Background

Oxytocin (10 IU) is the drug of choice for prevention of postpartum hemorrhage (PPH). Its use has generally been restricted to medically trained staff in health facilities. We assessed the effectiveness, safety, and feasibility of PPH prevention using oxytocin injected by peripheral health care providers without midwifery skills at home births.

Methods and Findings

This community-based, cluster-randomized trial was conducted in four rural districts in Ghana. We randomly allocated 54 community health officers (stratified on district and catchment area distance to a health facility: ≥10 km versus <10 km) to intervention (one injection of oxytocin [10 IU] one minute after birth) and control (no provision of prophylactic oxytocin) arms. Births attended by a community health officer constituted a cluster. Our primary outcome was PPH, using multiple definitions; (PPH-1) blood loss ≥500 mL; (PPH-2) PPH-1 plus women who received early treatment for PPH; and (PPH-3) PPH-2 plus any other women referred to hospital for postpartum bleeding. Unsafe practice is defined as oxytocin use before delivery of the baby. We enrolled 689 and 897 women, respectively, into oxytocin and control arms of the trial from April 2011 to November 2012. In oxytocin and control arms, respectively, PPH-1 rates were 2.6% versus 5.5% (RR: 0.49; 95% CI: 0.27–0.88); PPH-2 rates were 3.8% versus 10.8% (RR: 0.35; 95% CI: 0.18–0.63), and PPH-3 rates were similar to those of PPH-2. Compared to women in control clusters, those in the intervention clusters lost 45.1 mL (17.7–72.6) less blood. There were no cases of oxytocin use before delivery of the baby and no major adverse events requiring notification of the institutional review boards. Limitations include an unblinded trial and imbalanced numbers of participants, favoring controls.

Conclusion

Maternal health care planners can consider adapting this model to extend the use of oxytocin into peripheral settings including, in some contexts, home births.

Discussion

This community-based, cluster-randomized trial of prophylactic oxytocin (10 IU) administered via Uniject by peripheral health care providers without midwifery skills showed statistically significant reductions of 51% in the risk of PPH for blood loss ≥500 mL and 66% for blood loss ≥500 mL or with gushing and large blood clots. Results for severe PPH (≥1,000 mL) were not statistically significant. All secondary outcomes suggested the intervention was safe.

The magnitude of protective effect for blood loss ≥500 mL in this trial is similar to results shown for community-based prophylactic misoprostol (600 mcg) versus placebo in rural India (47% reduction in PPH) [10] and to a meta-analysis of health facility–based prophylactic use of intramuscular and intravenous oxytocin versus no uterotonics in high-income countries (50% reduction in PPH defined as ≥500 mL blood loss; 95% CI: 0·43–0·59) [9]. PPH reduction in this study was greater than trial results shown for prophylactic misoprostol (600 mcg) versus placebo in rural Pakistan (24% reduction in PPH) and in Guinea Bissau (11% non-significant reduction in PPH) . Mean blood loss among both oxytocin and control women in this trial was lower than that reported in these community-based misoprostol trials. Our results show mean blood loss of 185.5 mL and 229.2 mL among oxytocin and control deliveries, respectively, as compared to results from India (214.3 mL versus 262.3 mL), Pakistan (337 mL versus 366 mL), and Guinea Bissau (443 mL versus 496 mL) . Lower blood loss in this trial is expected, as early treatment of PPH with an additional injection of oxytocin (10 IU) in both our trial arms likely reduced ultimate blood loss among all PPH cases.

Several limitations of this study warrant discussion. The ratios of numbers of women in oxytocin and control arms of the trial range from 0.68 at the identification of eligible pregnancies to 0.77 at enrollment. Prior to randomization, CHO catchment areas were stratified by distance to emergency obstetric care, but not by population size, as these data were only available for Kintampo North and South. In these two districts, the ratio of population in the oxytocin versus control catchment areas is 0.88, explaining some, but not all, of the imbalance. As shown inTable 2, fertility between study arms is similar. There was no evidence that field workers in the oxytocin arm systematically missed identifying more pregnant women than in the control arm. However, if they did, it is unlikely that these women would have substantially different characteristics than the homogenous group that provided initial consent for the study (and which represented 99% of all identified pregnancies in both groups).

Two CHO behaviors differed by arm of the trial. First, control CHOs initiated blood-loss measurement (i.e., unfolded the drape) on average one minute later than oxytocin CHOs following delivery, possibly leading to an underestimate of blood loss in the control group. However, if delayed unfolding of the drape by control CHOs reduced blood loss measures, it would underestimate impact of oxytocin on outcomes. Second, CHOs in the oxytocin group referred women prior to delivery more frequently (17.3%) than control CHOs (12.5%), possibly indicating that the analyzable sample in the oxytocin group excluded a larger pool of women having a difficult delivery and thus potentially at higher risk of PPH. Data extracted from hospital records for referred women did not, however, indicate a higher risk (6 PPH cases among 198 referred women in the oxytocin group = 3.0%).

