta-agonist |
6 |
9/820 (1.1) |
36/844 (4.3) |
0.34 [0.17, 0.70] |
0.003 |
9/820 (1.1) |
36/844 (4.3) |
0.34 [0.17, 0.70] |
0.003 |
NA |
Skin and subcutaneous tissue disorders |
Pruritus |
CCB |
1 |
0/70 (0) |
1/75 (1.3) |
0.36 [0.01, 8.62] |
0.53 |
0/70 (0) |
1/75 (1.3) |
0.36 [0.01, 8.62] |
0.53 |
NA |
Ear and labyrinth disorders |
Vertigo |
CCB |
1 |
4/40 (10.0) |
9/40 (22.5) |
0.44 [0.15, 1.33] |
0.15 |
4/40 (10.0) |
9/40 (22.5) |
0.44 [0.15, 1.33] |
0.15 |
NA |
Pregnancy, puerperium and perinatal conditions |
Eclampsia |
CCB |
1 |
1/225 (0.4) |
0/248 (0) |
3.32 [0.13, 81.93] |
0.46 |
1/225 (0.4) |
0/248 (0) |
3.32 [0.13, 81.93] |
0.46 |
NA |
HELLP syndrome |
CCB |
1 |
2/225 (0.9) |
3/248 (1.2) |
0.73 [0.12, 4.36] |
0.73 |
2/225 (0.9) |
3/248 (1.2) |
0.73 [0.12, 4.36] |
0.73 |
NA |
|
Abbreviation: SOC, system organ class; T, treatment group; C, control group; RR, risk ratio; CI, confidence interval; CCB, calcium channel blocker; NA, not available. Significant differences (P value ≤ 0.05) are shown in bold. |
Primary SOC |
Neonatal comorbidities |
Control |
No. of studies |
Incidence |
RR [95% CI] |
P value |
Total |
Subgroup differences (P value) |
||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
T (%) |
C (%) |
Incidence |
RR [95% CI] |
P value |
|
|
|
|
|
|
|
|
T (%) |
C (%) |
|||||||||||
Respiratory, thoracic and mediastinal disorders |
Respiratory distress syndrome |
Placebo/none |
4 |
120/865 (13.9) |
88/674 (13.1) |
1.17 [0.90, 1.50] |
0.24 |
339/2033 (16.7) |
308/1739 (17.7) |
0.97 [0.79, 1.19] |
0.78 |
0.42 |
CCB |
2 |
14/116 (12.1) |
17/121 (14) |
0.79 [0.27, 2.34] |
0.67 |
|||||||
Beta-agonist |
7 |
205/1052 (19.5) |
203/944 (21.5) |
0.92 [0.69, 1.22] |
0.57 |
|||||||
Hyaline membrane syndrome |
Placebo/none |
1 |
20/236 (8.5) |
5/56 (8.9) |
0.95 [0.37, 2.42] |
0.91 |
21/276 (7.6) |
7/96 (7.3) |
0.87 [0.36, 2.08] |
0.75 |
0.62 |
|
Beta-agonist |
1 |
1/40 (2.5) |
2/40 (5) |
0.50 [0.05, 5.30] |
0.56 |
|||||||
Apnoea |
CCB |
3 |
27/410 (6.6) |
23/418 (5.5) |
1.19 [0.69, 2.04] |
0.53 |
97/1301 (7.5) |
65/1202 (5.4) |
1.40 [1.04, 1.90] |
0.03 |
0.47 |
|
Beta-agonist |
4 |
79/891 (8.9) |
42/784 (5.4) |
1.51 [1.05, 2.19] |
0.03 |
|||||||
Hypoxia/ Asphyxia |
CCB |
1 |
2/294 (0.7) |
2/297 (0.7) |
1.01 [0.14, 7.12] |
0.99 |
20/1243 (1.6) |
27/1135 (2.4) |
0.86 [0.30, 2.43] |
0.77 |
0.88 |
|
Beta-agonist |
5 |
18/949 (1.9) |
25/838 (3) |
0.84 [0.23, 3.01] |
0.79 |
|||||||
Acidosis |
Beta-agonist |
1 |
2/131 (1.5) |
8/153 (5.2) |
0.29 [0.06, 1.35] |
0.12 |
2/131 (1.5) |
8/153 (5.2) |
0.29 [0.06, 1.35] |
0.12 |
NA |
|
