Safety and efficacy of atosiban: a systematic review and a meta-analysis of randomized controlled trials and observational studies

DOI: https://doi.org/10.21203/rs.3.rs-2208516/v1

Abstract

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.

1 Introduction

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.[1215] 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.

2 Methods

2.1 Data sources

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.

2.2 Study selection

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).

2.3 Outcomes

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).

2.4 Data extraction

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.

2.5 Risk of bias assessment

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]

2.6 Statistical analysis

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).

3 Results

3.1 Study selection and characteristics

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.

 
Table 1

Characteristics of included studies.

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.


3.2 Primary outcomes

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.

 
Table 2

Outcomes of atosiban in PTB, IVF-ET, ECV.

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.

 
Table 3

Maternal adverse events according to different types of control group.

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.

Table 4

Neonatal comorbidities according to different types of control group.

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.


3.2.1 Maternal adverse events

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.

3.2.2 Neonatal comorbidities

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.

3.3 Secondary outcomes

The results of secondary outcomes are summarized in Table 2.

3.3.1 PTB

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.

3.3.2 IVF-ET

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.

3.3.3 ECV

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.

Discussion

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.
 

Conclusion

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.

Declarations

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.

AcknowledgementsNone.

References

  1. Walani SR. "Global burden of preterm birth," (in eng). Int J Gynaecol Obstet. 2020;150(1):31–3. doi:10.1002/ijgo.13195.
  2. C Coughlan et al., "Recurrent implantation failure: definition and management," (in eng), Reprod Biomed Online, vol. 28, no. 1, pp. 14–38, 2014, doi: 10.1016/j.rbmo.2013.08.011.
  3. Hofmeyr GJ, Kulier R, West HM. "External cephalic version for breech presentation at term," (in eng), Cochrane Database Syst Rev, 4, p. CD000083, 2015, doi:10.1002/14651858.CD000083.pub3.
  4. H Blencowe et al., "National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications," (in eng), Lancet, vol. 379, no. 9832, pp. 2162–2172, 2012, doi: 10.1016/S0140-6736(12)60820-4.
  5. L Liu et al., "Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals," (in eng), Lancet, vol. 388, no. 10063, pp. 3027–3035, 2016, doi: 10.1016/S0140-6736(16)31593-8.
  6. Frey HA, Klebanoff MA. "The epidemiology, etiology, and costs of preterm birth," (in eng). Semin Fetal Neonatal Med. 2016;21(2):68–73. doi:10.1016/j.siny.2015.12.011.
  7. Cimadomo D, Craciunas L, Vermeulen N, Vomstein K, Toth B, "Definition, diagnostic and therapeutic options in recurrent implantation failure: an international survey of clinicians and embryologists," (in eng), Hum Reprod, vol. 36, no. 2, pp. 305–317, 2021, doi: 10.1093/humrep/deaa317.
  8. Sun Y, Zhang Y, Ma X, Jia W, Su Y. "Determining Diagnostic Criteria of Unexplained Recurrent Implantation Failure: A Retrospective Study of Two Three or More Implantation Failure," (in eng). Front Endocrinol (Lausanne). 2021;12:619437. doi:10.3389/fendo.2021.619437.
  9. Hofmeyr GJ, Hannah M, Lawrie TA. "Planned caesarean section for term breech delivery," (in eng), Cochrane Database Syst Rev, no. 7, p. CD000166, 2015, doi:10.1002/14651858.CD000166.pub2.
  10. Hutton EK, Hofmeyr GJ, Dowswell T. "External cephalic version for breech presentation before term," (in eng), Cochrane Database Syst Rev, no. 7, p. CD000084, 2015, doi:10.1002/14651858.CD000084.pub3.
  11. Lamont RF, "The development and introduction of anti-oxytocic tocolytics," (in eng), BJOG, vol. 110 Suppl 20, pp. 108–112, 2003. [Online]. Available: https://pubmed.ncbi.nlm.nih.gov/12763125.
  12. Sanu O, Lamont RF, "Critical appraisal and clinical utility of atosiban in the management of preterm labor," (in eng), Ther Clin Risk Manag, vol. 6, pp. 191–199, 2010. [Online]. Available: https://pubmed.ncbi.nlm.nih.gov/20463780.
