Effect of ethnicity on live birth rates after in vitro fertilisation/intracytoplasmic sperm injection treatment: analysis of UK national database

To evaluate the effect of ethnicity of women on the outcome of in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment.


Introduction
Infertility is a major public health problem that affects 10-15% of the population and an exponentially growing number of people are seeking infertility treatment. Over the last decade, the advancement and acceptance of infertility treatment has been significant. Despite rapid advancement in infertility treatment, ethnicity as a primary prognostic factor has attracted limited attention, unlike other areas in medicine, because of the paucity of robust evidence. In the UK, for example, the treatment protocols for in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment chosen for women are based on factors such as age, body mass index and ultrasound and endocrine markers of ovarian reserve, 1  woman. Further, most treatment protocols devised are based on research studies conducted in the Caucasian population of Europe and North America with extrapolation of the resulting data and application of the practices to populations worldwide representing various ethnicities and races.
There are a few published studies highlighting ethnicity as a determining factor of importance in IVF/ICSI treatment outcome. [2][3][4][5][6][7][8][9] However, most studies are based on small sample size and subjects described are of selected ethnicities and races and not representative of a general population sample, whereas larger published studies are based on the population of the USA. Another major issue of most published data is the pooling of different ethnicities under single wider categories such as Asians, which can include women from China, Japan, Korea, India, Bangladesh or Pakistan, who are significantly different racially and ethnically among each other. Further, most studies, especially those with smaller sample sizes, were from a single fertility unit, 2 and a number of ethnic groups were under-represented to generate a valid conclusion.
We, therefore, accessed a large anonymised patient register held by the Human and Fertilisation and Embryology Authority (HFEA) of the UK with an overall objective to evaluate the effect of ethnicity of women on the clinical outcome of IVF or ICSI treatment in a large population. The HFEA regulates fertility clinics in the UK, and as part of its role, it requires that all clinics submit the baseline data for each treatment cycle, which also include the ethnicity of women.

Methods
This cohort study is carried out in the UK by reviewing the anonymised data obtained from the HFEA registry covering the period 2000-10. Only women undergoing their first cycle of IVF/ICSI treatment were included and this was done to ensure that the data were truly unbiased (see Figure S1). Approval for the study was granted by the National Health Service Research Ethics Committee and the Nottingham University NHS Trust Research and Development Department. The process of extracting data was in keeping with the rules governing data protection.
The variables extracted include women's age, ethnicity, cause and type of infertility, duration of infertility, IVF or ICSI, number of embryos transferred, and day of embryo transfer. Outcomes included number of oocytes retrieved, number of oocytes fertilised by IVF or ICSI, number of embryos created, fertilisation rate (number of oocytes fertilised per number of oocytes inseminated), clinical pregnancy rate (number of pregnancies with positive heart beat on ultrasound per number of women starting IVF treatment), implantation rate (number of clinical pregnancies per number of embryos transferred), whereas live birth rate (proportion of cycles started that resulted in a live birth) was the main outcome measure in this study. Ethnicity was self-reported then categorised using recently recommended guidelines by the Office for National Statistics. 10 Data analysis was carried out using STATA 8.1. Univariate analysis using the available variables was performed first to assess the differences in baseline characteristics between White British women and those from other ethnic groups. Based on the distribution, bivariate analysis of continuous data was done with the Student's t test or Mann-Whitney U test. The relationship between two categorical variables was analysed by performing unadjusted odds ratio (OR) with 95% confidence interval (95% CI), chi-square test and Fisher exact test. When the confidence interval around the odds ratio did not include 1.00, the difference was considered to be statistically significant in all statistical tests. Logistic regression models were used to assess the effects of ethnicity on the study outcomes controlling for confounding variables. The White British ethnic group was taken as reference group in the model given that it is the largest ethnic group in the data set. To estimate the independent contribution of ethnic minority group to treatment outcomes (relative to the White British reference group), multivariate logistic regression analyses were performed. Potential confounding factors found to be statistically significant in univariate analyses and variables regarded as clinically significant were included in the models. For continuous data, a multivariate linear regression model was used controlling for the same confounders in the logistic models.

