Abstract
Objective: To evaluate the side-effects of oxytocin for the prevention of postpartum hemorrhage (PPH) in randomized controlled trials (RCTs). Methods: Electronic databases (Web of Science, Embase, PubMed, Elsevier ScienceDirect, the Cochrane Library, and ClinicalTrials.gov) were searched from the beginning of indexing to Sep 2021. RCTs comparing oxytocin with non-oxytocin uterotonic agent(s) or non-pharmacologic interventions for the prevention of PPH were eligible. Results: Overall, sixty-one RCTs meeting the inclusion criteria were included, involving 68834 participants. Twenty-seven types of side-effects were reported in this study. There were 24, 35, or 2 trials assessed as high medium and low quality, respectively. Compared with non-oxytocin, oxytocin had significantly lower risk for shivering (RR=0.31, 95% CI=0.23-0.41, n=36680), fever (RR=0.27, 95% CI=0.20-0.37, n=34031), and diarrhea (RR=0.48, 95% CI=0.35-0.66, n=30883). Other side-effects were not found associated with oxytocin. Conclusion: Oxytocin use was association with a significantly lower incidence of shivering, fever, and diarrhea events and did not increase risk of other side-effects during the third stage of labor. These observations may aid obstetricians and gynecologists in weighing up the benefits and risks associated with oxytocin in prevention and treatment of PPH during the third stage of labor.
Keywords: Oxytocin, side-effects, postpartum hemorrhage, meta-analysis, systematic review, randomized controlled trials
Introduction
Approximately 300,000 women and adolescent girls die as a result of pregnancy and childbirth-related complications around the world, and over one quarter of all maternal deaths are attributable to postpartum hemorrhage (PPH) every year [1]. Abnormal uterine tone can cause PPH-related maternal mortality and it remains the most common etiology of severe PPH worldwide [2]. Prophylactic uterotonic drugs, such as oxytocin, could decrease excessive blood loss and reduce the incidence of PPH. They are routinely recommended as a choice for prevention and treatment of PPH during the third stage of labor [3].
Oxytocin is almost universally accepted as the first-line agent in the management and prevention of abnormal uterine tone after cesarean and vaginal delivery [4]. Many studies have shown that oxytocin is associated with a substantial reduction in PPH, blood transfusion and the use of additional uterotonics [5-8]. Meanwhile, a number of trials and observational studies have shown that the side-effects of oxytocin include nausea, vomiting, headache, and hemodynamic instability [9-12]. Recently, numerous system review and meta-analysis studies researched the efficacy of oxytocin, but few data have intentionally concentrated on side-effects in clinical trials of oxytocin. Hence, evidence about the safety of oxytocin is needed.
To help inform clinical practice and address this gap, we specifically focused on randomized control trials (RCTs) that examined the side-effects of oxytocin for the prevention of PPH during the third stage of labor in this systematic review and meta-analysis. The primary objective was to characterize side-effects occurring in clinical trials of oxytocin, compared to any non-oxytocin uterotonic agent(s) and non-pharmacologic interventions. Further objectives were to explore the possible confounding risk factors of side-effects for oxytocin.
Materials and methods
The PRISMA Statement and Checklist have been followed in this systematic review and meta-analysis [13]. The protocol was registered in advance in PROSPERO (Identifier: CRD42019119768) [14].
Search strategy
An academic librarian developed the search strategies (Supplementary File 1). Searched databases included Web of Science, Embase, PubMed, Elsevier ScienceDirect, the Cochrane Library, and ClinicalTrials.gov from the earliest available online indexing year until January 1, 2019, and updated on Sep 1, 2021. There were no language restrictions. Additional eligible bibliographies of included studies were also identified and authors were contacted to obtain unpublished data.
Eligibility criteria
The inclusion criteria included: (1) RCTs comparing oxytocin with non-oxytocin uterotonic agent(s) (misoprostol, carbetocin, ergometrine/methylergometrine, prostaglandins, placebo, or no treatment), non-pharmacologic interventions (uterine massage, controlled cord traction, cord clamping); (2) trials enrolling women in cesarean section or vaginal birth; and (3) trials providing adverse events or side effects data. Exclusion criteria were: (1) RCTs without oxytocin group; (2) RCTs comparing oxytocin with syntometrine (oxytocin plus ergometrine) or misoprostol plus oxytocin group; and (3) quasi-randomised trials. Using a standardized form, reviewers screened titles, abstracts, and full-text articles to assess their eligibility. Any disagreements were resolved by consensus.
Data extraction
A blank electronic form was created on Microsoft Excel to extract the eligible studies’ data. From each included RCT, the information of the first author, year of publication, country of origin, clinical trial registration number, trial duration, funding source, participant characteristics (age, route of delivery, risk of PPH, and number of participants in each group), oxytocin characteristics (dosage and route of administration), and the types and frequency of side-effects, was extracted from each included study.
Risk of bias assessment
The methodological quality was stated based on the Cochrane handbook [15]. Each quality item in the included study was assessed and classified as high-, unclear-, or low-risk of bias. The studies included were defined as high-, medium-, or low-quality. Regardless of the results of other items, if random sequence generation or allocation concealment was defined as high-risk of bias, the studies were graded as low-quality. If random sequence generation and allocation concealment were all defined as low-risk of bias, while all other items were not defined as high-risk of bias, the studies were graded as high-quality. Other included studies were graded as unclear-quality.
