The problem of IVF cost in developing countries: has natural cycle IVF a place?

Infertility represents a national health problem in some African countries. Limited financial health resources in developing countries are a major obstacle facing infertility management. IVF is the definitive line of treatment for many couples. Stimulation cycles are associated with risks of ovarian hyperstimulation syndrome and multiple pregnancy. This study evaluates the client acceptability of stimulated versus natural cycle IVF among couples attending one infertility clinic, with respect to cost and pregnancy outcome. Of the patients who were indicated for IVF, 15% (16/107) cancelled, due mostly (12/16, 75%) to financial reasons. The majority of patients who completed their IVF treatment (82/91, 90.1%) felt the price of the medical service offered was high, and 68.1% (62/91) accepted the idea of having cheaper drugs with fewer side effects but with possibly lower chances of pregnancy. Natural cycle IVF has emerged as a potential option that might be suitable for patients worldwide, especially in developing countries.     

Natural cycle frozen-thawed embryo transfer—can we improve cycle outcome?

Purpose

Several replacement protocols for frozen-thawed ET (FET) exist, with no advantage of one protocol over the others. In the present study, we aim to evaluate the outcome of natural cycle FET with modified luteal support.

Methods

All consecutive patients undergoing natural or artificial hormone replacement (AHR) day-2/3 FET cycles between May 2012 and June 2015 in our IVF unit were evaluated. While AHR FET cycles were consistent, those undergoing natural cycle FET received progesterone luteal support, and from June 2014, patients received two additional injections, one of recombinant hCG and the other of GnRH-agonist, on day of transfer and 4 days later, respectively (modified luteal support).

Results

Patients’ clinical characteristics and laboratory/embryological variables were comparable between those undergoing natural vs. AHR cycles, during the earlier as compared to the later period. Moreover, while implantation, clinical, and ongoing pregnancy rates were significantly higher during the later period in patients undergoing the natural cycle FET with the modified luteal support (31, 51, and 46 %, respectively), as compared to natural (17, 26, and 20 %, respectively), or AHR FET in the late study period (15, 22, and 17 %, respectively), the natural cycle FET without the additional two injections yielded the same results, as the AHR cycles.

Conclusions

We therefore suggest that in ovulatory patients undergoing FET, natural cycle FET with the modified luteal support should be the preparation protocol of choice. Further large prospective studies are needed to elucidate the aforementioned recommendation prior to its routine implementation.

     

Cumulative probability of clinical pregnancy and live birth after a multiple cycle IVF package: a more realistic assessment of overall and age-specific success rates?

OBJECTIVE: To provide an assessment of pregnancy and live birth probabilities for women presenting for in vitro fertilisation treatment for the first time, when committed in advance to have up to three cycles of treatment in one year. DESIGN: Up to three cycles of in vitro fertilisation within one year, committed in advance. SETTING: A tertiary referral centre for assisted reproduction. PARTICIPANTS: Two hundred and thirty-two women, undergoing a total of 536 cycles of in vitro fertilisation or intracytoplasmic sperm injection between August 1993 and December 1995. METHODS: Analysis of cumulative clinical pregnancy and live birth rates for women having IVF treatment for the first time and undertaking a three-cycle package, using the life-table approach. MAIN OUTCOME MEASURES: Cumulative clinical pregnancy and live birth rates. RESULTS: The cumulative probabilities of clinical pregnancy and live birth after two cycles of treatment were 38.2% and 33.2%, respectively, compared with 54.2% and 48.2%, respectively, after three cycles of treatment. Cumulative clinical pregnancy and live birth rates after three cycles of treatment for women up to the age of 40 years were 57.8% and 51.3%, respectively. Cumulative clinical pregnancy and live birth rates declined with increasing age (P = 0.02 and P= 0.01, respectively). CONCLUSION: The three-cycle package encourages couples to have multiple treatment cycles, thereby improving their ultimate chances of a live birth. The cumulative clinical pregnancy and live birth rates after such a package provide a more realistic assessment of overall and age-specific success rates after multiple treatment cycles.     

Does hysteroscopic polypectomy without cycle cancellation affect IVF?