Demographic information and prevalence of causes of infertility in women of different ethnic background
Women undergoing their first cycle of treatment were analysed in this study ( The mean age of women ranged from 29.7 years to 35.8 years (Table 1). Women from South-Asian Indian, South-Asian Pakistani, Black Caribbean and Middle-Eastern backgrounds were significantly younger than the White British women, and White Irish, White European and Black British women were significantly older than the reference ethnic group (P < 0.05). The causes of infertility vary between ethnic groups as shown in Table 1 (and see Figure S2).

Effects of ethnicity of women on ovarian response and clinical pregnancy rates
After adjusting for all variables, including age of patient at time of treatment, cause of female or male infertility, and type of treatment (ICSI versus IVF) South Asian Bangladeshi, South Asian Pakistani, Black African, Middle Eastern and Other Asian women have a significantly lower number of eggs collected than White British women ( Table 2). Women of a mixed race also demonstrated a significantly lower number of eggs collected per treatment cycle. On the other hand, White Europeans had significantly higher numbers of eggs collected (P < 0.0001). There were no significant differences in the method of fertilisation (IVF or ICSI) used between women of different ethnicities. The data on number of embryos transferred, cryopreserved and the day of embryo transfer are shown in Table 2. South Asian Indian, South Asian Bangladeshi, South Asian Pakistani, Black British, Black African, Black Caribbean and Middle Eastern women were at higher risk of not reaching embryo transfer stage (cycle cancellation before embryo transfer after treatment started) ( Table 2). The reported ovarian hyperstimulation syndrome rates have been generally similar across all the ethnic groups except for higher incidence reported at egg collection in Black British and Black Caribbean women.
White Irish, South Asian Indian, South Asian Bangladeshi, South Asian Pakistani, Black African, and Other Asian groups had a significantly lower odds of clinical pregnancy than White British women after adjusting for age, cause of subfertility and type of treatment (Table 3). In contrast, White Europeans had significantly higher odds (OR 1.09; 95% CI 1.01-1.18) after adjusting for the aforementioned characteristics. Other Ethnicities had comparable outcome to that of White British women.

Effects of ethnicity of women on the primary outcome, live birth rate
After adjusting for all variables including age of patient at time of treatment, cause of female or male infertility, and type of treatment (ICSI versus IVF), White Irish, South Asian Indian, South Asian Bangladeshi, South Asian Pakistani, Black African and Other Asian women had significantly lower odds of live birth than White British women (Table 3 and Figure 1). It is also worth noting that Middle Eastern women had an odds ratio indicating a tendency (borderline significance P = 0.08) of lower odds of live birth outcomes (OR 0.73; 95% CI 0.51-1.04). Other Ethnicities had comparable outcome to that of White British women.

Main findings
The data from this large UK national database (HFEA) suggests that ethnicity is a major independent factor determining the chances of IVF or ICSI treatment success. Live birth rates following IVF or ICSI treatment were significantly lower in some of the ethnic groups (White Irish, Indian, Bangladeshi, Pakistani, Black African and Other Asian) compared with White British women, which suggests that ethnicity is a major determinant of live birth following IVF or ICSI treatment. Although the reason for this association is difficult to explain, the potential factors could be the observed differences in cause of infertility, ovarian response, fertilisation rates and implantation rates, which are all independent predictors of IVF success.