Data analysis
Data analysis was performed by using R software 3.0.3 and Review Manager 5.3. The dichotomous outcome was shown as the risk ratios (RRs) and 95% confidence intervals (CIs). Based on the Cochrane Handbook, 0.5 was added to each cell in the fourfold table if one group reported zero event; studies were excluded if both groups reported zero event [15].
Fixed- or random-effect was used to pool the results. Random-effect was presented given heterogeneity among studies. Tau2 and I2 statistics were used to calculate the statistical heterogeneity. We planned to perform subgroup analysis when ten or more studies were included in the side-effects. Subgroup analysis was performed in route of administration (intramuscular [i.m.] or intravenous [i.v.]), dose (standard dose [10 iu], high dose, or low dose), mode of delivery (cesarean section [CS] or vaginal birth [VD]), risk of PPH (low risk, high and low risk, or high risk), controlled-intervention (misoprostol, carbetocin, ergometrine, prostaglandins, or placebo), trial registration (yes or no), funding source (public institution, drug company, or none), published year (before-2000, 2000-2010, or 2011-present) and region (Africa, America, Asia, Europe, or Mixed). Meanwhile, we also performed a cumulative meta-analysis ranked by year published to examine the stability and sufficiency of evidence as it was accumulated over time. Publications bias was evaluated using Begg and Egger tests. Funnel plot was also provided if ten or more studies were included.
Results
Study selection and characteristics
There are 1420 records through the initial search. Six hundred and sixteen records were screened for full-text review after removing duplicates and 555 were excluded. Overall, sixty-one RCTs meeting the inclusion criteria were included, involving 68834 participants (Figure 1).
Figure 1.
Flow chart of systematic review and meta-analysis.
Table 1 showed the clinical and methodological characteristics of the included studies. These studies were published between 1979 and 2018. The median number of sample sizes per study was 220 (range, 30-29497). Totally, twenty-seven types of side-effects were reported in this study. Eight side-effects, including vomiting, shivering, nausea, fever, headache, diarrhea, flushing, and dizziness, were reported in more than ten trials. Only one study reported serious adverse event [12], leukocytosis [16], wheezing [17], arm pain [17] and xerostomia [6] (Figure 2).
Table 1.
General characteristics of included studies
| First author | Publish Year | Trial Phase | Trail No. | Funded | Country | Risk for PPH | Delivery Mode | Interventions (sample size; dose; adm) | Side effects |
|---|---|---|---|---|---|---|---|---|---|
| Mannaerts D [56] | 2018 | NA | ISRCTN95504420 | NA | Belgium | L | CS | Oxytocin (26; 20 iu, i.v.) vs. Carbetocin (32; 100 ug, i.v.) | Nausea |
| Flushing | |||||||||
| Hypotension | |||||||||
| Vomiting | |||||||||
| Taheripanah R [11] | 2018 | II | NCT02079558 | Shahid Beheshti University of Medical Sciences | Iran | H | CS | Oxytocin (110; 30 iu, i.v.) vs. Carbetocin (110; 100 ug, i.v.) | Vomiting |
| Headache | |||||||||
| Nausea | |||||||||
| Tremor | |||||||||
| Dizziness | |||||||||
| Pruritus | |||||||||
| Widmer M [12] | 2018 | III | Australian New Zealand Clinical Trials Registry number, ACTRN12614000870651; EudraCT number, 2014-004445-26; and Clinical Trials Registry-India number, CTRI/2016/05/006969 | Merch Sharpe & Dohme | Argentina; Egypt; India; Kenya; Nigeria; Singapore; South Africa; Thailand; Uganda; the United Kingdom | L | VD | Oxytocin (14743; 10 iu, i.m.) vs. Carbetocin (14754; 100 ug, i.m.) | Chest pain |
| Flushing | |||||||||
| Abdominal pain | |||||||||
| Vomiting | |||||||||
| Shady NW [55] | 2017 | NA | NA | NA | Egypt | L | VD | Oxytocin (120; 10 iu, i.v.) vs. Misoprostol (120; 600 ug, oral) vs. Tranexamic acid + Misoprostol (120; 1000 mg + 600 ug, oral) | Vomiting |