In an un-blinded study, differential measurement errors across arms of the trial are possible and thus, lack of blinding constitutes a study limitation. However, in this study the intervention was provided by CHOs who were not birth attendants. They were not responsible for managing the births nor were they responsible for the birth outcome, two issues which we believe would decrease the chances that they influenced the study outcome. The CHO’s job was to respond to the call, to give (or not give) the injection and measure blood. They had no previous experience with birth, or visual blood loss estimation and possible associations with bad maternal outcomes.

This trial provides evidence that administration of intramuscular prophylactic oxytocin in Uniject by peripheral health care providers without midwifery skills can effectively decrease the risk of PPH at home births under research conditions. Furthermore, none of the secondary outcomes reflecting safety suggested that this intervention was unsafe. Across trial arms, service was successfully provided to three-quarters of all calls requesting CHO assistance. However, CHO compliance varied widely, and was likely due to CHOs working alone in their catchment area per trial protocol; that is, they were on call 24 hours per day for 19 months. In a scaled-up program, additional staffing or the ability to refer calls to a neighboring CHO would be required to increase and sustain CHO compliance. There is no evidence that the intervention decreased health facility–based births. However, 17% of pregnant women (n = 5919) chose to deliver at home without a CHO and research is needed to understand the barriers to reaching these women. Another concern was the frequent lack of compliance with free referral to hospital for PPH cases. Refusal of referrals was unexpected and underscores the importance of providing community-based early treatment to women reluctant to seek care outside the home.

Cost is an important component of intervention feasibility. Oxytocin in Uniject is currently commercially available only in a few Latin American countries and thus its eventual market-driven cost is unknown. The United Nations Commission on Life-Saving Commodities for Women and Children includes oxytocin among 13 medicines unavailable to women due to issues such as cost or supply because they are not subsidized by global bulk purchase agreements or advance market commitments. The Commission has developed specific recommendations to address these issues as well as to promote oxytocin in a Uniject-type device [24]. It is anticipated that oxytocin in Uniject will cost US$1.00 or less, and potentially substantially less once sustained demand is established. The oxytocin in Unijects used in this study, were purchased on a non-commercial basis at a cost of $1.40 per dose. A commercial price for the product, should sustainable demand emerge, could be lower as economies of scale play a significant role in the cost of producing pharmaceutical products.

These results also raise additional questions. For example, if oxytocin in Uniject is not an option, could providers entrusted to vaccinate children and provide other injections use a traditional syringe and ampoule for oxytocin administration? The skills required are the same as are issues regarding needle disposal. As a cost-saving measure, could a time/temperature indicator be placed on a flat of oxytocin ampoules (versus individual ampoules), since ampoules within a flat are generally exposed to the same environmental conditions? This issue is mentioned in the UN Commission on Life-Saving Commodities for Women and Children and will likely be determined by the willingness of pharmaceutical companies to allow it. Regarding the duration that oxytocin can remain out of the cold chain in hot climates, additional analyses from this trial are currently underway to assess the number of days that oxytocin can remain out of the cold chain under field conditions in central Ghana prior to indication by the time/temperature indicator that the device should be discarded. Such information will serve health care planners in determining the required resupply schedule and the feasibility of this schedule locally. Could a lay provider safely and effectively use oxytocin in Uniject? (A randomized trial assessing use of oxytocin in Uniject by traditional birth attendants to prevent PPH is underway in Senegal now; clinicaltrials.gov: NCT01713153.) Is the BRASSS-V calibrated plastic drape used here necessary or could a simplified drape that indicates only when treatment and referral are needed (versus a quantitative blood loss measure), or other PPH detection pads suffice? This choice will be determined by the objectives of local health planners and the ability to easily obtain or import supplies. In Ghana, local manufacture of the blood loss measurement drape is considered a priority for scaled-up use.

While the move towards use of skilled birth attendants is gathering global momentum, poverty and inequity—particularly in selected areas in countries—will remain issues for the foreseeable future. Prophylactic use of uterotonics to prevent PPH, the biggest killer of women during childbirth, is a key intervention and use of oxytocin as the drug of choice should be considered where its use is feasible. It is unhelpful to pose this issue as oxytocin versus misoprostol. The more appropriate question is: Where and under what circumstances can each of these proven effective drugs be used? Ultimately, decisions regarding the balance of advantages and disadvantages of using oxytocin or misoprostol for PPH prevention at home births will depend on local conditions, human resources, infrastructure, and national policies.

Source:PLOS