Bronchopulmonary dysplasia |
Placebo/none |
1 |
21/294 (7.1) |
11/297 (3.7) |
1.93 [0.95, 3.93] |
0.07 |
21/294 (7.1) |
11/297 (3.7) |
1.93 [0.95, 3.93] |
0.07 |
NA |
|
Pneumothorax |
CCB |
1 |
5/294 (1.7) |
2/297 (0.7) |
2.53 [0.49, 12.91] |
0.27 |
5/294 (1.7) |
2/297 (0.7) |
2.53 [0.49, 12.91] |
0.27 |
NA |
|
Transient tachypnoea |
CCB |
1 |
2/25 (8) |
1/23 (4.3) |
1.84 [0.18, 18.96] |
0.61 |
2/25 (8.0) |
1/23 (4.3) |
1.84 [0.18, 18.96] |
0.61 |
NA |
|
Cardiac disorders |
Bradycardia |
CCB |
2 |
1/116 (0.9) |
1/121 (0.8) |
0.98 [0.10, 9.85] |
0.99 |
83/1222 (6.8) |
66/1120 (5.9) |
1.21 [0.89, 1.64] |
0.23 |
0.86 |
Beta-agonist |
5 |
82/1106 (7.4) |
65/999 (6.5) |
1.21 [0.89, 1.65] |
0.22 |
|||||||
Arrhythmia |
CCB |
1 |
1/25 (4) |
0/23 (0) |
2.77 [0.12, 64.76] |
0.53 |
5/562 (0.9) |
0/608 (0) |
4.47 [0.76, 26.28] |
0.10 |
0.72 |
|
Beta-agonist |
2 |
4/537 (0.7) |
0/585 (0) |
5.57 [0.65, 47.48] |
0.12 |
|||||||
Bblood and lymphatic system disorders |
Anaemia |
Beta-agonist |
4 |
60/891 (6.7) |
74/784 (9.4) |
0.63 [0.31, 1.25] |
0.19 |
60/891 (6.7) |
74/784 (9.4) |
0.63 [0.31, 1.25] |
0.19 |
0.45 |
Thrombocytopenia |
Beta-agonist |
4 |
5/891 (0.6) |
7/784 (0.9) |
0.68 [0.21, 2.20] |
0.52 |
5/891 (0.6) |
7/784 (0.9) |
0.68 [0.21, 2.20] |
0.52 |
NA |
|
Leukocytosis |
Beta-agonist |
1 |
1/40 (2.5) |
0/40 (0) |
3.00 [0.13, 71.51] |
0.50 |
1/40 (2.5) |
0/40 (0) |
3.00 [0.13, 71.51] |
0.50 |
NA |
|
Polycythaemia |
Placebo/none |
1 |
1/57 (1.8) |
2/57 (3.5) |
0.50 [0.05, 5.36] |
0.57 |
1/57 (1.8) |
2/57 (3.5) |
0.50 [0.05, 5.36] |
0.57 |
NA |
|
Haemorrhagic disease |
Placebo/none |
3 |
48/721 (6.7) |
33/571 (5.8) |
1.03 [0.66, 1.62] |
0.90 |
191/2299 (8.3) |
150/1957 (7.7) |
0.88 [0.73, 1.05] |
0.17 |
0.70 |
|
CCB |
4 |
103/624 (16.5) |
71/539 (13.2) |
0.87 [0.70, 1.09] |
0.23 |
|||||||
Beta-agonist |
5 |
40/954 (4.2) |
46/847 (5.4) |
0.79 [0.52, 1.21] |
0.28 |
|||||||
Nnervous system disorders |
Brain injury |
Beta-agonist |
1 |
28/58 (48.3) |
34/54 (63) |
0.77 [0.55, 1.07] |
0.12 |
28/58 (48.3) |
34/54 (63.0) |
0.77 [0.55, 1.07] |
0.12 |
NA |
Periventricular leukomalacia |
CCB |
1 |
2/294 (0.7) |
1/297 (0.3) |
2.02 [0.18, 22.16] |
0.56 |
2/294 (0.7) |
1/297 (0.3) |
2.02 [0.18, 22.16] |
0.56 |
NA |
|
Convulsion /Seizure |
CCB |
1 |
0/25 (0) |
1/23 (4.3) |
0.31 [0.01, 7.20] |
0.46 |
0/88 (0) |
1/86 (1.2) |
0.31 [0.01, 7.20] |
0.46 |
NA |
|
Beta-agonist |
1 |
0/63 (0) |
0/63 (0) |
Not estimable |
NA |
|||||||
Gastrointestinal disorders |
Necrotising enterocolitis |
Placebo/none |
3 |
11/808 (1.4) |
4/617 (0.6) |
1.79 [0.39, 8.20] |
0.45 |
19/1193 (1.6) |