| Nausea | |||||||||
| Diarrhea | |||||||||
| El Behery MM [57] | 2016 | NA | NA | NA | Egypt | H | CS | Oxytocin (90; 20 iu, i.v.) vs. Carbetocin (90; 100 ug, i.v.) | Headache |
| Nausea | |||||||||
| Vomiting | |||||||||
| Sweating | |||||||||
| Palpitation | |||||||||
| Fever | |||||||||
| Gavilanes P [18] | 2016 | NA | NA | NA | Ecuador | H | CS | Oxytocin (50; 10 iu, i.v.) vs. Misoprostol (50; 400 ug, s.l.) | Shivering |
| Nausea | |||||||||
| Vomiting | |||||||||
| Headache | |||||||||
| Maged AM [59] | 2016 | NA | NA | NA | Egypt | H | VD | Oxytocin (100; 100 ug, i.m.) vs. Carbetocin (100; 100 ug, i.m.) | Nausea |
| Vomiting | |||||||||
| Tachycardia | |||||||||
| Flushing | |||||||||
| Dizziness | |||||||||
| Headache | |||||||||
| Shivering | |||||||||
| Anemia | |||||||||
| Metallic taste | |||||||||
| Dyspnea | |||||||||
| Palpitations | |||||||||
| Itching | |||||||||
| Maged AM [58] | 2016 | III | NCT02304055 | Cairo University | Egypt | H | VD | Oxytocin (50; 5 iu, i.v.) vs. Carbetocin (50; 100 ug, i.v.) | Nausea |
| Vomiting | |||||||||
| Tachycardia | |||||||||
| Flushing | |||||||||
| Dizziness | |||||||||
| Headache | |||||||||
| Shivering | |||||||||
| Metallic taste | |||||||||
| Dyspnea | |||||||||
| Palpitations | |||||||||
| Itching | |||||||||
| Othman ER [20] | 2016 | II | NCT02562300 | Assiut University | Egypt | L | CS | Oxytocin (60; 20 iu, i.v.) vs. Misoprostol (60; 400 ug, sub) | Pyrexia |
| Shivering | |||||||||
| Vomiting | |||||||||
| Headache | |||||||||
| Metallic taste | |||||||||
| Giddiness | |||||||||
| Razali N [61] | 2016 | NA | ISRCTN18976822 | the University of Malaya | Malaysia | L | CS | Oxytocin (271; 10 iu, i.v.) vs. Carbetocin (276; 100 ug, i.v.) | Arrhythmias |
| Sunil Kumar KS [60] | 2016 | NA | NA | NA | India | L | VD | Oxytocin (100; 10 iu, i.m.) vs. Carbetocin (100; 125 ug, i.m.) | Nausea |
| Vomiting | |||||||||
| Shivering | |||||||||
| Diarrhea | |||||||||
| Fever | |||||||||
| Musa AO [19] | 2015 | NA | PACTR201407000825227 | University of Ilorin Teaching Hospital | Nigeria | L | VD | Oxytocin (100; 10 iu, i.m.) vs. Misoprostol (100; 600 ug, p.o.) | Nausea |
| Diarhea | |||||||||
| Shivering | |||||||||
| Pyrexia | |||||||||
| Pakniat H [21] | 2015 | II | NCT01571323 and ACTRN12612000095864 | Qazvin University Of Medical Sciences | Iran | L | CS | Oxytocin (50; 20 iu, i.v.) vs. Misoprostol (50; 400 ug, sub) | Nausea |
| Vomiting | |||||||||
| Dyspnea | |||||||||
| Shivering | |||||||||
| Fever | |||||||||
| Chest pain | |||||||||
| Priya GP [22] | 2015 | NA | NA | NA | India | L | VD | Oxytocin (250; 10 iu, i.m.) vs. Misoprostol (250; 400 ug, sub) | Nausea |
| Vomiting | |||||||||
| Diarrhea | |||||||||
| Fever | |||||||||
| Shivering | |||||||||
| Atukunda EC [23] | 2014 | III | NCT01866241 | the Father Bash Foundation and Divine Mercy Hospital scholarship awards to ECA | Uganda | HL | VD | Oxytocin (570; 10 iu, i.m.) vs. Misoprostol (570; 600 ug, s.l.) | Vomiting |
| Nausea | |||||||||
| Headache | |||||||||
| Fever | |||||||||
| Shivering | |||||||||
| Diarrhea | |||||||||
| Afterpains | |||||||||
| Ezeama CO [66] | 2014 | NA | Pan African Clinical Trial Registry: 201105000292708 | NA | Nigeria | HL | VD | Oxytocin (151; 10 iu, i.m.) vs. Ergometrine (149; 500 ug, i.m.) | Nausea |
| Vomiting | |||||||||
| Headache | |||||||||
| Hypertension | |||||||||
| Rajaei M [24] | 2014 | I | NCT01863706 | Hormozgan University of Medical Sciences | Iran | HL | VD | Oxytocin (200; 20 iu, i.v.) vs. Misoprostol (200; 400 ug, p.o.) | Hypotension |
| Fever | |||||||||
| Chills | |||||||||
| Tewatia R [25] | 2014 | NA | NA | NA | India | L | VD | Oxytocin (50; 10 iu, i.v.) vs. Misoprostol (50; 600 ug, s.l.) | Fever |
| Shivering | |||||||||
| Nausea | |||||||||
| Vomiting | |||||||||
