Review question
What are the benefits and risks of using medication to block the hormone oxytocin for women undergoing embryo transfer?
Background
Embryo transfer (ET) is a crucial step of assisted reproductive technology (ART), and involves placing one or more embryos (fertilised eggs) into the womb. Contractions in the lining of the womb are wave-like motions of the lining surface; their presence around the time of embryo transfer is associated with lower pregnancy rates. No treatment is currently used to counteract their negative effects on the embryo’s attachment to the womb. Oxytocin is a natural hormone, known to trigger contractions during labour. Medication to block its function is routinely used to stop contractions in preterm labour. Some think the same hormone is involved in contractions around the time of ET. For this reason, researchers have questioned whether medication that stops labour contractions could stop contractions around the time of ET, and potentially improve pregnancy rates.
Study characteristics
We found eleven studies, in 3733 women undergoing embryo transfer, which assessed the use of medication to block oxytocin function. Medication to block oxytocin function was given by injection into a vein (atosiban) in seven RCTs, under the skin (barusiban) in one RCT, and by mouth (nolasiban) in three RCTs. The evidence is current to March 2021.
Key results
Medication by injection (atosiban) versus no medication
We are uncertain of the effect of atosiban on live birth and miscarriage rates. In a clinic with a live birth rate of 38% without medication to block oxytocin, the use of atosiban would be associated with a live birth rate ranging from 33% to 47%. In a clinic with a miscarriage rate of 7% without medication to block oxytocin, the use of atosiban would be associated with a miscarriage rate ranging from 5% to 11%.
Medication given under the skin (barusiban) versus no medication
There were no studies that reported live birth or miscarriage data for the use of barusiban. We are uncertain whether barusiban influences clinical pregnancy rates.
Medication given by mouth (nolasiban) versus no medication
The evidence suggests that nolasiban does not improve live birth rates when compared to those not taking medication to block oxytocin. In a clinic with a live birth rate of 33% per cycle without medication to block oxytocin, the use of nolasiban would be associated with a live birth rate ranging from 33% to 42%.
We are uncertain of the effect of oral nolasiban on miscarriage rate. In a clinic with a miscarriage rate of 2% per cycle without medication to block oxytocin, the use of nolasiban would be associated with a miscarriage rate ranging from 1% to 4%.
The evidence suggests that nolasiban improves clinical pregnancy rates compared to not taking medication to block oxytocin. In a clinic with a clinical pregnancy of 35% per cycle without medication to block oxytocin, the use of nolasiban would be associated with a clinical pregnancy rate ranging from 35% to 45%.
Evidence for all types of medication on other adverse events such as multiple pregnancy (pregnant with twins, triplets or more), pregnancy growing outside the womb, adverse reaction to medication or congenital anomalies (defects present from birth) was poorly reported or inconclusive.
Certainty of the evidence
The evidence was of very low to high certainty. The main limitations in the evidence were poor reporting of study methods, and lack of exactness due to small study numbers and few events.
We are uncertain whether intravenous atosiban improves pregnancy outcomes for women undergoing assisted reproductive technology. This conclusion is based on currently available data from seven RCTs, which provided very low- to low-certainty evidence across studies.
We could draw no clear conclusions about subcutaneous barusiban, based on limited data from one RCT.
Further large well-designed RCTs reporting on live births and adverse clinical outcomes are still required to clarify the exact role of atosiban and barusiban before ET.
Oral nolasiban appears to improve clinical pregnancy rate but not live birth rate, with an uncertain effect on miscarriage and adverse events. This conclusion is based on a phased study comprising three trials that provided low- to high-certainty evidence. Further large, well-designed RCTs, reporting on live births and adverse clinical outcomes, should focus on identifying the subgroups of women who are likely to benefit from this intervention.