11/1012 (1.1) |
1.54 [0.47, 5.06] |
0.48 |
0.99 |
CCB |
2 |
8/385 (2.1) |
7/395 (1.8) |
1.75 [0.11, 29.02] |
0.69 |
|||||||
Infections and infestations |
Sepsis |
Placebo/none |
1 |
12/236 (5.1) |
1/56 (1.8) |
2.85 [0.38, 21.45] |
0.31 |
96/1595 (6.0) |
106/1312 (8.1) |
0.84 [0.64, 1.10] |
0.21 |
0.34 |
CCB |
3 |
29/410 (7.1) |
30/418 (7.2) |
0.98 [0.60, 1.60] |
0.93 |
|||||||
Beta-agonist |
5 |
27/385 (7) |
28/395 (7.1) |
0.75 [0.54, 1.05] |
0.10 |
|||||||
Pneumonia |
Placebo/none |
1 |
6/236 (2.5) |
0/56 (0) |
3.13 [0.18, 54.70] |
0.43 |
21/319 (6.6) |
22/133 (16.5) |
0.69 [0.40, 1.17] |
0.17 |
0.51 |
|
CCB |
1 |
0/25 (0) |
1/23 (4.3) |
0.31 [0.01, 7.20] |
0.46 |
|||||||
Beta-agonist |
1 |
15/58 (25.9) |
21/54 (38.9) |
0.67 [0.38, 1.15] |
0.15 |
|||||||
Infection |
Beta-agonist |
1 |
4/63 (6.3) |
2/63 (3.2) |
2.00 [0.38, 10.53] |
0.41 |
4/63 (6.3) |
2/63 (3.2) |
2.00 [0.38, 10.53] |
0.41 |
NA |
|
Meningitis |
CCB |
1 |
2/294 (0.7) |
5/297 (1.7) |
0.40 [0.08, 2.07] |
0.28 |
2/294 (0.7) |
5/297 (1.7) |
0.40 [0.08, 2.07] |
0.28 |
NA |
|
Hepatobiliary disorders |
Hyperbilirubinaemia |
Placebo/none |
1 |
6/57 (10.5) |
5/57 (8.8) |
1.20 [0.39, 3.71] |
0.75 |
11/82 (13.4) |
16/80 (20.0) |
0.67 [0.24, 1.87] |
0.44 |
0.15 |
CCB |
1 |
5/25 (20) |
11/23 (47.8) |
0.42 [0.17, 1.02] |
0.06 |
|||||||
Metabolism and nutrition disorders |
Hypoglycaemia |
Placebo/none |
1 |
3/57 (5.3) |
4/57 (7) |
0.75 [0.18, 3.20] |
0.70 |
58/1036 (5.6) |
56/927 (6.0) |
0.96 [0.67, 1.38] |
0.82 |
0.76 |
CCB |
5 |
54/954 (5.7) |
52/847 (6.1) |
0.96 [0.66, 1.40] |
0.83 |
|||||||
Beta-agonist |
1 |
1/25 (4) |
0/23 (0) |
2.77 [0.12, 64.76] |
0.53 |
|||||||
Poor feeding |
CCB |
1 |
5/25 (20) |
9/23 (39.1) |
0.51 [0.20, 1.30] |
0.16 |
5/25 (20.0) |
9/23 (39.1) |
0.51 [0.20, 1.30] |
0.16 |
NA |
|
Vascular disorders |
Hypotension |
Beta-agonist |
5 |
21/954 (2.2) |
33/847 (3.9) |
0.64 [0.36, 1.11] |
0.11 |
21/954 (2.2) |
33/847 (3.9) |
0.64 [0.36, 1.11] |
0.11 |
NA |
Eye disorders |
Retinal disorder |
CCB |
1 |
2/91 (2.2) |
1/98 (1) |
2.15 [0.20, 23.35] |
0.53 |
24/774 (3.1) |
24/818 (2.9) |
1.09 [0.49, 2.42] |
0.83 |
0.57 |
Beta-agonist |
3 |
22/683 (3.2) |
23/720 (3.2) |
1.03 [0.41, 2.60] |
0.95 |
|||||||
Congential, familial and genetic disorders |
Patent ductus arteriosus |
Placebo/none |
4 |
33/865 (3.8) |
25/674 (3.7) |
1.18 [0.71, 1.97] |
0.52 |
79/1819 (4.3) |
69/1521 (4.5) |
1.10 [0.80, 1.52] |
0.55 |
0.74 |
CCB |
5 |
46/954 (4.8) |
44/847 (5.2) |
1.05 [0.69, 1.61] |
0.80 |
|||||||
Congenital abnormality |
Placebo/none |
2 |
4/227 (1.8) |
2/227 (0.9) |