| Diarrhea | |||||||||
| Fazel MR [26] | 2013 | NA | NA | Kashan University of Medical Sciences | Iran | H | CS | Oxytocin (50; 10 iu, i.v.) vs. Misoprostol (50; 400 ug, i.v.) | Nausea |
| Vomiting | |||||||||
| Shivering | |||||||||
| Hyperpyrexia | |||||||||
| Chest pain | |||||||||
| Mukta M [27] | 2013 | NA | NA | NA | India | HL | VD | Oxytocin (100; 10 iu, i.m.) vs. Misoprostol (100; 600 ug, p.o.) | Shivering |
| Pyrexia | |||||||||
| Abdominal pain | |||||||||
| Diarrhea | |||||||||
| Nausea | |||||||||
| Vomiting | |||||||||
| Rosseland LA [6] | 2013 | IV | NCT00977769 | Ferring Pharmaceutical | Norway | H | CS | Oxytocin (26; 5 iu, i.v.) vs. Carbetocin (25; 100 ug, i.v.) vs. placebo | Metallic taste |
| Xerostomia | |||||||||
| Nasal congestion | |||||||||
| Headache | |||||||||
| Flushing | |||||||||
| Palpitations | |||||||||
| Shortness of breath | |||||||||
| Chest pain | |||||||||
| Feeling of warmth | |||||||||
| Adanikin AI [28] | 2012 | NA | NA | NA | Nigeria | H | CS | Oxytocin (109; 20 iu, i.v.) vs. Misoprostol (109; 600 ug, rec) | Nausea |
| Vomiting | |||||||||
| Shivering | |||||||||
| Pyrexia | |||||||||
| Badejoko OO [29] | 2012 | NA | ERC/2009/03/04 | NA | Nigeria | HL | VD | Oxytocin (132; 20 iu, i.v.) vs. Misoprostol (132; 600 ug, rec) | Vomiting |
| Pyrexia | |||||||||
| Shivering | |||||||||
| Bellad MB [31] | 2012 | III | NCT01373359 | Jawaharlal Nehru Medical College | India | L | VD | Oxytocin (331; 10 iu, i.m.) vs. Misoprostol (321; 400 ug, s.l.) | Nausea |
| Vomiting | |||||||||
| Shivering | |||||||||
| Fever | |||||||||
| Chaudhuri P [30] | 2012 | NA | CTRI/2009/091/000672 | NA | India | L | VD | Oxytocin (265; 10 iu, i.m.) vs. Misoprostol (265; 400 ug, s.l.) | Shivering |
| Fever | |||||||||
| Vomiting | |||||||||
| Nausea | |||||||||
| Diarrhea | |||||||||
| Moertl MG [63] | 2011 | NA | EudraCT number: 2007-005498-78; NCT01277978 | Medical University of Graz | Austria | H | CS | Oxytocin (28; 5 iu, i.v.) vs. Carbetocin (28; 100 ug, i.v.) | Nausea |
| Flushing | |||||||||
| Headache | |||||||||
| Tachycardia | |||||||||
| Shortness of breath | |||||||||
| Feeling warm | |||||||||
| Owonikoko KM [32] | 2011 | NA | NA | NA | Nigeria | H | CS | Oxytocin (50; 20 iu, i.v.) vs. Misoprostol (50; 400 ug, s.l.) | Nausea |
| Vomiting | |||||||||
| Headache | |||||||||
| Shivering | |||||||||
| Hypotension | |||||||||
| Reyes OA [62] | 2011 | NA | NA | NA | Panama | H | VD | Oxytocin (29; 20 iu, i.v.) vs. Carbetocin (26; 100 ug, i.v.) | Headaches |
| Palpitations | |||||||||
| Fever | |||||||||
| Nausea | |||||||||
| Vomiting | |||||||||
| Hot sensation | |||||||||
| Flushing | |||||||||
| Malaise | |||||||||
| Shrestha A [33] | 2011 | NA | NA | NA | Nepal | L | VD | Oxytocin (100; 10 iu, i.m.) vs. Misoprostol (100; 1000 ug, p.r.) | Shivering |
| Abdominal pain | |||||||||
| Afolabi EO [34] | 2010 | NA | NA | NA | Nigeria | Low | VD | Oxytocin (100; 10 iu, i.m.) vs. Misoprostol (100; 400 ug, p.o.) | Nausea |
| Shivering | |||||||||
| Attilakos G [17] | 2010 | NA | EudraCT number: 2005-002812-94 | Ferring UK funded the cost of preparation of the ‘blinded’drug ampoules | UK | High | CS | Oxytocin (189; 5 iu, i.v.) vs. Carbetocin (188; 100 ug, i.v.) | Nausea |
| Vomiting | |||||||||
| Headache | |||||||||
| Tachycardia | |||||||||
| Metallic taste | |||||||||
| Backache | |||||||||
| Abdominal pain | |||||||||
| Arm pain | |||||||||
| Trigeminy | |||||||||
| Flushed | |||||||||
| Shortness of breath | |||||||||
| Wheezing | |||||||||
| Tremors | |||||||||
| Hypotension | |||||||||
| Sweating | |||||||||
| Tightness throat | |||||||||
| ST depression | |||||||||
| Blurred vision | |||||||||
| Blum J [35] | 2010 | NA | NCT00116350 | The Bill & Melinda Gates Foundation | Burkina Faso; Egypt; Turkey; Vietnam | L | CS | Oxytocin (402; 40 iu, i.v.) vs. Misoprostol (407; 800 ug, sub) | Vomiting |
