Abstract
Objectives
Current retrospective cohort study analyses clinical database records of 4792 assisted reproduction procedures to assess the significance of target effectiveness endpoints from a safety perspective.
Methods
Stimulation protocols with urinary, recombinant or combination of both types gonadotrophin preparations are compared according to the following primary endpoints: incidence of ovarian hyperstimulation syndrome (OHSS), cycle cancellation, follicle count, induced estradiol values, clinical pregnancy achieved and cycles reached embryo transfer/freezing. We have investigated the incidence of cases evaluated as 'risky for OHSS' by secondary efficacy endpoints (exogenous gonadotrophin exposure, luteinising hormone and progesterone values, oocyte yield, eggs with normal maturation). The following statistical methods were applied: descriptive statistics, Mann-Whitney U test, Kruskal-Wallis test, Pearson chi-square test, Fisher's exact test, binary logistic regression.
Results
Only 16 cases (0.42%) of moderate and delayed OHSS were established. Three hundred and seven (8.6%) stimulation cycles have been cancelled, principally among urinary protocols. Although the clinical pregnancy rate does not differ significantly in compared groups, punctured follicle count, oocyte yield and progesterone level were higher for recombinant preparations, followed by combined and urinary protocols. Follicle count, mean estradiol and luteinising hormone levels are within the 'safe window' for all investigated groups, associated with minimised risk of stimulation cancellation. The mean follicle-stimulating hormone (FSH) dose was highest in urinary protocols at the same duration of stimulation compared with recombinant products. The younger age, bigger follicle count, oocytes yield, mature oocytes count, percentage of fertilised oocytes, more embryos transferred and the later day of embryo transfer are critical for both assisted reproduction techniques (ART) success rate and the safety profile of sterility treatment.
Conclusions
Safety surveillance of ART exceeds the incidence of OHSS. Suboptimal effectiveness of stimulation protocols may also jeopardise the well-being of ART patients. Gonadotrophin exposure, induced values of sex hormones, and quantity and quality of extracted oocytes should be considered to minimise any unintended suffering of treated couples.
Keywords: assisted reproduction, controlled ovarian hyperstimulation, medication safety, drug effectiveness, ovarian hyperstimulation syndrome, gonadotrophin
Introduction
Between 50 and 70 million couples worldwide suffer from infertility, with a steady trend in increasing the number of newly diagnosed cases of sterility.1 2 During early development of assisted reproduction techniques (ART) the main goal was to achieve clinical pregnancy at any cost. Today most authors assume that the aim of an ART procedure is the birth of only one live child, with minimal physical and mental suffering of the treated couple. Against the backdrop of the growing success rate of in vitro fertilisation procedures, the introduction of more effective measures to ensure patient safety and tolerability is one of the current ART challenges. A significant example of 'vigilance' tendency in ART is the recommendation for implanting only one cultured embryo.3 Controlled ovarian hyperstimulation (COH) is the fundamental point from which each cycle of ART begins. This process aims to induce multifollicular development in the woman's ovaries. COH is essential for both the success of the ART treatment cycle and the safety of the patient being treated. Perfect COH should result in the optimal ratio between the number of mature oocytes obtained and potential adverse effects or delayed complications of caused ovarian induction.4 The efficacy of various alternatives for inducing hyperovulation has been investigated in numerous controlled randomised clinical trials. Based on the similar therapeutic benefit from urinary and recombinant gonadotropins, it is essential for the prescribing decision to analyse the possible safety issues of different COH approaches.
The current study aims to analyse a real-life clinical database records for ART procedures. Based on results we assessed the significance of target effectiveness endpoints from a safety perspective.
This analysis represents a conceptual alternative of previously published articles concerned with the safety and efficacy of COH due to the diversity of the sample population and exposure to three different stimulation approaches. Unlike previous articles5–9 this article surmounts the limitations of specific patient subpopulations (poor responders or strictly defined WHO group patients) or available data for outcomes of isolated types of gonadotrophin preparations (usually only recombinant or urinary hormones).