2.00 [0.37, 10.72] |
0.42 |
4/345 (1.2) |
3/345 (0.9) |
1.36 [0.31, 5.99] |
0.69 |
0.33 |
|
Beta-agonist |
1 |
0/118 (0) |
1/118 (0.8) |
0.33 [0.01, 8.10] |
0.50 |
|||||||
Pregnancy, puerperium and perinatal disorders |
Jaundice |
Beta-agonist |
1 |
3/40 (7.5) |
4/40 (10) |
0.75 [0.18, 3.14] |
0.69 |
3/40 (7.5) |
4/40 (10.0) |
0.75 [0.18, 3.14] |
0.69 |
NA |
Abbreviation: SOC, system organ class; T, treatment group; C, control group; RR, risk ratio; CI, confidence interval; CCB, calcium channel blocker; NA, not available. Significant differences (P value ≤ 0.05) are shown in bold. |
The incidence of overall maternal adverse events in atosiban group and control group were 4.0% and 12.4%, respectively. The incidence of treatment discontinuation due to adverse events was 10 times lower in atosiban group (1.4%) than in control group (14%). The risk of maternal adverse events and the discontinuation of treatment due to adverse events were significantly lower with atosiban compared with controls (RR 0.38, 95% CI [0.23, 0.61], P < 0.0001; RR 0.11, 95% CI [0.04, 0.29], P < 0.00001; respectively). According to the classification of different control groups, the risk of maternal adverse events was significantly lower in patients treated with atosiban compared with beta-agonists and CCBs (RR 0.35, 95% CI [0.19, 0.68], P = 0.002; RR 0.44, 95% CI [0.20, 0.95], P = 0.04; respectively). Additionally, compared to atosiban, beta-agonists had a significantly increased risk of treatment discontinuation due to adverse events (RR 0.07, 95% CI [0.04, 0.14], P < 0.00001) and was significantly different from CCBs (P = 0.001).
For cardiac disorders, the incidence was lower in atosiban group than in control group, except for arrhythmia. Among them, the risk of palpitation, chest pain and tachycardia was significantly lower in patients treated with atosiban compared with controls (RR 0.15, 95% CI [0.08, 0.28], P < 0.00001; RR 0.27, 95% CI [0.16, 0.45], P < 0.00001; RR 0.09, 95% CI [0.06, 0.15], P < 0.00001; respectively). In terms of different types of control group, CCBs significantly increased the risk of palpitation and tachycardia (RR 0.37, 95% CI [0.10, 1.33], P < 0.00001; RR 0.19, 95% CI [0.06, 0.66], P = 0.008; respectively), and beta-agonists significantly increased the risk of chest pain and tachycardia (RR 0.27, 95% CI [0.14, 0.55], P = 0.0003; RR 0.08, 95% CI [0.05, 0.13], P < 0.00001; respectively). In addition, the incidence of chest pain was also significantly higher in the placebo group than in the atosiban group (RR 0.22, 95% CI [0.09, 0.51], P = 0.0004).