| Nausea | |||||||||
| Shivering | |||||||||
| Fever | |||||||||
| Dizziness | |||||||||
| Diarrhoea | |||||||||
| Butwick AJ [71] | 2010 | NA | NA | Stanford University School of Medicine | USA | H | CS | Oxytocin (15, 15, 14, 15; 0.5 iu, 1 iu, 3 iu, 5 iu, i.v.) vs. placebo | Hypotension |
| Tachycardia | |||||||||
| Nausea | |||||||||
| Chaudhuri P [36] | 2010 | NA | CTRI/2009/091/000075 | NA | India | H | CS | Oxytocin (94; 40 iu, i.v.) vs. Misoprostol (96; 800 ug, p.r.) | Shivering |
| Pyrexia | |||||||||
| Vomiting | |||||||||
| Winikoff B [37] | 2010 | NA | NCT00116350 | the Bill & Melinda Gates Foundation | Ecuador, Egypt, Vietnam | L | VD | Oxytocin (490; 40 iu, i.v.) vs. Misoprostol (488; 800 ug, sub) | Vomiting |
| Nausea | |||||||||
| Shivering | |||||||||
| Fever | |||||||||
| Fainting | |||||||||
| Diarrhoea | |||||||||
| Borruto F [64] | 2009 | NA | NA | NA | Italy | H | CS | Oxytocin (52; 10 iu, i.v.) vs. Carbetocin (52; 100 ug, i.v.) | Anemia |
| Arrhythmias | |||||||||
| Abdominal pain | |||||||||
| Nausea | |||||||||
| Vomiting | |||||||||
| Metallic taste | |||||||||
| Heat sensation | |||||||||
| Back pain | |||||||||
| Headache | |||||||||
| Tremor | |||||||||
| Dizziness | |||||||||
| Difficulty in breathing | |||||||||
| Dyspnea | |||||||||
| Chest pain | |||||||||
| Pruritus | |||||||||
| Flushing | |||||||||
| Hypotension | |||||||||
| Nasr A [38] | 2009 | NA | NA | NA | Egypt | L | VD | Oxytocin (257; 5 iu, i.m.) vs. Misoprostol (257; 800 ug, p.o.) | Nausea |
| Vomiting | |||||||||
| Diarrhea | |||||||||
| Shivering | |||||||||
| Fever | |||||||||
| Singh G [72] | 2009 | NA | NA | NA | India | L | VD | Oxytocin (75; 5 iu, i.v.) vs. Misoprostol (75, 75; 400 ug, 600 ug, s.l.) vs. Ergometrine (75; 200 ug, i.v.) | Fever |
| Shivering | |||||||||
| Orji E [67] | 2008 | NA | NA | NA | Nigeria | HL | VD | Oxytocin (297; 10 iu, i.v.) vs. Ergometrine (303; 250 ug, i.v.) | Nausea |
| Vomiting | |||||||||
| Headaches | |||||||||
| Hypertension | |||||||||
| Baskett TF [39] | 2007 | NA | NA | Nova Scotia Health Research Foundation | Canada | HL | VD | Oxytocin (311; 5 iu, i.v.) vs. Misoprostol (311; 400 ug, p.o.) | Shivering |
| Fever | |||||||||
| Parsons SM [40] | 2007 | NA | NA | MaterCare International and the Canadian Foundation for Women’s Health | Ghana | HL | VD | Oxytocin (226; 10 iu, i.m.) vs. Misoprostol (224; 800 ug, p.r.) | Nausea |
| Vomiting | |||||||||
| Shivering | |||||||||
| Fever | |||||||||
| Hypertension | |||||||||
| Saito K [68] | 2007 | NA | NA | NA | Japan | L | VD | Oxytocin (156; 5 iu, i.m.) vs. Ergometrine (187; 200 ug, i.m.) | Nausea |
| Headache | |||||||||
| Dyspnea | |||||||||
| Hypertension | |||||||||
| Gupta B [41] | 2006 | NA | NA | NA | India | HL | VD | Oxytocin (100; 10 iu, i.m.) vs. Misoprostol (100; 600 ug, p.r.) | Shivering |
| Nausea | |||||||||
| Fever | |||||||||
| Parsons SM [42] | 2006 | NA | NA | Matercare International and the Society of Obstetricians and Gynaecologists of Canada | Ghana | HL | VD | Oxytocin (225; 10 iu, i.m.) vs. Misoprostol (225; 800 ug, p.o.) | Nausea |
| Vomiting | |||||||||
| Diarrhea | |||||||||
| Shivering | |||||||||
| Fever | |||||||||
| Hypertension | |||||||||
| Vimala N [43] | 2006 | NA | NA | Division of Reproductive Health and Nutrition, Indian Council of Medical Research (ICMR), New Delhi | India | H | CS | Oxytocin (50; 20 iu, i.v.) vs. Misoprostol (50; 400 ug, s.l.) | Pyrexia |
| Shivering | |||||||||
| Vomiting | |||||||||
| Headache | |||||||||
| Metallic taste | |||||||||
| Giddiness | |||||||||
| Zachariah ES [73] | 2006 | NA | NA | NA | India | HL | VD | Oxytocin (617; 10 iu, i.m.) vs. Misoprostol (730; 400 ug, p.o.) vs. Ergometrine (676; 2000 ug, i.v.) | Fever |
| Nausea | |||||||||
| Vomiting | |||||||||
| Shivering | |||||||||
| Diarrhea | |||||||||
| Headache | |||||||||
