How was the predictive model of pregnancy built?
The first step was to identify the probability markers of pregnancy and find risk factors with a negative influence on getting pregnant. The principles of EBM (Evidence Based Medicine – “the use of mathematical estimates of the risk of benefit and harm, derived from high-quality research on population samples, to inform clinical decision-making in the diagnosis, investigation or management of individual patients." ) were combined with the specialists’ long-standing experiences. Scientific literature databases (Pubmed, EMBASE) were systematically screened and following factors were identified:
2. Body mass index
4. Sexually transmitted disease history
8. Previous operations on reproductive organs
9. Polycystic ovary syndrome
11. Fallopian tube blockade
12. Cycle length
13. Endometrial thickness
14. AMH, FSH, E2 level
15. Follicle count
16. Diabetes Mellitus
17. Thyroid gland disorders
The second step was to find the most relevant scientific evidence and results of epidemiological studies for each factor and its impact on fertility. The goal was to find the highest-level evidence according to EBM evidence hierarchy (Fig. 1). Relevant studies were systematically assessed (study design, sample size etc.) by our specialists and the final selection of studies against pre-determined criteria for eligibility and relevance was made.
The third step was the extraction of data from selected studies and developing the predictive model of pregnancy for the current cycle. For examples of research findings used, please, visit www.fertilomat.com/research.
Fertilomat development: a dynamic, continuous process
The development of the formula is still not at the end. We have been continuously collecting data from different sources to improve our predictive model. Therefore, we periodically screen scientific literature databases for the purpose of updating our formula and we cooperate with clinical specialists to assess the outcomes in clinical practice.
 Greenhalgh, Trisha. How To Read a Paper: The Basics of Evidence-Based Medicine. Wiley-Blackwell, fourth edition, 2010, p.1.
F.J.Broekmans, J.Kwee2, D.J.Hendriks, B.W.Mol, C.B.Lambalk
A systematic review published in 2006 in the Human Reproduction Update (Impact factor: 9.234) that evaluates the dependence of ovarian reserve on age and the efficacy of ovarian reserve tests.
The age-related decline of the success in IVF is largely attributable to a progressive decline of ovarian oocyte quality and quantity. Over the past two decades, a number of so-called ovarian reserve tests (ORTs) have been designed to determine oocyte reserve and quality and have been evaluated for their ability to predict the outcome of IVF in terms of oocyte yield and occurrence of pregnancy. Many of these tests have become part of the routine diagnostic procedure for infertility patients who undergo assisted reproductive techniques. The unifying goals are traditionally to find out how a patient will respond to stimulation and what are their chances of pregnancy. Evidence-based medicine has progressively developed as the standard approach for many diagnostic procedures and treatment options in the field of reproductive medicine. We here provide the first comprehensive systematic literature review, including an a priori protocolized information retrieval on all currently available and applied tests, namely early-follicular-phase blood values of FSH, estradiol, inhibin B and anti-Müllerian hormone (AMH), the antral follicle count (AFC), the ovarian volume (OVVOL) and the ovarian blood flow, and furthermore the Clomiphene Citrate Challenge Test (CCCT), the exogenous FSH ORT (EFORT) and the gonadotrophin agonist stimulation test (GAST), all as measures to predict ovarian response and chance of pregnancy. We provide, where possible, an integrated receiver operating characteristic (ROC) analysis and curve of all individual evaluated published papers of each test, as well as a formal judgement upon the clinical value. Our analysis shows that the ORTs known to date have only modest-to-poor predictive properties and are therefore far from suitable for relevant clinical use. Accuracy of testing for the occurrence of poor ovarian response to hyperstimulation appears to be modest. Whether the a priori identification of actual poor responders in the first IVF cycle has any prognostic value for their chances of conception in the course of a series of IVF cycles remains to be established. The accuracy of predicting the occurrence of pregnancy is very limited. If a high threshold is used, to prevent couples from wrongly being refused IVF, a very small minority of IVF-indicated cases (approximately 3%) are identified as having unfavourable prospects in an IVF treatment cycle. Although mostly inexpensive and not very demanding, the use of any ORT for outcome prediction cannot be supported. As poor ovarian response will provide some information on OR status, especially if the stimulation is maximal, entering the first cycle of IVF without any prior testing seems to be the preferable strategy.