Embryo transfer (ET) is a crucial step of in vitro fertilisation (IVF) treatment, and involves placing the embryo(s) in the woman’s uterus. There is a negative association between endometrial wave-like activity (contractile activities) at the time of ET and clinical pregnancy, but no specific treatment is currently used in clinical practice to counteract their effects. Oxytocin is a hormone produced by the hypothalamus and released by the posterior pituitary. Its main role involves generating uterine contractions during and after childbirth. Atosiban is the best known oxytocin antagonist (and is also a vasopressin antagonist), and it is commonly used to delay premature labour by halting uterine contractions. Other oxytocin antagonists include barusiban, nolasiban, epelsiban, and retosiban. Administration of oxytocin antagonists around the time of ET has been proposed as a means to reduce uterine contractions that may interfere with embryo implantation. The intervention involves administering the medication before, during, or after the ET (or a combination).
To evaluate the effectiveness and safety of oxytocin antagonists around the time of ET in women undergoing assisted reproduction.
We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in March 2021; and checked references and contacted study authors and experts in the field to identify additional studies.
We included randomised controlled trials (RCTs) of the use of oxytocin antagonists for women undergoing ET, compared with the non-use of this intervention, the use of placebo, or the use of another similar drug.
We used standard methodological procedures recommended by Cochrane. Primary review outcomes were live birth and miscarriage; secondary outcomes were clinical pregnancy and other adverse events.
We included nine studies (including one comprising three separate trials, 3733 women analysed in total) investigating the role of three different oxytocin antagonists administered intravenously (atosiban), subcutaneously (barusiban), or orally (nolasiban). We found very low- to high-certainty evidence: the main limitations were serious risk of bias due to poor reporting of study methods, and serious or very serious imprecision.
Intravenous atosiban versus normal saline or no intervention
We are uncertain of the effect of intravenous atosiban on live birth rate (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.88 to 1.24; 1 RCT, N = 800; low-certainty evidence). In a clinic with a live birth rate of 38% per cycle, the use of intravenous atosiban would be associated with a live birth rate ranging from 33.4% to 47.1%.
We are uncertain whether intravenous atosiban influences miscarriage rate (RR 1.08, 95% CI 0.75 to 1.56; 5 RCTs, N = 1424; I² = 0%; very low-certainty evidence). In a clinic with a miscarriage rate of 7.2% per cycle, the use of intravenous atosiban would be associated with a miscarriage rate ranging from 5.4% to 11.2%.
Intravenous atosiban may increase clinical pregnancy rate (RR 1.50, 95% CI 1.18 to 1.89; 7 RCTs, N = 1646; I² = 69%; low-certainty evidence), and we are uncertain whether multiple or ectopic pregnancy and other complication rates were influenced by the use of intravenous atosiban (very low-certainty evidence).
Subcutaneous barusiban versus placebo
One study investigated barusiban, but did not report on live birth or miscarriage.
We are uncertain whether subcutaneous barusiban influences clinical pregnancy rate (RR 0.96, 95% CI 0.69 to 1.35; 1 RCT, N = 255; very low-certainty evidence). Trialists reported more mild to moderate injection site reactions with barusiban than with placebo, but there was no difference in severe reactions. They reported no serious drug reactions; and comparable neonatal outcome between groups.
Oral nolasiban versus placebo
Nolasiban does not increase live birth rate (RR 1.13, 95% CI 0.99 to 1.28; 3 RCTs, N = 1832; I² = 0%; high-certainty evidence). In a clinic with a live birth rate of 33% per cycle, the use of oral nolasiban would be associated with a live birth rate ranging from 32.7% to 42.2%.
We are uncertain of the effect of oral nolasiban on miscarriage rate (RR 1.45, 95% CI 0.73 to 2.88; 3 RCTs, N = 1832; I² = 0%; low-certainty evidence). In a clinic with a miscarriage rate of 1.5% per cycle, the use of oral nolasiban would be associated with a miscarriage rate ranging from 1.1% to 4.3%.
Oral nolasiban improves clinical pregnancy rate (RR 1.15, 95% CI 1.02 to 1.30; 3 RCTs, N = 1832; I² = 0%; high-certainty evidence), and probably does not increase multiple or ectopic pregnancy, or other complication rates (moderate-certainty evidence).