| Boucher M [16] | 2004 | NA | NA | NA | Canada | H | VD | Oxytocin (77; 10 iu, i.v.) vs. Carbetocin (83; 100 ug, i.m.) | Headache |
| Chills | |||||||||
| Abdominal pain | |||||||||
| Dizziness | |||||||||
| Tremor | |||||||||
| Vasodilatation | |||||||||
| Leukocytosis | |||||||||
| Nausea | |||||||||
| Vomiting | |||||||||
| Pruritis | |||||||||
| Caliskan E [44] | 2003 | NA | NA | NA | Turkey | HL | VD | Oxytocin (384; 10 iu, i.v.) vs. Misoprostol (388; 600 ug, p.o.) | Shivering |
| Vomiting | |||||||||
| Diarrhea | |||||||||
| Fever | |||||||||
| Oboro VO [45] | 2003 | NA | NA | NA | Nigeria | L | VD | Oxytocin (249; 10 iu, i.m.) vs. Misoprostol (247; 600 ug, p.o.) | Nausea |
| Vomiting | |||||||||
| Diarrhoea | |||||||||
| Dizziness | |||||||||
| Shivering | |||||||||
| Fever | |||||||||
| Calişkan E [47] | 2002 | NA | NA | NA | Turkey | HL | VD | Oxytocin (407; 10 iu, i.v.) vs. Misoprostol (396; 600 ug, p.r.) | Shivering |
| Vomiting | |||||||||
| Diarrhea | |||||||||
| Fever | |||||||||
| Karkanis SG [46] | 2002 | NA | NA | The Physicians Services Incorporated Foundation | Canada | L | VD | Oxytocin (110; 10 iu, i.m.) vs. Misoprostol (105; 400 ug, p.r.) | Nausea |
| Vomiting | |||||||||
| Headache | |||||||||
| Shivering | |||||||||
| Abdominal pain | |||||||||
| Fever | |||||||||
| Acharya G [48] | 2001 | NA | NA | NA | UK | High | CS | Oxytocin (30; 10 iu, i.v.) vs. Misoprostol (30; 400 ug, p.o.) | Vomiting |
| Headache | |||||||||
| Bugalho A [49] | 2001 | NA | NA | Maputo Central Hospital and the Special Program on Research and Research Training in Human Reproduction of WHO | Mozambique | HL | VD | Oxytocin (339; 10 iu, i.m.) vs. Misoprostol (324; 400 ug, p.r.) | Vomiting |
| Diarrhea | |||||||||
| Shivering | |||||||||
| Gerstenfeld TS [50] | 2001 | NA | NA | NA | USA | HL | VD | Oxytocin (166; 20 iu, i.v.) vs. Misoprostol (159; 400 ug, p.r.) | Shivering |
| Gülmezoglu AM [51] | 2001 | NA | NA | UNDP/UNFPA/WHO/World Bank Special Programme of Research | Argentina; China; Egypt; Ireland; Nigeria; South Africa; Switzerland; Thailand; Vietnam | HL | VD | Oxytocin (9266; 10 iu, i.v./i.m.) vs. Misoprostol (9264; 600 ug, p.o.) | Shivering |
| Fever | |||||||||
| Nausea | |||||||||
| Vomiting | |||||||||
| Diarrhoea | |||||||||
| Kundodyiwa TW [52] | 2001 | NA | NA | NA | Zimbabwe | L | VD | Oxytocin (256; 10 iu, i.m.) vs. Misoprostol (243; 400 ug, p.o) | Shivering |
| Vomiting | |||||||||
| Nausea | |||||||||
| Diarrhea | |||||||||
| Fever | |||||||||
| Hypertension | |||||||||
| Lokugamage AU [53] | 2001 | NA | NA | NA | UK | H | CS | Oxytocin (20; 10 iu, i.v.) vs. Misoprostol (20; 500 ug, p.o.) | Shivering |
| Walley RL [54] | 2000 | NA | NA | MaterCare International and the Canadian International Development Agency | Ghana | L | VD | Oxytocin (198; 10 iu, i.m.) vs. Misoprostol (203; 400 ug, p.o.) | Nausea |
| Vomiting | |||||||||
| Diarrhoea | |||||||||
| Shivering | |||||||||
| Fever | |||||||||
| Dansereau J [65] | 1999 | NA | NA | A Clinical Research Grant from Ferring Inc., Canada | Canada | H | CS | Oxytocin (330; 25 iu, i.v.) vs. Carbetocin (329; 100 ug, i.v.) | Abdominal pain |
| Back pain | |||||||||
| Headache | |||||||||
| Nausea | |||||||||
| Metallic taste | |||||||||
| Flushing | |||||||||
| Sweating | |||||||||
| Tremors | |||||||||
| Vomiting | |||||||||
| Feeling of warmth | |||||||||
| Chou MM [70] | 1994 | NA | NA | Tachung Veterans General Hospital | China | HL | CS | Oxytocin (30; 20 iu, i.v.) vs. Prostaglandin (30; 125 ug, i.m.) | Vomiting |
| Diarrhea | |||||||||
| Flushing | |||||||||
| Dizziness | |||||||||
| Pyrexia | |||||||||
| Moir DD [69] | 1979 | NA | NA | NA | UK | L | VD | Oxytocin (44; 10 iu, i.v.) vs. Ergometrine (44; 500 ug, i.v.) | Vomiting |
CS: cesarean section; H: high risk for PPH; HL: high and low risk for PPH; L: low risk for PPH; NA: none; PPH: postpartum hemorrhage; VD: vaginal birth.