Methods
This retrospective cohort study is based on the records of the validated integrated information system of a hospital with national coverage of patients in Bulgaria (Joystick, ver.2.1). The records of a total of 4792 assisted reproduction (AR) procedures performed from 1 January 2013 until 31 July 2016 were analysed. The data exclude 66 cases due to incorrectly filled records in the hospital database or discontinuation of treatment immediately after the procedure initiation. 85.7% of investigated patients (4048) conducted a procedure with their own oocytes, 6.8% (323) were oocyte donors and 7.5% (355) were recipients. In all studied cases, short-protocol COH with/without GnRH antagonist have been performed. Oocyte’s recipients, procedures discontinued at pre-screening, natural cycles and stimulations with clomiphene citrate were not analysed.
Patients are divided into three groups according to the type of hormones administered: urinary hormones stimulations (61%); recombinant hormone cycles (13%); and mixed protocol – a combination of recombinant and urinary products (26%).
The statistical analysis was carried out by specialised software SPSS, version 19. The following statistical methods were applied: descriptive statistics, Mann-Whitney U test, Kruskal-Wallis test, Pearson chi-square test and Fisher's exact test, binary logistic regression. All P values smaller than 0.05 were considered significant.
Primary endpoints
Incidence of ovarian hyperstimulation syndrome (OHSS)
COH cancellation
Estradiol levels on the day of choriogonadotropin (hCG)
Follicles' count
Percentage of clinical pregnancy achieved
Number of cycles, reached embryo transfer/embryo freezing
Secondary endpoints
Average duration of COH
Total dose of FSH administered
Luteinising hormone (LH) on the day of hCG
Progesterone on the day of hCG
Patient age
Oocyte yield
Eggs with normal maturation
Results
Data analysis showed that for the study period only 16 cases (0.42%) of OHSS, requiring patient hospitalisation were established. Cases of mild OHSS, managed by outpatient treatment have not been registered. The prevailing cases of OHSS are classified as delayed (OHSS).
All the results regarding primary study endpoints are presented in table 1.
Table 1.
Comparison between the three stimulation protocols according to the primary criteria
| Total | Urinary | Recombinant | Combined | P values | |
| OHSS | 16 (0.42%) | 9 | 6 | 1 | <0.0001 |
| Stimulations cancelled prior to FP | 307 (8.6%) | 236 (10.9%) | 32 (6.9%) | 39 (4.2%) | <0.0001 |
| Estradiol level on hCG day* | 1516.48 (837.65–2480.80) | 1345.14 (701.17–2329.34) | 2038.41 (1362.30–2895.40) | 1619.18 (964.59–2509.13) | <0.0001 |
| Punctured follicles' count | 5 (3-9) | 4 (2-8) | 8 (5-11) | 5 (3-9) | <0.0001 |
| Clinical pregnancy (intrauterine) | 804 (32.5%) | 452 (32.5%) | 140 (37.5%) | 212 (29.9%) | 0.09 |
| Cycles reached embryotransfer/freezing | 2619 (80.8%) | 1481 (77%) | 399 (92.6%) | 739 (83.1%) | <0.0001 |
*Only patients with their own oocytes who have reached FP.
Ovarian stimulation cycles have been terminated in 307 (8.6%) of the cases analysed due to one or more of the following reasons: absence or poor response to administered therapy; excessive ovarian response; or an adverse event occurred.
The slightest number of cancelled stimulations is in the mixed protocol group. (table 2)
Table 2.
Frequency of cycle cancellation among investigated patient groups*
| Criteria | Total number of cycles performed | Cancelled procedures | Cycles that reached FP |
| Urinary FSH | 2159 | 236 (10.9%) | 1923 (89.1%) |
| Recombinant FSH | 463 | 32 (6.9%) | 431 (93.1%) |
| Combined FSH | 928 | 39 (4.2%) | 889 (95.8%) |
*only patients with their own oocytes.
Estradiol levels on the day of the hCG administration vary significantly between the three groups, as well as between each pair of them.