As for gastrointestinal disorders, the overall incidence of vomiting was significantly lower in atosiban group (5.0%) than in control group (18.5%) with an RR of 0.28 (95% CI [0.17, 0.46], P < 0.00001), and there was a significant difference between the different controls (P = 0.006). Beta-agonists significantly increased the risk of nausea and vomiting compared to atosiban (RR 0.77, 95% CI [0.59, 0.99], P < 0.00001; RR 0.32, 95% CI [0.24, 0.43], P < 0.00001; respectively). Conversely, according to 1 study, atosiban group had a higher incidence of constipation than beta-agonist group (5.7% vs. 2.9%).
In terms of nervous system disorders, a significant lower incidence of headache and tremor was observed in atosiban group compared to control group (RR 0.51, 95% CI [0.40, 0.64], P < 0.00001; RR 0.10, 95% CI [0.06, 0.19], P < 0.00001; respectively). Beta-agonists significantly increased the risk of headache and tremor compared with atosiban (RR 0.53, 95% CI [0.41, 0.69], P < 0.00001; RR 0.10, 95% CI [0.06, 0.19], P < 0.00001; respectively). Besides, one study showed that the atosiban group had a significant lower incidence of headache compared to placebo (4.9% vs. 13.8%, RR 0.36, 95% CI [0.15, 0.83], P = 0.02).
As for vascular disorders, a significant lower incidence of hypotension was found in atosiban group compared to control group (1.8% vs. 4.7%, RR 0.49, 95% CI [0.29, 0.82], P = 0.007). Both beta-agonists and CCBs significantly increased the risk of hypotension compared with atosiban (RR 0.60, 95% CI [0.36, 0.98], P = 0.04; RR 0.35, 95% CI [0.13, 0.92], P = 0.03; respectively).
For general disorders and administration site conditions, the incidence of injection site reactions was significantly higher in patients administrated with atosiban compared with placebo/no comparator (34.9% vs. 21.1%, RR 1.59, 95% CI [1.37, 1.83], P < 0.00001). Beta-agonists substantially increased the risk of chest tightness compared with atosiban with an RR of 0.18 (95% CI [0.06, 0.59], P = 0.005).
Compared to beta-agonists, patients treated with atosiban had a significantly lower risk of dysponea in respiratory thoracic and mediastinal disorders (RR 0.09, 95% CI [0.04, 4.98], P < 0.00001); hyperglycaemia and hypokalemia in metabolic and nutritional disorders (RR 0.58, 95% CI [0.37, 0.90], P = 0.02; RR 0.14, 95% CI [0.06, 0.30], P < 0.00001; respectively); and anxiety/nervousness in psychiatric disorders (RR 0.34, 95% CI [0.17, 0.70], P = 0.003).
Finally, for skin and subcutaneous tissue disorders, ear and labyrinth disorders, and pregnancy, puerperium and perinatal conditions, we did not find a significant relationship between any drug and the occurrence of adverse events.
The overall incidence of neonatal comorbidities was similar in atosiban group and control group (16.7% vs. 16.5%). A higher overall incidence of fatal/neonatal deaths was found in the control group (3.5% vs. 4.7%), and beta-agonists significantly increased the risk of fatal/neonatal deaths compared with atosiban with an RR of 0.49 (95% CI [0.29, 0.83], P = 0.009). However, there was no meaningful association between placebo/no comparator or CCBs and fatal/neonatal deaths was observed, and there were significant differences between the different control groups (P = 0.02).
A higher risk of apnoea was observed in atosiban group compared with controls (RR 1.40, 95% CI [1.04, 1.90], P = 0.03). Based on the analysis of neonatal comorbidities classified according to different control groups, atosiban significantly increased the risk of apnoea compared to beta-agonists (RR 1.51, 95% CI [1.05, 2.19], P = 0.03). Besides, none of the other results showed a statistically significant difference.
The results of secondary outcomes are summarized in Table 2.
The incidence of not delivering at 48 hours was slightly higher in the atosiban group than in the control group, but the results did not show significant differences whether comparing with placebo/no comparator, beta-agonists, or CCBs. Similar results were found in the incidence of not delivering within 7 days, except for 1 study that showed a substantial increased incidence with atosiban compared to placebo (RR 1.26, 95% CI [1.08, 1.48], P = 0.004), which also led to a significant difference between groups (P = 0.02). The proportion of deliver within 28 weeks was similar between the two groups and showed no significant difference regardless of the control group. One study showed that compared to CCBs, atosiban significantly increased the proportion of delivery before 37 weeks with a RR of 1.56 (95% CI [1.13, 2.14], P = 0.007).