Jan Eggert M.D., Holger Theobald M.D. Ph.D., Peter Engfeldt M.D. Ph.D
An article published in the Fertility and sterility journal (impact factor 3,85) in 2004. It is a large prospective (cohort) study of the influence of alcohol on female infertility in a cohort of 7393 healthy women (18 to 28 years of age) during an 18 year period.
OBJECTIVE: To investigate the long-term effects of alcohol consumption on female fertility.
DESIGN: Prospective study of a random sample of 7,393 women, selected from the 445,000 inhabitants of Stockholm County, Sweden, in 1969. Self-estimated alcohol consumption was obtained from postal questionnaires. Data on hospitalizations for pregnancy outcomes including infertility examinations were analyzed until 1987.
SETTING: Healthy women in Stockholm County, Sweden.
PATIENT(S): Seven thousand three hundred ninety-three women in the age range 18-28 years.
MAIN OUTCOME MEASURE(S): Rates of hospitalization for deliveries, miscarriages, legal abortions, extrauterine pregnancies, pelvic inflammatory disease, endometriosis, and infertility examinations were analyzed in relation to the intake of alcohol.
RESULT(S): Two hundred fifty-two women underwent infertility examinations. High consumers had an increased risk for such examinations, as compared with moderate consumers: relative risk ratio (RR) = 1.59 (95% confidence interval [CI]: 1.09-2.31); and low consumers had a decreased risk (RR = 0.64; CI: 0.46-0.90). Moreover, for both high and low consumers we observed a significantly lower number of first and second partus. Rates of miscarriage, extrauterine pregnancy, and pelvic inflammatory disease did not differ between high and low consumers of alcohol.
CONCLUSION(S): High alcohol consumption was associated with increased risk of infertility examinations at hospitals and with lower numbers of first and second partus. It may be important for the female partner in an infertile couple to limit alcohol intake or to not drink at all.
Janne Schurmann Tolstrup, Susanne Krüger KJÆR, Claus Holst, Heidi Sharif, Christian Munk, Merete Osler, Lone Schmidt, Anne-Marie Nybo Andersen, Morten Gronbaek
Cohort study done in Denmark and published in the year 2003 in Acta Obstetricia et Gynecologica Scandinavica (IF 1,771). In this study was included a cohort of 7760 of patients aged 20-29 years. All eligible women were nulliparous and not pregnant.
BACKGROUND: Our aim was to examine the association between use of alcohol and subsequent incidence of primary infertility.
METHODS: The study subjects were chosen from a population-based cohort of Danish women aged 20-29 years. Eligible women were nulliparous and not pregnant (n = 7760). Information on alcohol intake and potential confounders (age, education, marital status, diseases in the reproductive organs, and cigarette smoking) was assessed at enrollment. The incidence of fertility problems during follow-up was obtained by record linkage with the Danish Hospital Discharge Register and the Danish Infertility Cohort Register. Main outcome measures were hazard ratios of infertility according to alcohol intake at baseline estimated in a multivariate Cox proportional hazards model.
RESULTS: During a mean follow-up of 4.9 years, 368 women had experienced infertility. Alcohol intake at baseline was unassociated with infertility among younger women, but was a significant predictor for infertility among women above age 30. In this age group, the adjusted hazard ratio for consuming seven or more drinks per week was 2.26 (95% confidence interval: 1.19-4.32) compared with women consuming less than one drink per week.
CONCLUSIONS: These findings suggest that alcohol intake is a predictor for infertility problems among women in the later reproductive age group.
Francine Grodstein, ScD, Marlene B., Daniel W. Cramer, MD, ScD
An article published in the year 1994 in the American Journal of public health (Impact factor 3,85). It is a case (1050 patients)- control (3833 patients) study. The study proved a higher incidence of infertility in the case group, due to ovulatory factors or endometriosis. In addition the dependency of infertility on alcohol consumption seemed to be higher in the high consumption group (odds ratio 1,6) then in the moderate consumption group (OR 1,3). The conclusion was that moderate alcohol use may contribute to the risk of specific types of infertility.
OBJECTIVE: The purpose of this study was to investigate the relationship between moderate alcohol intake and fertility.