Compared groups differ significantly in the number of punctured follicles, oocyte yield and number of mature oocytes. However, if we compare only urinary vs combined hormones there is no statistically significant difference in the above criteria. Better oocyte yield and highest fertilisation rate in the recombinant group should be carefully interpreted against the average age of women in each study arm.
The success rate in ART is evaluated mainly by the frequency of clinical pregnancy achieved. Intrauterine gestation was achieved in 32.5% of women, undergoing assisted fertilisation of their own oocytes. A statistically significant difference is proven after the adoption that ectopic pregnancy is a failed outcome of the procedure. Thus success rate in recombinant and urinary protocols do not differ significantly. Comparing recombinant and mixed protocols, more pregnancies have been achieved after recombinant stimulation.
Results from secondary endpoint analysis are presented in table 3.
Table 3.
Comparison of patient groups according to secondary criteria for analysis
| Criteria | Total | Urinary | Recombinant | Combined | P values |
| Mean FSH dose per cycle* | 1818.5 (1050–2700) | 2025 (1050–2850) | 1575 (1050–2000) | 1875 (1050–2700) | <0.0001 |
| COH duration (days)† | 10 (9-11) | 10 (9-11) | 10 (9-11) | 11 (10-12) | <0.0001 |
| LH levels on the day of hCG | 2.10 (1.24–3.62) | 2.20 (1.35–3.8) | 1.87 (1.14–3.07) | 1.94 (1.08–3.33) | <0.001 |
| Progesterone levels on the day of hCG | 0.93 (0.63–1.40) | 0.94 (0.65–1.42) | 1.06 (0.79–1.5) | 0.85 (0.54–1.25) | <0.001 |
| Oocyte yield | 5 (3-9) | 5 (2-9) | 8 (5-11) | 5 (3-9) | <0.0001 |
| Oocytes with normal maturation* | 4 (2-7) | 3 (1-6) | 5 (3-8) | 3 (2-6) | <0.0001 |
| Age | 37 (32–40) | 37 (33–41) | 29 (33–37) | 36 (32–40) | <0.0001 |
*only patients with their own oocytes.
†only patients who have reached puncture.
To minimise bias associated with the specificity of donor stimulation protocols, all the oocyte donors have been excluded from secondary criteria analysis.
The mean total dose of exogenous gonadotrophin administered over the entire course of stimulation (measured in IU) varies significantly in the three groups.
The average duration of stimulation is 10 days, with a significant difference observed only between the group of women stimulated with combined hormones (11 days) and the other two groups.
Regarding the LH level on the day of triggering agent only the recombinant cohort differs significantly (2.2 IU/L) from the other two groups.
The mean progesterone on the day ovulation triggering is 0.93 IU/L. Progesterone levels vary considerably among the three groups (lowest in the combined group, highest in the recombinant group).
The number of punctured follicles, oocyte yield and number of mature oocytes varies significantly between compared protocols, being highest in the recombinant group, followed by combination therapy and urinary preparations.
The median age of the patients was 37 years (IQR 32–40 years), significantly different in the three groups (Kruskal-Wallis test, P<0.001), as well as between each pair of groups (Mann-Whitney U test, P<0.001).
Discussion
Data from real-life clinical practice is most representative of the efficacy and safety assessment of a medicinal product. As a result a non-interventional design was adopted for this study. Selected endpoints correspond both to the main efficacy criteria and the basic concerns about COH shared by patients: therapy duration, possible complications (adverse effects), pain and discomfort, recovery period and the amount of medication applied.10
The main criterion for safety assessment of COH is the incidence and extent of OHSS.11 Authors report the frequency of hyperstimulation syndrome between 0.6% and 10% of the IVF cycles. The severe form of OHSS occurs in 0.5%–2% of IVF cases.12 An OHHS prevalence of 0.42% (n=16), found in this study, is less frequent than described in the literature (table 1, row 1). Investigated OHSS cases are evaluated as moderate (according to the standard OHSS classification scale) and delayed. As agreed in the literature, with scope of clinical relevance, only moderate and severe OHSS cases were evaluated.13 OHSS prevails in the urinary group, but the extent of association between the FSH type and the OHSS is controversial due to the complicated multifactorial pathogenesis of this iatrogenic condition. Moreover, we prefer to analyse the incidence of clinical cases, evaluated as 'risky for OHSS'. This means cases of elevated predictors of OHSS even without clinical symptoms' manifestation (estradiol, Prog, LH values, follicles count, gonadotrophin exposure, and so on).