Atosiban group showed no significant association with the incidence of newborns with birth weight less than 2500 grams, Apgar score less than 7 at 5 minutes, and NICU admission, regardless of whether the control group was placebo/no comparator, beta-agonists, or CCBs.
Atosiban significantly imcreased implantation rate and clinical pregnancy rate compared to placebo/no comparator (RR 1.52, 95% CI [1.29, 1.79], P < 0.00001; RR 1.39, 95% CI [1.18, 1.62], P < 0.0001; respectively). However, we did not observe a significant effect of atosiban on the incidence of live births, miscarriages, multiply pregnancies, or ectopic pregnancies compared to placebo or no control drug.
Compared with atosiban group, beta-agonist group had higher rates of successful ECV (36.6% vs. 42.5%), cephalic presentation at labor (35.2% vs. 46.1%), and vaginal delivery (38.5% vs. 42.4%), and also had a higher rates of neonatal Apgar score < 7 at 5 minutes (1.1% vs. 2.1%) and NICU admission (4.4% vs. 4.9%). However, with the exception of the rate of cephalic presentation at labor, which demonstrated a substantial difference (RR 0.75, 95% CI [0.60, 0.93], P = 0.01), none of the other results showed a statistically significant difference.
Our study detailed the potential maternal adverse events and neonatal comorbidities of atosiban compared with placebo/no comparator, CCBs, and beta-agonists. We identified risks not addressed by previous studies and provided more comprehensive data for clinical practice.
Our study demonstrated that the effectiveness of atosiban in the treatment of PTB was basically similar to CCBs and beta-agonists, both in maternal outcomes and neonatal outcomes. These results are in line with previous findings that atosiban does not improve the effectiveness of the treatment of PTB compared with conventional treatment regimens. According to the Cochrane review published in 2014,[19] atosiban showed no advantage over placebo, beta-agonists or CCBs (primarily nifedipine), although it was associated with less maternal adverse events. Similarly, the results of a network meta-analysis conducted by Xiong et al.[20] showed that indomethacin was the most effective intervention in the treatment of PTB, followed by nifedipine, ritodrine, atosiban, and placebo.
As for the efficacy of atosiban in RIF, our study demonstrated that compared with placebo or no comparator, atosiban significantly increased implantation rates of per embryo transferred and clinical pregnancy rates, but not live birth rates. There was no significant difference in the incidence of adverse outcomes including miscarriage, multiple pregnancy, and ectopic pregnancy. Similarly, the Cochrane review published in 2021[21] based on available data from RCTs has shown inconclusive conclusions about whether atosiban improves pregnancy outcomes in women receiving ART. Furthermore, according to Huang et al.,[22] atosiban may be more appropriate for women undergoing RIF and has limited effect on the general female population undergoing IVF.
Beta-agonists were effective in facilitating successful ECV, increasing cephalic presentation rate, and reducing the caesarean section rate, as demonstrated in previous Cochrane review.[23] A meta-analysis in 2021 showed that atosiban did not significantly improve the successful rate of ECV compared with beta-agonists, although it had a lower incidence of adverse effects.[24] Our findings suggested that atosiban is not effective in improving breech production, and the rate of cephalic presentation at labor was significantly lower than beta-agonists.
Generally, atosiban had a better safety profile compared with CCBs and beta-agonists. The risk of maternal adverse events was significantly lower in patients treated with atosiban compared with CCBs and beta-agonists. In addition, atosiban had a significantly lower risk of discontinuation of drug due to adverse events and fatal/neonatal deaths compared to beta-agonists. When categorizing maternal adverse events by systemic disorders, compared with CCBs, atosiban had a significantly lower risk of cardiac disorders as palpitation and tachycardia; vascular disorders as hypotension. Compared with beta-agonists, a significantly lower risk was observed in cardiac disorders as chest pain and tachycardia; gastrointestinal disorders as nausea and vomiting; nervous system disorders as headache and tremor; vascular disorders as hypotension; general disorders as chest tightness; respiratory thoracic and mediastinal disorders as dysponea; and psychiatric disorders as anxiety/nervousness. However, in terms of neonatal complications, a significantly higher risk of apnoea was found in atosiban group compared with beta-agonist group.