Endometrial polyp (measuring <2 cm) was diagnosed by transvaginal ultrasonography performed on days 7 and 9 of the cycle in six patients who underwent IVF. These six patients were treated by hysteroscopic polypectomy preceding oocyte retrieval under general anaesthesia after informed consent was obtained. The cause of infertility was male factor in three patients, tubal factor in one, and two cases were unexplained. All patients had undergone ovulation induction and luteal support according to the long luteal protocol. As a result, in three cases pregnancy was achieved (one multiple and two singleton) and three cases were unsuccessful. One of the pregnant women gave birth at term, while the other two pregnancies are still ongoing. There is still no consensus regarding the management of patients diagnosed with endometrial polyp in IVF cycles. Cryopreservation, cycle cancellation and embryo transfer preceding polypectomy is the current management choice. The treatment modalities will be clarified only if embryo transfer preceding polypectomy in the same cycle is proven to be safe. This approach has been used in only six patients so far, and further studies with more patients are needed to confirm these findings.     

Cumulative probability of clinical pregnancy and live birth after a multiple cycle IVF package: a more realistic assessment of overall and age-specific success rates?

Objective To provide an assessment of pregnancy and live birth probabilities for women presenting for in vitro fertilisation treatment for the first time, when committed in advance to have up to three cycles of treatment in one year.
Design Up to three cycles of in vitro fertilisation within one year, committed in advance.
Setting A tertiary referral centre for assisted reproduction.
Participants Two hundred and thirty-two women, undergoing a total of 536 cycles of in vitro fertilisation.
Methods Analysis of cumulative clinical pregnancy and live birth rates for women having IVF treatment for the first time and undertaking a three-cycle package, using the life-table approach.
Main outcome measures Cumulative clinical pregnancy and live birth rates.
Results The cumulative probabilities of clinical pregnancy and live birth after two cycles of treatment were 38.2% and 33.2%. respectively, compared with 54.2% and 48.2%, respectively, after three cycles of treatment. Cumulative clinical pregnancy and live birth rates after three cycles of treatment for women up to the age of 40 years were 57.8% and 51.3%, respectively. Cumulative clinical pregnancy and live birth rates declined with increasing age (   P = 0.02  and   P = 0.01  , respectively).
Conclusion The three-cycle package encourages couples to have multiple treatment cycles, thereby improving their ultimate chances of a live birth. The cumulative clinical pregnancy and live birth rates after such a package provide a more realistic assessment of overall and age-specific success rates after multiple treatment cycles.     

Cryopreservation of IVF embryos: which stage?

Embryo freezing is a mandatory tool in IVF technology as controlled ovarian hyperstimulation usually leads to extra embryos which are not transferred. One dilemma is the embryonic stage at which the embryos are to be frozen. Early stage freezing (PNs or cleavage stage) leads to a two step selection: at the time of thawing and a few hours or a day after. Then the recovering embryos are submitted to the classical in vitro developmental arrests in relation with maternal, paternal and cytogenetic factors. The "take home baby rate" per frozen embryo is low, rarely over 5%. Blastocyst have overcome the blocks in vitro: a first selection has already been made. The quality of freezing at this stage depends greatly on the culture conditions. It allows freezing of fewer embryos, but with higher yields: a >10% take home baby rate can be expected. It is clear to us that vitrification, beside the technical problems, has to be handled with care, especially if ethylene glycol (EG) is used. Metabolic products of EG might have negative effects on organogenesis.     

Improvement of accuracy of clinical reports—the case of IVF cycle rank

Purpose

Accurate clinical reports of In Vitro Fertilization Cycle Rank (IVF-CR) are important because of their predictive value of treatment success—clinical pregnancy. Our district currently provides more than a hundred IVF pick-up cycles per month. The study objective was to evaluate and improve the accuracy of IVF units’ reports of IVF-CR.

Methods

Reports of IVF-CR from local IVF units were correlated with administrative data. Couples who were having IVF treatments during the 3-month study period were included in the study. Data were collected before and after an intervention program.

Results

During the study period accurate IVF-CR reporting rate improved from 27% (29 out of 108) to 83% (91 out of 110).

Conclusions

Accuracy of clinical reports of IVF-CR from local units significantly improved after the intervention. It is recommended that national regulatory bodies should issue compulsory guidelines for the recording and reporting of IVF-CR.     

Outcomes of IVF conceptions: are they different?

Perinatal outcomes, such as preterm delivery, low birth weight and some obstetric complications, are increased significantly after in-vitro fertilization (IVF) compared with spontaneously conceived pregnancies. The degree of difference is greater for singletons than for twins, especially with regard to preterm delivery which is increased two fold in IVF singletons and by 40% in twins. It is difficult to obtain accurate outcome information because of unmeasured confounders such as smoking status and fetal reduction. It is also unknown whether IVF technologies or patient infertility is the major contributor to adverse outcomes. Birth defects are increased, shown in a number of systematic reviews, and there has been a particular interest in imprinting syndromes. Epigenetic modifications may play a larger role in IVF outcomes, as yet unidentified. There is no apparent increase in adverse outcomes in children up to adolescence, although further studies are needed to examine longer-term risks, including those for cancer.     