Plasma estradiol levels above 5000 ng and more than 18 punctured follicles are determined as risk for development of severe OHSS.14 More than 14 developing follicles, sized more than 16 mm indicate hyperresponse to exogenous FSH and require stimulation cancellation. Investigated mean levels of estradiol and follicle count are within the cited 'safe' limits for all groups. The ratio between the punctured follicles count and estradiol levels is optimal in the recombinant group (probably due to the lower age of the patients in this group).
COH termination is one of the main measures to prevent an OHSS. Therefore, the incidence of discontinued stimulations is considered to be a significant marker for the safety of hormone therapy.3 The small total share (8.6%) of terminated procedures may be associated with good tolerance of applied protocols (table 1, row 2). A small percentage of COH cancellation in the mixed protocol group indicates that the individual approach guarantees better stimulation safety. The mean total dose of gonadotrophin and COH duration determine the risk associated with the extent of FSH exposure. It has been published that patients insist on shorter exposure at lower doses, though a moderate pregnancy prognosis instead of more aggressive stimulation that hampers the risk of premature cancellation and additional cycles of treatment.15 16
The current study shows that the mean FSH dose was highest in urinary protocols at the same duration of stimulation as compared with recombinant products (table 3, row 2,3). We found that lower dose stimulation does not impair the quality of the embryological parameters. Better follicle, oocyte and embryo counts have been achieved by lower doses of gonadotrophin in addition to a lower percentage of OHSS, but also at a lower average patient age. The oocytes retrieval is a quantitative measure of the ovarian response. However, dose adjustment should be tailored to a particular woman's ovarian reserve. It is necessary to consider higher patient age in the urinary group and hence the diminished ovarian reserve and degraded quality of oocytes. Results from the urinary hormones group confirm previously published data that administration of higher doses of FSH paradoxically leads to a lower oocyte yield.17 Based on the data for oocyte retrieval and non-significant difference in pregnancy rate, in case of similar conditions and average daily dose between 150 and 225 IU, we could conclude that the use of higher doses unnecessarily aggravates therapy tolerability and jeopardises the quality of embryologic parameters.4
COH duration, as an exposure variable, is not determined by the type of the stimulation hormone. Investigated average duration (10 days) coincides with results from most randomised clinical trials.
Observed cases of delayed OHSS and analysis of mean dose administered to hyperresponders show that there is no direct association between mean total FSH dose and hyperstimulation syndrome. Mean total FSH dose and COS duration in hyperstimulated patients is below the mean for the study population. Therefore, an additional study of pathogenesis of delayed OHSS is needed.
The total mean dose of administered FSH influences the safety profile of COH indirectly by its association with progesterone level on the day of hCG administration. According to previous articles,18 patients with progesterone levels<1.5 IU on the day of ovulation triggering, regardless of GnRH analogue administration, have a lower probability of developing OHSS. The mean level of progesterone (Prog) for the studied cohort is 0.93 IU (table 3, row 4). Current analysis supports data from the MERIT study19 that recombinant protocols result in higher Prog values as compared with purified menotrophin stimulations.
Our results are inconsistent with scientific reports that exposure to higher FSH doses and a longer period of stimulation lead to higher Prog values on the hCG day. Current findings repeat previous statements about the relationship between the higher follicles' count and the higher estradiol and progesterone values. There is a proven association between higher progesterone values and better endometrial status. However, it is not enough to conclude that there is explicit association between progesterone plasma concentrations and successful outcome from ART treatment. Prog levels do not directly influence the quality of the oocytes obtained and the cultured embryo.