Figure 2.
Number and proportions of each side-effect in this study.
Participants received oxytocin via intramuscular injection in twenty-two trials, and underwent vaginal birth in thirty-nine trials. Twenty trials provided the trial registration number. Twenty-five trials comprised women at low risk for PPH, 17 trials comprised women at high and low risk, and 34 trials comprised women at high risk. Twenty-three trials stated that their funding came from public institution, 4 trials from drug company, and 34 trials did not state the source of the funds. Thirty-four trials used standard dose, 10 trials used low dose, and 17 trials reported high dose. Fifty-eight trials were identified as two-arms, including oxytocin vs. misoprostol (38 trials) [18-55], carbetocin (14 trials) [11,12,16,17,56-65], ergometrine (4 trials) [66-69], prostaglandins (1 trial) [70], and placebo (1 trial) [71]; and three trials were identified as three-arms, including oxytocin vs. misoprostol vs. ergometrine (2 trials) [72,73], and oxytocin vs. carbetocin vs. placebo (1 trial) [6].
Risk of bias
Figures 3 and 4 showed the detailed risk of bias of the included studies. Fifty RCTs were randomized, and 37 of them underwent an adequate allocation and setting blinding. Thirty-five trials blinded outcome assessors and 44 RCTs described the incomplete outcome data or provided the complete outcome data. There were 24, 35, or 2 trials assessed as high, medium and low quality, respectively.
Figure 3.
Proportions of trials that met each criterion for risk of bias across the 61 included randomized clinical trials.
Figure 4.
Results of the risk of bias for 61 included randomized clinical trials. Green means low risk; yellow means unclear risk; red means high risk.
Outcomes
Figure 5 showed pooled RRs for side-effects. Compared with non-oxytocin, oxytocin had significantly lower risk for shivering (RR=0.31, 95% CI=0.23-0.41, n=36680), fever (RR=0.27, 95% CI=0.20-0.37, n=34031), and diarrhea (RR=0.48, 95% CI=0.35-0.66, n=30883). However, other side-effects, such as vomiting, nausea, headache, flushing, dizziness, etc., were not associated with oxytocin.
Figure 5.
Results of side-effects in this meta-analysis.
Subgroup analysis showed that oxytocin was associated with lower risk for vomiting in i.m. group (RR=0.65, 95% CI=0.54-0.80, n=39041) and VD group (RR=0.50, 95% CI=0.36-0.69, n=62493), low risk in PPH group (RR=0.69, 95% CI=0.53-0.90, n=36624), high risk in PPH group (RR=0.42, 95% CI=0.25-0.71, n=26874), misoprostol group (RR=0.59, 95% CI=0.50-0.69, n=31887), ergometrine group (RR=0.12, 95% CI=0.07-0.19, n=2283), and public institution funding group (RR=0.62, 95% CI=0.45-0.85, n=25094), slightly lower risk in trial registration group (RR=0.65, 95% CI=0.43-0.99, n=35341), and higher risk for headache in CS group (RR=1.81, 95% CI=1.16-2.82, n=2184) (Supplementary File 2).
However, oxytocin was not associated with lower risk for shivering in drug company funding group (RR=1.35, 95% CI=0.92-1.99, n=1036), carbetocin group (RR=1.29, 95% CI=0.92-1.81, n=2024), and ergometrine group (RR=0.59, 95% CI=0.31-1.12, n=1293); high risk for fever in PPH group (RR=0.67, 95% CI=0.36-1.23, n=949), drug company funding group (RR=1.26, 95% CI=0.29-5.47, n=102), carbetocin group (RR=0.57, 95% CI=0.17-1.91, n=490), ergometrine group (RR=0.34, 95% CI=0.11-1.03, n=1293), prostaglandins group (RR=2.00, 95% CI=0.19-20.90, n=60), and placebo group (RR=1.92, 95% CI=0.19-19.90, n=51); for diarrhea in low dose group (RR=0.83, 95% CI=0.26-2.70, n=514) and high dose group (RR=0.85, 95% CI=0.29-2.51, n=1849), CS group (RR=0.80, 95% CI=0.22-2.92, n=871), ergometrine group (RR=0.22, 95% CI=0.01-4.55, n=1295), and placebo group (RR=3.00, 95% CI=0.13-70.83, n=62) (Supplementary File 2).
Supplementary File 3 showed the results of cumulative meta-analysis. Cumulative meta-analysis showed that oxytocin use was association with a significantly lower incidence of shivering, fever, and diarrhea events since 2001 (Supplementary File 3, Figures S2, S4 and S6). However, other side-effects were not associated with oxytocin use (Supplementary File 3, Figures S1, S3, S5, S7 and S8).