Influence of resveratrol supplementation on IVF–embryo transfer cycle outcomes

Research questionDoes resveratrol, a polyphenolic compound, affect IVF–embryo transfer outcomes?DesignThis single-centre, cross-sectional retrospective study was designed to compare the outcomes of embryo transfer cycles in women receiving resveratrol supplementation (200 mg/day) continuously (RES group) with a control group (non-RES group). Of 8686 embryo transfer cycles, 1409 cycles with poor prognostic factors were excluded, including cycles in women aged ≥43 years and those with poor-quality embryos. The RES group (204 cycles, 102 women) was compared with the non-RES group (7073 cycles, 2958 women).ResultsAfter matching patients by age at the time of oocyte retrieval, grade and developmental stage of embryos, number of embryos transferred, and fresh or vitrified-warmed embryo transfer, multivariate logistic regression analysis showed that resveratrol supplementation is strongly associated with a decrease in clinical pregnancy rate [odds ratio (OR) 0.539, 95% confidence interval (CI) 0.341–0.853] and an increased risk of miscarriage (OR 2.602, 95% CI 1.070–6.325).ConclusionsResveratrol supplementation during embryo transfer cycles appears to be detrimental for pregnancy outcomes. An analysis of the supplementation protocol and randomized controlled studies are needed.     

Does local injury to the endometrium before IVF cycle really affect treatment outcome? Results of a randomized placebo controlled trial

Aim: To evaluate the effect of local injury to the endometrium during spontaneous menstrual cycles before in vitro fertilization (IVF) treatment on implantation and pregnancy rates in women with recurrent implantation failure (RIF). Methods: In a prospective randomized controlled trial (RCT), a total of 36 patients, with RIF undergoing IVF, were randomized to two groups. In 18 patients, endometrial biopsies were performed using a pipelle curette on days 9–12 and 21–24 of the menstrual cycle preceding IVF treatment. In 18 control patients, a cervical pipelle was performed. Results: The implantation rate (2.08% versus 11.11%; p?=?0.1), clinical (0% versus 31.25%; p?<?0.05) and live births rates (0% versus 25%; p?=?0.1) were lower in the experimental group compared with controls. Conclusion: Our RCT did not find any benefit from local injury to the endometrium in women with a high number of RIFs. Further studies are warranted to better define the target population of patients who may benefit from this procedure.     

How to improve IVF results from a clinical point of view?

This study reports the last data of the literature on the possibilities of optimizing chances of pregnancy during in vitro fertilization attempts, our research concerning only the clinical point of view while excluding biologic possibilities. The selection of the patients, the management of controlled ovarian hyperstimulation protocols, the optimalisation of the transfer and the luteal phase support will be cross-reviewed.     

Initiation of ovarian stimulation independent of the menstrual cycle: a case–control study

Purpose

In the GnRH-antagonist protocol, ovarian stimulation with gonadotropins typically commences on cycle day 2 or 3. Initiation of ovarian stimulation with a spontaneously occurring menstruation, however, poses significant organizational challenges for treatment centres and patients alike. It has previously been demonstrated in the context of fertility preservation that initiation of stimulation in the luteal phase is feasible in terms of retrieval of mature oocytes for cryopreservation. Herein, we report the extension of this concept to a routine IVF setting with the aim of establishing an ovarian stimulation protocol, which can be utilized independent of menstruation. Because of asynchrony of endometrium and embryo in such a setting, all fertilized oocytes have to be cryopreserved for a later transfer.

Methods

This was a prospective, case–control study (trial registration: NCT00795041) on the feasibility of starting ovarian stimulation in a GnRH-antagonist protocol in the luteal phase. Inclusion criteria were: IVF or ICSI; 18–36 years; ≤3 previous IVF/ICSI attempts; BMI 20–30 kg/m²; regular cycle (28–35 days); luteal phase progesterone >7 ng/ml at initiation of stimulation. Exclusion criteria were: PCOS, endometriosis ≥AFS III°, unilateral ovary, expected poor response. Stimulation was performed with highly purified uFSH (Bravelle^®) 300 IU/day and 0.25 mg/day GnRH-antagonist starting on cycle day 19–21 of a spontaneous menstrual cycle and commencing until hCG administration when three follicles ≥17 mm were present. All 2PN stage oocytes were vitrified for later transfers in programmed cycles. Feasibility was defined as the achievement of ongoing pregnancies progressing beyond the 12th gestational week in at least 2/10 study subjects (primary outcome). Secondary outcomes were gonadotropin consumption per oocyte obtained, stimulation duration, and fertilization rates. Study subjects were matched in a 1:3 ratio with concomitantly treated control cases of similar age, BMI, and duration of infertility who were treated in a conventional GnRH-antagonist protocol with 150–225 rFSH or HP-HMG/day.