LH values also may be used for the safety evaluation of ovarian induction. It has been agreed that LH blood level should be in the range of 1.2 to 5 IU/L for optimal results and minimised risk of COH cancellation. The median LH value for the current study was 1.94 IU / l, and 'LH-peak' was not detected even in the urinary products (table 3, row 3).
The current study shows that the highest success rate (achieved clinical intrauterine pregnancy) was observed as a result of COH with recombinant products (table 1, row 5). In the urinary and mixed product group, success rate was reached inbetween, respectively, 5% and 7.6% fewer cases. It is important to specify that additional factors such as the lower average age in the recombinant group, as well as the higher oocyte yield, larger fertilised embryos count and the delayed embryo-transfer also influence the success rate. Achieving a clinical pregnancy is a multifactorial event, depending not only on the type of COH, but laboratory fertilisation activities, sterility type, congenital genetic diseases, luteal support therapy, concomitant conditions and medication, and so on.
A binary logistic regression analysis (both mono- and multifactorial) has been performed to evaluate the factors for the occurrence of pregnancy. Consequently, it becomes clear that the younger age, bigger follicle count, oocytes yield, mature oocytes count, percentage of fertilised oocytes, more embryos transferred and the later day of embryo transfer contribute to success rate (table 3, row 5,6, 7). Absolutely the same factors are among the critical points with regard to the safety of the woman undergoing ART. It is important to determine which values are the limit of these quantitative variables, below/above which ART success rate is not increasing. Based on the current data, age up to 35 years increases the chance for a clinical intrauterine pregnancy of 2.155 times (recalculated by 1/0.464), but at the same time, according to current analysis, the same age in combination with additional factors, is a potential risk for the development of OHSS.
Limitations of analysis
Consistency of data strongly depends on the correct registration of clinical observations in the hospital database. Besides, the current study does not investigate data from the medical records of male partners of studied women (spermograms). Yet, statistical analysis showed that specific types of assisted fertilisation method performed (IVF or ICSI), which is strongly predetermined by male fertilising capacity, does not influence significantly the success rate in the compared groups.
Conclusion
The ovarian response is a multicomponent function of the COH effectiveness and the individual patient characteristics. Due to the specificity of COH as a treatment procedure, the safety surveillance of ART exceeds adverse drug reaction reporting and the incidence of OHSS. Suboptimal effectiveness of stimulation protocols may also jeopardise the well-being of an ART patient. Factors such as duration and degree of FSH exposure, achieved values of sex hormones, and quantity and quality of extracted oocytes should be considered to minimise any unintended suffering of treated couples. Well-established efficacy endpoints are also a valid indicator of COH safety.
What this paper adds.
What is already known on this subject
Introduction of more effective measures to ensure patient safety and tolerability of controlled ovarian hyperstimulation is needed.
Controlled ovarian hyperstimulation is essential for both the success of the ART treatment cycle and the safety of the patient being treated.
Based on the similar therapeutic efficacy of urinary and recombinant gonadotropins, it is essential for the prescribing decision to evaluate the safety profile of different stimulation preparations.
Pharmacovigilance activities for safety surveillance of medicines used for controlled ovarian hyperstimulation are reduced to adverse drug reaction detection and reporting.
What this study adds
Safety surveillance of ART exceeds adverse drug reaction reporting and the incidence of ovarian hyperstimulation syndrome.
The current study determines these efficacy endpoints that are vital for the safety profile of conducted controlled ovarian hyperstimulation (extent of gonadotrophin exposure, induced values of sex hormones, quantity and quality of extracted oocytes, and so on.)
Recombinant and urinary hormone preparations do not differ significantly in rates of achieved clinical pregnancy but may vary noticeably in the safety aspects.
A patient-tailored approach may lead to a better efficacy and safety profile of controlled ovarian hyperstimulation.
Footnotes
Contributors: Conception or design of the work: SS, IG, TT, HL. Data collection: SS, TT. Data analysis and interpretation: SS, EN, IG, TT. Drafting the article: SS, EN, IG, TT, HL. Critical revision of the article: IG, TT. Translation and technical support: BP. Final approval of the version to be published: SS, IG, TT, HL, EN, BP.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
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