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      Does nifedipine improve outcomes of embryo transfer? : Interim analysis of a randomized, double blinded, placebo-controlled trial

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          Implantation failure is the main factor affecting the success rate of in vitro fertilization (IVF) procedures. Studies have reported that uterine contractions (UC) at the time of embryo transfer (ET) were inversely related to implantation and pregnancy rate, hence reducing the success of IVF treatments. Various pharmacological agents, with the exception of calcium channel blockers, have been investigated to improve ET outcomes by reducing UC. Thus, a double-blinded randomized, placebo-controlled trial was conducted to determine whether nifedipine, a calcium channel blocker with potent smooth muscle relaxing activity and an excellent safety profile, can improve the outcome of patients undergoing ET treatments.


          Ninety-three infertile women were recruited into 1 of 2 groups: placebo (n = 47) or nifedipine 20 mg (n = 46). Study participants were admitted 30 minutes prior to ET and given either tablet after their baseline vital signs were recorded. They then underwent ET and were observed for adverse events for another 30 minutes post-ET. Follow up of the participants’ outcomes was conducted via electronic medical records. The primary outcomes are implantation and clinical pregnancy rates. Secondary outcomes include any maternal or fetal adverse events, miscarriage, pregnancy, live births, and neonatal outcomes. Resulting data were then analyzed using t test, Pearson chi-square test, and Fisher exact test to compare outcomes between the 2 groups.


          No statistical differences in the implantation rate (42.6% vs 39.1%, P = .737, rate ratio 0.868, 95% confidence interval [CI]: 0.379–1.986) and the clinical pregnancy rate (23.4% vs 26.1%, P = .764, rate ratio 1.155, 95% CI: 0.450–2.966) were detected between the placebo and the treatment groups. In addition, no statistical significance between the placebo and the treatment groups for any secondary outcomes were detected.


          This double blinded, randomized, and placebo-controlled trial demonstrated that the single use of 20 mg nifedipine given 30 minutes before embryo transfer did not improve the implantation rate or the clinical pregnancy rate of the infertility treatment. Further studies are required to demonstrate the clinical benefits and risks of nifedipine usage in embryo transfer.

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          Most cited references 46

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          Uterine contractions at the time of embryo transfer alter pregnancy rates after in-vitro fertilization.

          To investigate the possible consequences of uterine contractions (UC) as visualized by ultrasound (US) on in-vitro fertilization (IVF)-embryo transfer outcome, we studied prospectively 209 infertile women undergoing 220 cycles of controlled ovarian stimulation. Inclusion criteria were age 5.0 (n = 74) UC/min respectively. Patients, controlled ovarian hyperstimulation and embryology characteristics were comparable in all groups. A stepwise decrease in clinical and ongoing pregnancy rates as well as in implantation rates occurred from the lowest to the highest UC frequency groups (53, 36, 21; 46, 32, 20; 23, 19, 10; and 14, 11, 4%; P < 0.001). Plasma progesterone and UC frequency were negatively correlated (r = -0.34, P < 0.001). Direction of UC did not affect embryo transfer outcome. As this study was controlled strictly for confounding variables and UC were assessed objectively by a computerized system, its results indicate that high frequency UC on the day of embryo transfer hinder IVF-embryo transfer outcome, possibly by expelling embryos out of the uterine cavity. The negative correlation between UC frequency and progesterone concentrations supports the uterine relaxing properties of progesterone.
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            Low-dose aspirin treatment improves ovarian responsiveness, uterine and ovarian blood flow velocity, implantation, and pregnancy rates in patients undergoing in vitro fertilization: a prospective, randomized, double-blind placebo-controlled assay.

            To determine the effects of low-dose aspirin on ovarian response, uterine and ovarian blood flow velocity, and implantation and pregnancy rates in patients undergoing IVF. Prospective, randomized, double-blind placebo-controlled assay. Department of Reproductive Medicine, CER Medical Institute, Buenos Aires, Argentina. Two hundred ninety-eight infertile patients (mean [+/- SDI age, 35.6+/-4.09 years) undergoing IVF cycles. In the treatment group, 149 patients underwent controlled ovarian hyperstimulation and received a daily dose of 100 mg of aspirin. In the control group, 149 patients underwent controlled ovarian hyperstimulation in association with placebo. Number of follicles, number of oocytes retrieved, serum E2 levels, uterine and ovarian pulsatility index, cancellation rate, number of embryos transferred, and implantation and pregnancy rates. There were statistically significant differences between the treatment group and the control group, respectively, in the number of follicles (19.8+/-7.2 versus 10.2+/-5.3), number of oocytes retrieved (16.2+/-6.7 versus 8.6+/-4.6), serum E2 levels (2,923.8+/-1,023.4 versus 1,614.3+/-791.7 pg/mL), uterine pulsatility index (1.22+/-0.34 versus 1.96+/-0.58), ovarian pulsatility index (1.18+/-0.31 versus 1.99+/-0.56), pregnancy rate (45% versus 28%), and implantation rate (17.8% versus 9.2%). Low-dose aspirin treatment significantly improves ovarian responsiveness, uterine and ovarian blood flow velocity, and implantation and pregnancy rates in IVF patients.
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              Nifedipine trials: effectiveness and safety aspects.

              Nifedipine (Adalat) is marketed as an anti-hypertensive agent. Nifedipine inhibits voltage-dependent L-type calcium channels, which leads to vascular (and other) smooth muscle relaxation and negative inotropic and chronotropic effects on the heart. Vasodilation, followed by a baroreceptor-mediated increase in sympathetic tone then results in indirect cardiostimulation. Nifedipine was introduced as a tocolytic agent at a time when beta-agonists and magnesium sulphate dominated the arena for the prevention of preterm birth. The oral administration route, the availability of immediate and slow-release preparations, the low incidence of (mild) side effects, and its limited costs explain the attraction to this medication from the obstetric field and its rapid and widespread distribution. Currently, over 40 studies have been published on nifedipine's tocolytic effectiveness, including seven meta-analyses. The quality of the studies suffers particularly from performance bias because the majority of them failed to ensure adequate blinding to treatment both for providers and patients. Concerns about other methodological flaws include measurements, outcome assessment and attrition bias. In particular, the safety aspects of nifedipine for tocolysis have been under-assessed. Conclusions from the meta-analyses, favouring the use of nifedipine as a tocolytic agent, are not supported by close examination of the data. The tocolytic effectiveness and "safety" of nifedipine has been studied primarily in normal pregnancies. Based on its pharmacological properties, one should be cautious to administer nifedipine when the maternal cardiovascular condition is compromised, such as with intrauterine infection, twin pregnancy, maternal hypertension, cardiac disease, etc. Life-threatening pulmonary oedema and/or cardiac failure are definite risks and have been reported. Under such circumstances, the baroreceptor-mediated increase in sympathetic tone may not balance the cardiac-depressant activity of nifedipine.

                Author and article information

                Medicine (Baltimore)
                Medicine (Baltimore)
                Wolters Kluwer Health
                January 2019
                25 January 2019
                : 98
                : 4
                [a ]Royal Melbourne Hospital
                [b ]Royal Women's Hospital, Parkville
                [c ]Melbourne IVF, East Melbourne, Victoria, Australia.
                Author notes
                []Correspondence: Kelvin Kwok Lap Ng, 300 Grattan street, Parkville, VIC 3052, Australia (e-mail: kklng24@ ).
                MD-D-18-06381 14251
                Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

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