Results

The study group consisted of ten subjects, mean age 31.4 years, BMI 25.4 kg/m², of which one had fertilization failure. Mean stimulation duration was 11.7 (SD 1.6) vs. 9.1 (SD 1.3) days, mean cumulative FSH dose was 3,495.0 (SD 447.5) vs. 2,040.5 (SD 576.2) IU, and mean number of oocytes was 8.8 (SD 5.0) vs. 10.0 (SD 5.4) in study vs. control group, respectively. Per follicle ≥10 mm, the cumulative FSH dose was 274.5 (SD 130.8) IU vs. 245.2 (SD 232.3) IU in study and control groups, respectively. Cumulative ongoing pregnancy rates were 1/10 (10 %) and 6/30 (20.0 %) in study and control group, respectively (difference: 10 %, 95 % confidence interval of the difference: ?29.2–22.2 %, p = 0.47). Fertilization rate was similar between groups, with 63.5 % (SD 32.9) in the study and 61.3 % (SD 26.7) in the control group, respectively. Serum estradiol levels were significantly lower on the day of triggering final oocyte maturation with 1,005.3 (SD 336.2) vs. 1,977.4 pg/ml (SD 1,106.5) in study and control group, respectively. Similarly, peak estradiol biosynthesis per growing follicle ≥10 mm was lower in the study group (134 pg/ml, SD 158.4 vs. 186.7 pg/ml, SD 84.7).

Conclusions

Per retrieved oocyte, a nearly threefold higher dose of FSH had to be administered when ovarian stimulation had been initiated in the luteal phase. Furthermore, the present study casts doubt on the efficacy of initiating ovarian stimulation in the luteal phase in terms of pregnancy achievement. Thus, this concept is currently not feasible for routine use, and it should also be explored further before using it at larger scale in the context of emergency stimulation for fertility preservation.     

The immune response during the luteal phase of the ovarian cycle: a Th2-type response?

OBJECTIVE: To test the hypothesis that during the luteal phase of the ovarian cycle, as compared with the follicular phase, the peripheral immune response is shifted toward a type-2 response. DESIGN: Prospective study. SETTING: Academic research setting. PATIENT(S): Women with regular menstrual cycles. INTERVENTION(S): Blood samples were collected between days 6 and 9 of the menstrual cycle and 6-9 days after the LH surge. MAIN OUTCOME MEASURE(S): Intracellular cytokine production of interferon (IFN)-gamma, interleukin (IL)-2, IL-4, and IL-10 after in vitro stimulation of lymphocytes as well as total white blood cell (WBC) count, differential WBC count, and plasma 17 beta-E(2) and P concentrations. RESULT(S): Mean plasma 17 beta-E(2) and P concentrations, WBC count, and mean granulocyte, monocyte, and lymphocyte counts were significantly increased in the luteal phase as compared with the follicular phase of the ovarian cycle. Production of type-1 cytokines (IFN-gamma and IL-2) and production of the type-2 cytokine IL-10 did not vary between the phases of the ovarian cycle. Production of the type-2 cytokine IL-4, however, was significantly increased in the luteal phase as compared with the follicular phase of the ovarian cycle. CONCLUSION(S): During the luteal phase of the ovarian cycle, the immune response is shifted toward a Th2-type response, as reflected by increased IL-4 production in this phase of the cycle. These results may suggest that increased levels of P and 17 beta-E(2) in the luteal phase of the ovarian cycle play a role in the deviation of the immune response toward a type-2 response.     

Narrow band imaging hysteroscopy: a new diagnostic technique in recurrent IVF failure?

Narrow band imaging (NBI) is an optical filter technology that improves the visibility of capillaries, veins and other subtle tissue structures, by narrowing the bandwidth of spectral transmittance using optical filters. In this short communication, we want to share our preliminary experience in assisted reproductive technology patients where we had used NBI hysteroscopy for the evaluation of uterine cavity abnormalities who had previous IVF failure.