The reason for the improved safety of atosiban may be due to the mechanisms of oxytocin receptor antagonists. Oxytocin stimulates uterine contractions and the binding of oxytocin to its receptors increases intracellular calcium levels.[11, 25] Therefore, uterine contractions can be reduced to some extent by inhibiting oxytocin receptors. Atosiban is a nonapeptide, desamino-oxytocin analogue and is primarily an arginine vasopressin V1a receptor antagonist.[12, 26] Atosiban inhibits oxytocin-mediated release of inositol trisphosphate, which has a regulatory effect on calcium ions (Ca2+), from the myometrial cell membrane.[12, 26] This process reduced the intracellular storage of Ca2+ released from the sarcoplasmic reticulum of the myometrial cells, thereby reducing Ca2+ influx from the extracellular space via voltage-gated channels.[12, 26] Previous studies have shown that oxytocin receptor antagonists have increased specificity for the uterus, which reduces the occurrence of drug-related adverse reactions and thus improve drug safety. In contrast, CCBs and beta-agonists extensively act on various parts of the body and are involved in the regulation of several normal physiological activities,[27, 28] suggesting that they may cause more adverse effects.
Current economic studies on atosiban in the treatment of PTB mainly come from the Netherlands,[29] Germany,[30] Italy,[31] and China,[32] evaluating atosiban versus nifedipine, beta-agonists and non-drug treatments, respectively. A cost-effectiveness analysis in the Netherlands showed that more costs were incurred in the atosiban group compared to the nifedipine group due to the higher rate of neonatal transfer to the NICU.[29] The results of the minimum cost analysis illustrated that the cost of atosiban is lower and more economical compared with beta-agonists under diagnosis related groups (DRGs) systems in Germany[30] and Italy.[31] The cost-effectiveness analysis conducted in China demonstrated an advantage of atosiban compared with non-drug treatments after reducing its price.[32]
There are several limitations to our study that need to be considered. First, due to insufficient RCTs in pregnant women, both RCTs and observational studies were included. However, the risk of bias of included studies was low. Second, the purpose of each study was different, and safety outcomes were not the primary consideration, which may have led to an underestimation of the risk of adverse events. Third, data were extracted from trial results, and individual information on patient was not available. Therefore, the potential risk factors for developing adverse events were not included in our study. Finally, studies regarding woman undergoing PTB, IVF-ET, and ECV were included in our meta-analysis. Maternal adverse events were more frequently reported in the case of PTB than in woman undergoing IVF-ET and ECV, which may be due to more complications associated with PTB. Further studies are needed to determine whether atosiban can be administered safely and effectively as a single-agent regimen or in combination with other drugs. Adverse events related to atosiban in women undergoing RIF or ECV could be used as a primary outcome indicator when designing trials, and more attention should be paid to long-term follow-up outcomes in preterm infants.
Compared with CCBs and beta-agonists, the effectiveness of atosiban applied to PTB, IVF-ET and ECV was essentially equivalent. Atosiban has a substantial better safety profile, mainly demonstrated by a significantly lower risk of maternal adverse events. In addition, the incidence of neonatal comorbidities was comparable, but vigilance is needed for the occurrence of neonatal apnoea. The optimal treatment for individual patient needs to be considered in the context of the local circumstances, patient presentation and other related factors in clinical practice.
Ethics approval and consent to participate: Not applicable.
Consent for publication: Not applicable.
Availability of data and materials: All data generated or analysed during this study are included in this published article and its supplementary information files.
Competing interests: The authors have no competing interests to declare that are relevant to the content of this article.
Funding: This work was supported by 2021 "Yangfan" program (grant number: ZYLX 202119; major: clinical pharmacy in obstetrics and gynecology; affiliation: Beijing Obstetrics and Gynecology Hospital, Capital Medical University; supervisor: Xin Feng).
Authors' contributions: Xin Feng concepted, designed, administrated and supervised this study. The extraction, statistical analysis of data were conducted by Yi Zhang and Xin Feng. Yi Zhang drafted the manuscript and all authors reviewed and revised the article.
Acknowledgements: None.