Publication bias
Begg and Egger tests found that there was no publication bias for side-effects (Supplementary File 2). Meanwhile, funnel plots also observed symmetry for vomiting, shivering, nausea, fever, headache, diarrhea, flushing and dizziness (Supplementary File 4, Figures S9, S10, S11, S12, S13, S14, S15 and S16).
Discussion
This is the first large systematic review and meta-analysis, to our knowledge, to intentionally assess the side-effects of oxytocin for the prevention of PPH during the third stage of labor. Sixty-one RCTs based on 68834 participants reported 27 types of side-effects. Results showed that oxytocin could decrease the risk of shivering, fever, and diarrhea, and did not show evidence of an increased risk of other side-effects.
Oxytocin is currently regarded as the gold standard for prevention and treatment of PPH during the third stage of labor. Observational articles and RCTs indicated that vomiting, nausea, shivering and fever are the most frequent side-effects encountered when oxytocin is used for the prevention of PPH. Other side-effects include gastro-intestinal disorders (diarrhea, metallic taste, and abdominal pain), heart disorders (arrhythmias and palpitations), blood system disorders (anemia and leukocytosis), vascular disorders (flushing, hypotension, and hypertension), respiratory disorder (dyspnea, wheezing, and nasal congestion), nervous system disorders (headache, and dizziness) and other general disorders (pruritis, sweating, backache, chills, xerostomia, chest pain and arm pain). These side-effects are generally related to the maternal condition, mode of delivery, dose, and route of administration.
As a secondary outcome, the side-effects of oxytocin use have been mentioned in previous studies. There is difference between our finding and previous studies for the side-effects after using oxytocin for preventing PPH during the third stage of labor. Many guidelines, including Royal College of Obstetricians and Gynaecologists [74] and World Health Organization [3], recommend oxytocin 10 iu intramuscularly or intravenously. Interestingly, it was found that recommended dose of oxytocin (10 iu) could reduce the risk of diarrhea in this meta-analysis. However, this phenomenon was not found in the low- and high-groups. However, it needs to be cautious to interpret this finding because data for low- or high-dose group were rare. Small sample size could lead to false negatives in clinical trials. The meta-analysis by Zhou et al. [75] found no significant differences between the intramuscular and intravenous groups. RCTs [76-78] and systematic review [79,80] also demonstrated that intravenous and intramuscular routes have a similar efficacy and side-effects. In this side-effects focused study, although the route administration did not have significant effect on the side-effects, the risk of vomiting was significantly reduced via IM injection. The main reason for this difference is that previous studies mostly grouped all sided-effects into only one indicator, while our study analyzed the effect of each side-effect in a more detailed way.
Compared with other several different uterotonics, oxytocin is the most widely recommended and used as the main intervention for preventing PPH during the third stage of labor. However, despite its widespread use, there is no consensus with clear evidence on the side-effects of oxytocin for the prevention of PPH. This study involved a large number of RCT articles and all side-effects. Sufficient sample size could improve the precision and comprehension of risk estimates, especially for rare side-effects. And, the results more closely reflect the real clinical practice than the rigorous single clinical trial. Through these results, obstetricians and gynaecologists could weigh up the benefits and risks associated with oxytocin in the prevention and treatment of PPH during the third stage of labor, and further help inform best practice in clinical care.
This meta-analysis has several strengths. The major strength of this study is the large number of included studies, sufficient sample size, and all side-effects. This can improve the precision and comprehension of risk estimates. Given that side-effect is a rare outcome, the relatively large number of participants is necessary to obtain reliable conclusions. A further strength is the data from multiple studies and centers, including participants with different conditions. It more closely reflects the real clinical practice than the rigorous single clinical trial. In addition, most of the included trials had high and moderate quality. Only two trials [60,68] had low quality base on Cochrane handbook tool assessment. This could ensure the quality of the results in meta-analysis.
Meanwhile, several limitations of this study should be mentioned. First, some low incidence of certain side-effects was not reported in one or two groups in some articles. The continuity correction of adding 0.5 to each cell in the fourfold table was applied in the studies with zero events for one group to improve the analysis and they were excluded for trials with double zero events in both groups from the analysis. This implies that there is a certain error between the pooled RR and the true value. Second, these sixty-one included RCTs ranged nearly 40 years from 45 countries and regions. Although subgroup and cumulative analyses were performed, there could have been inconsistency in the definition and diagnosis of the side-effects in different time, researchers and countries and regions, resulting in difficulty in comparison of studies. These could result in a bias of reported incidence rates in the clinical trials. Third, side-effects were reported, but no data were provided in two trials [5,81], and we excluded them in these studies. Although no publication bias was found, this could increase the publication bias risk. Fourth, heterogeneity was found in some side-effects. Subgroup analysis could partially explain the existence of heterogeneity, but not completely. Some findings might be statistically significant by chance.
In brief, oxytocin use was associated with a significantly lower incidence of shivering, fever, and diarrhea events and did not increase the risk of other side-effects during the third stage of labor. These observations may aid obstetricians and gynaecologists in weighing up the benefits and risks associated with oxytocin in the prevention and treatment of PPH during the third stage of labor.
Acknowledgements
We appreciate the efforts of all the researchers whose articles were included in this study. And, no funding or sponsorship was received for this study or publication of this article.
Disclosure of conflict of interest
None.
Supporting Information
References
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