  13. Jenkin G, "Oxytocin and prostaglandin interactions in pregnancy and at parturition," (in eng), J Reprod Fertil Suppl, vol. 45, 1992. [Online]. Available: https://pubmed.ncbi.nlm.nih.gov/1304035.
  14. Fuchs AR, Husslein P, Fuchs F, "Oxytocin and the initiation of human parturition. II. Stimulation of prostaglandin production in human decidua by oxytocin," (in eng), Am J Obstet Gynecol, vol. 141, no. 6, pp. 694–697, 1981. [Online]. Available: https://pubmed.ncbi.nlm.nih.gov/7315896.
  15. M Steinwall et al., "The effect of relcovaptan (SR 49059), an orally active vasopressin V1a receptor antagonist, on uterine contractions in preterm labor," (in eng), Gynecol Endocrinol, vol. 20, no. 2, pp. 104–109, 2005. [Online]. Available: https://pubmed.ncbi.nlm.nih.gov/15823830.
  16. MJ Page et al., "The PRISMA 2020 statement: an updated guideline for reporting systematic reviews," (in eng), BMJ, vol. 372, p. n71, 2021, doi: 10.1136/bmj.n71.
  17. JPT Higgins et al., "The Cochrane Collaboration's tool for assessing risk of bias in randomised trials," (in eng), BMJ, vol. 343, p. d5928, 2011, doi: 10.1136/bmj.d5928.
  18. JA Sterne et al., "ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions," (in eng), BMJ, vol. 355, p. i4919, 2016, doi: 10.1136/bmj.i4919.
  19. Flenady V, Reinebrant HE, Liley HG, Tambimuttu EG, Papatsonis DNM, "Oxytocin receptor antagonists for inhibiting preterm labour," (in eng), Cochrane Database Syst Rev, no. 6, p. CD004452, 2014, doi: 10.1002/14651858.CD004452.pub3.
  20. Xiong Z, Pei S, Zhu Z. "Four kinds of tocolytic therapy for preterm delivery: Systematic review and network meta-analysis," (in eng). J Clin Pharm Ther. 2022;47(7):1036–48. doi:10.1111/jcpt.13641.
  21. Craciunas L, Tsampras N, Kollmann M, Raine-Fenning N, Choudhary M. "Oxytocin antagonists for assisted reproduction," (in eng), Cochrane Database Syst Rev, 9, p. CD012375, 2021, doi:10.1002/14651858.CD012375.pub2.
  22. Q-Y Huang et al., "The impact of atosiban on pregnancy outcomes in women undergoing in vitro fertilization-embryo transfer: A meta-analysis," (in eng), PLoS One, vol. 12, no. 4, p. e0175501, 2017, doi: 10.1371/journal.pone.0175501.
  23. Cluver C, Hofmeyr GJ, Gyte GM, Sinclair M. "Interventions for helping to turn term breech babies to head first presentation when using external cephalic version," (in eng). Cochrane Database Syst Rev. 2012;1:CD000184. doi:10.1002/14651858.CD000184.pub3.
  24. G Riemma et al. "Usefulness of atosiban for tocolysis during external cephalic version: Systematic review and meta-analysis," (in eng). Eur J Obstet Gynecol Reprod Biol. 2021;258:86–92. doi:10.1016/j.ejogrb.2020.12.053.
  25. SH Kim et al., "Oxytocin Receptor Antagonists, Atosiban and Nolasiban, Inhibit Prostaglandin F-induced Contractions and Inflammatory Responses in Human Myometrium," (in eng), Sci Rep, vol. 9, no. 1, p. 5792, 2019, doi: 10.1038/s41598-019-42181-2.
  26. Arthur P, Taggart MJ, Mitchell BF, "Oxytocin and parturition: a role for increased myometrial calcium and calcium sensitization?," (in eng), Front Biosci, vol. 12, pp. 619–633, 2007. [Online]. Available: https://pubmed.ncbi.nlm.nih.gov/17127323.
  27. St-Onge M, et al. "Experts Consensus Recommendations for the Management of Calcium Channel Blocker Poisoning in Adults," (in eng). Crit Care Med. 2017;45(3):e306-e. doi:10.1097/CCM.0000000000002087. 315.
  28. Maideen NMP, Rajkapoor B, Muthusamy S, Ramanathan S, Thangadurai SA, Sughir AA. "A Review on Pharmacokinetic and Pharmacodynamic Drug Interactions of Adrenergic β-blockers with Clinically Relevant Drugs-An Overview," (in eng). Curr Drug Metab. 2021;22(9):672–82. doi:10.2174/1389200222666210614112529.
  29. T Nijman et al., "Cost effectiveness of nifedipine compared with atosiban in the treatment of threatened preterm birth (APOSTEL III trial)," (in eng), BJOG, vol. 126, no. 7, pp. 875–883, 2019, doi: 10.1111/1471-0528.15625.
  30. Wex J, Connolly M, Rath W, "Atosiban versus betamimetics in the treatment of preterm labour in Germany: an economic evaluation," (in eng), BMC Pregnancy Childbirth, vol. 9, p. 23, 2009, doi: 10.1186/1471-2393-9-23.
  31. Wex J, Abou-Setta AM, Clerici G, Di Renzo GC. "Atosiban versus betamimetics in the treatment of preterm labour in Italy: clinical and economic importance of side-effects," (in eng). Eur J Obstet Gynecol Reprod Biol. 2011;157(2):128–35. doi:10.1016/j.ejogrb.2011.04.009.
  32. Qiu Y, Zhao K, Qi X, Li Y, Liu C, Zhu S. "Pharmacoeconomics Evaluation on the Treatment of Sontaneous Preterm Birth with Atosiban". Chin Health Econ. 2016;35(09):73–6. doi:10.7664/CHE20160921.