Strengths and limitations
Although there are a number of similar studies, [2][3][4][5]7,9,[11][12][13][14][15][16][17][18][19] this study is unique in the sub-categorising of ethnicities to represent more homogeneous subgroups of racial, cultural and lifestyle similarities: for example, Asian ethnicity clearly has very distinct ethnic subgroups such as Chinese, Indian, Pakistani and Bangladeshi, among others. Moreover, this is the largest study to date to evaluate the effect of individual sub-ethnic groups as an independent factor on the success rates of IVF/ICSI treatment with the data derived from a reasonably large number of women from various individual ethnic groups treated in all the UK fertility units.
The HFEA has been a regulator of fertility treatment in the UK since 1991, and as it requires clinics to submit information on all treatment cycles with the clinical outcomes, it now holds the robust data set about fertility treatments. As a result, one of the key strengths of this population study is the sample size, it is the largest cohort study with UK-wide representation for all ethnic and subethnic minorities. As the sample size is significantly large, it was possible to statistically analyse the success rates of the IVF cycles among each of the sub-ethnic groups without merging the categories, which was one of the drawbacks of the largest USA-based population studies that were previously published. 5 However, the numbers in some of the sub-ethnic minorities (e.g. Bangladeshi population) were low in our study. The use of the UK HFEA National database as a basis for this analysis provides an additional major strength of the paper as the HFEA's robust auditing and stringent regulations that standardise treatment across all clinics with regards to variables such as the number of embryos transferred back to the woman and number of previous treatment cycles. Further, only first cycles are included, which again gives a genuinely true comparison of IVF outcome between various ethnic groups as opposed to inclusion of multiple cycles from each woman, which would have added bias to the results. The quality of the data included in the study may be limited because of missing the ethnicity data in a significant proportion of cases reported to the HFEA ( Figure S1). Factors like body mass index, smoking and alcohol consumption were not collected by the HFEA and therefore could not be accounted for in this study. Socio-economic factors are also not accounted for; however, private and government-funded patients are evenly represented in the register, and also, the number of patients analysed in the different ethnic subgroups is large and represents the UK national distribution.

Interpretation
As noted in most studies, [11][12][13][14][15][16][17][18][19] varied underlying causes of infertility and age at which women undergo IVF were evident in the ethnic groups; however, the data suggest that after controlling for age and cause of subfertility, ethnicity of women remained a significant factor influencing the outcome of the treatment.
minority groups may be reflective of varied qualitative ovarian reserve or sperm factor as indicated by reduced fertilisation rates in South Asian Indian, South Asian Bangladeshi, South Asian Pakistani, Black British, Black African, Black Caribbean, Middle Eastern and Other Asian populations. Although genetic background could be a potential determinant of egg and sperm quality, variations in environmental exposures relating to different lifestyle, dietary, socio-economic and cultural factors could be influencing issues including the egg and sperm quality, accessibility of fertility treatment services and behaviour towards seeking medical care for fertility, and consequently the reproductive outcomes. The observed implantation rates have also been varied among different ethnic groups with reduced implantation noted in White Irish and Black African populations. The possible increased prevalence of polycystic ovarian syndrome in the South Asian population may have an adverse influence on oocyte quality and endometrial function, resulting in low implantation rates. While the increased prevalence of uterine and tubal factor infertility in the Black African population could explain the reason for reduced endometrial receptivity and implantation, the reason for low implantation rate in the Irish population is unclear. The observed variation in IVF treatment success among different ethnic groups raises a number of challenges for current clinical practices in terms of counselling women about their realistic probabilities of successful outcome, individually tailored treatment protocols, and policies regarding referral and treatment criteria for women of different ethnic backgrounds. Research is needed to understand the reasons behind the variation in treatment outcome between ethnic groups and studies evaluating treatment strategies for modifying IVF outcome should incorporate ethnicity as a major determinant factor. Modifications in clinical strategies to bring about equivalent success rates among all ethnic groups can be achieved after the relationship between ethnicity and IVF outcome is better understood.

Conclusion
Live birth rates following IVF treatment were significantly lower in some of the ethnic groups compared with white British women, which suggests that ethnicity is a major determinant of live birth following IVF or ICSI treatment. Although the prevalence of various causes of infertility varies in different ethnic groups, the ethnicity of the woman is independently correlated with success rates of IVF treatment cycle after controlling for age and causes of infertility. Even though data on other variables such as diet and socio-economic factors are not reported and they can potentially alter the outcome of clinical treatment, such variables are non-modifiable and therefore ethnicity should be considered when counselling women and couples about their realistic chances of IVF success. This study is just a Significantly lower (*P < 0.05).
first step and further research is needed to understand the mechanisms leading to this variation in treatment outcome between ethnic groups and move towards tailoring tangible protocols specifically suited to each ethnic group to maximise their IVF/ ICSI success without compromising their safety.

Disclosure of interests
None declared. Completed disclosure of interests form available to view online as supporting information.
Contribution to authorship

Funding
The study was supported by the University of Nottingham.