In- Vitro Fertilization (IVF) is a process which is initiated by stimulation of ovaries through exogenous gonadotropins, followed by oocytes retrieval under transvaginal ultrasound guidance after fertilization and embryo culture in the laboratory and transcervical transfer of embryos into the uterus¹.
 The first pregnancy resulting from IVF was reported in 1976.(2,3)
Despite remarkable improvements in IVF techniques, implantation rate and clinical pregnancy rate are still lower than expected follwing IVF.
The factors which affect the embryo implantation are divided into three categories of embryo quality, endometrial receptivity and transfer efficacy (4).
One of the IVF failure causes is excessive uterine contraction after embryo transfer (5,6,7).  Many anti-peristaltic agents  such as Ritodrine, a Beta2 agnonist⁸ ; Terbutaline, a Beta2  agonist⁹ ; Atosiban,  an oxytocin antagonist (10,11)  ; and Piroxicam,  a Non-steroidal anti-inflammatory drug (NSAID) (12) ; and Hyoscine , an anticolinergic (13) have been experimented in various studies to improve IVF success rate with conflicting results.
Calcium channel blockers are known agents that reduce smooth muscle contractions via diminishing intracellular calcium transfer, accordingly causing uterus relaxation. Nifedipine is one of the calcium channel blockers that is utilized for treatment of preterm labor as a tocolytic in pregnancy¹⁴ whose safety has been shown over years of experience (15,16). It is also used for emergent and non-emergent hypertension during pregnancy (17,18).
Nifedipine’s common adverse effects include flushing, peripheral edema, vertigo,headache, dyspepsia, and nausea.
Because of above-mentioned properties and associated side effects and lack of sufficient knowledge, we decided to evaluate nifedipine’s effect on increasing IVF success rate before embryo transfer.
 

All patients were able to be followed completely.  Median ages of the patients were 31 and 34 in placebo and nifedipine groups, respectively. 39 out of 48 patients (79.5%) and 31 out of 48 patients (63.2%) had primary infertility in placebo and nifedipine groups respectively (Table 1).

Table 1. Baseline Characteristics. N: Total number of patients, n: number of patients in each subgroup, IQR: Interquratile.

Fresh embryo transfer (ET) was performed in 15 patients (30.6%) of placebo group and 24 patients (48.9%) of nifedipine group.
Primary Outcomeand clinical pregnancy occurred in eighteen patients (36.7%) in placebo group and seventeen patients (34.7%) in nifedipine group (OR: 0.91, 95%CI (0.4-2.09)) which was not statistically significant (Table 2).

Tables 2. Table of Outcomes. N: Total number of patients, n: number of patients per treatment group.

 
 
Figure 1. Subgroup Analysis Forest Plot. Odds ratio more than one favours treatment and less than one favours placebo.

 
In evaluation of interaction term of subgroups and treatment, there was no significant interaction between any subgroups and treatment (p value = 0.99 for Embryo type, p value = 0.62 for infertility type).

Discussion

In- vitro fertilization has become one of the main treatment modalities for infertility since 1976 (1). Many studies have confirmed its relative efficacy. But despite significant improvements in IVF techniques, its success rate is still lower than expected (19). According to literature approximately 20 – 25% of the patients who had undergone IVF, had successful implantation. Because of its relatively high cost and potential adverse effects, many attempts have been made to improve IVF results. Among them is administering drugs which increase IVF success rate. One possible mechanism of IVF failure is excessive uterine contraction during IVF process which prevents proper embryo implantation. Thus,utilization of agents that reduce uterine contraction theoritically seems to increase IVF success rate by reducing uterine contraction (6, 7). Oral short acting nifedipine, is a dihydropyridine calcium channel blocker which causes smooth muscle relaxation in varoius organs. Due to presence of calcium channel in uteirne, it has the ability to reduce uterine contraction. We conducted this double- blinded controlled trial to investigate the effect of administration of oral short acting nifedipine just before embryo transfer, on improving IVF results. In our study, nifedipine had no effect on either clinical pregnancy or live birth. Albeit not statistically significant, actually there was lower clinical pregnancy in nifedipine group. In none of the subgroups of the patients there was a difference in treatment response between placebo and nifedipine. Despite being not statisticaly significant, in nifedipine group of patients who had undergone frozen embryo transfer there was a higher clinical pregnancy. In the only study that evaluates the effect of nifedipine on IVF, nifedipine did not show any effect on IVF results (19). There is no other study assessing similar agent for IVF. The negative results of our study may be due to inadequate dose of nifedipine or inadequate estimation of sample volume. It seems that further studies with larger sample volume and/or higher dose of nifedipine are needed to assess its effect on infertility treatment by IVF.

 

Conclusion

A single dose of 20 mg nifedipine tablet administered thirty minutes before IVF had no effect on improving clinical pregnancy and live birth rate. Using higher dose, or different administration protocol in specific patient subgroups could have more effect on embryo transfer success.

 

Acknowledgements

None.

 

Conflicts of Interest

None declared.