METHODS: Interviews were conducted with 3833 women who recently gave birth and 1050 women from seven infertility clinics. The case subjects were categorized based on the infertility specialist's assignment of the most likely cause of infertility: ovulatory factor, tubal disease, cervical factor, endometriosis, or idiopathy. Separate logistic regression models were used to assess the relationship between alcohol use and each type of infertility, adjusted for age, infertility center, cigarette smoking, caffeine use, number of sexual partners, use of an intrauterine device (for tubal disease), and body mass index and exercise (for ovulatory factor).
RESULTS: We found an increase in infertility, due to ovulatory factor or endometriosis, with alcohol use. The odds ratio for ovulatory factor was 1.3 (95% confidence interval [CI] = 1.0, 1.7) for moderate drinkers and 1.6 (95% CI = 1.1, 2.3) for heavier drinkers, compared with nondrinkers. The risk of endometriosis was roughly 50% higher in case subjects with any alcohol intake than in control subjects (OR = 1.6, 95% CI = 1.1, 2.3, at moderate levels; OR = 1.5, 95% CI = 0.8, 2.7, at heavier levels).
CONCLUSIONS: Moderate alcohol use may contribute to the risk of specific types of infertility.
F. Bolúmar, J. Olsen, M. Rebagliato, L Bisanti and European Study Group on Infertility and Subfecundity
An older retrospective study that on the other hand proved a significant effect of caffeine intake on reduction of female fecundity. It was published in 1996 in the American Journal of Epidemiology (impact factor 5.216). It proved an significantly risk of subfecundity in women that consume 500 mg and more caffeine per day.
The effects of caffeine consumption on delayed conception were evaluated in a European multicenter study on risk factors of infertility. Information was collected retrospectively on time of unprotected intercourse for the first pregnancy and the most recent waiting time episode in a randomly selected sample of 3,187 women aged 25–44 years from five European countries (Denmark, Germany, Italy, Poland, and Spain) between August 1991 and February 1993. The consumption of caffeinated beverages at the beginning of the waiting time was used to estimate daily caffeine intake, which was categorized as 0–100, 101–300, 301–500, and >501 mg. Risk of subfecundity (>9.5 months) and the fecundability ratio, respectively, were assessed by logistic regression and Cox proportional hazard analyses, adjusting for age, parity, smoking, alcohol consumption, frequency of intercourse, educational level, working status, use of oral contraceptives, and country. A significantly increased odds ratio (OR) of 1.45 (95% confidence interval (Cl) 1.03–2.04) for subfecundity in the first pregnancy was observed for women drinking more than 500 mg of caffeine per day, the effect being relatively stronger in smokers (OR = 1.56, 95% Cl 0.92–2.63) than in nonsmokers (OR = 1.38, 95% Cl 0.85–2.23). Women in the highest level of consumption had an increase in the time leading to the first pregnancy of 11 % (hazard ratio = 0.90, 95% Cl 0.78–1.03). These associations were observed consistently in all countries as well as for the most recent waiting time episode. The authors conclude that high levels of caffeine intake may delay conception among fertile women. Am J Epidemiol1997; 145: 324–34.
A.M.H. Koning , M.A.Q. Mutsaerts, W.K.H. Kuchenbecher, F.J. Broekmans, J.A. Land, B.W. Mol, A. Hoek
It is a systematic review, that evaluates the efect of increased BMI on the results and complications of assisted reproduction. The results suggest that high BMI significantly increases the incidence of complications of assisted reproduction and only slightly decreases its yeild.
BACKGROUND: Based on a presumed negative impact of overweight and obesity on reproductive capacity and pregnancy outcome, some national guidelines and clinicians have argued that there should be an upper limit for a woman’s BMI to access assisted reproductive technologies (ART). However, evidence on the risk of complications or expected success rate of ART in obese women is scarce. We therefore performed a systematic review on the subject.
METHODS: We searched the literature for studies reporting on complications or success rates in overweight and obese women undergoing ART. Articles were scored on methodological quality. We calculated pooled odds ratios (ORs) to express the association between overweight and obesity on the one hand, and complications and success rates of ART on the other hand. We only pooled results if data were available per woman instead of per cycle or embryo transfer.
RESULTS: We detected 14 studies that reported on the association between overweight and complications during or after ART, of which 6 reported on ovarian hyperstimulation syndrome (OHSS), 7 on multiple pregnancies and 6 on ectopic pregnancies. None of the individual studies found a positive association between overweight and ART complications. The pooled ORs for overweight versus normal weight for OHSS, multiple pregnancy and ectopic pregnancy were 1.0 [95% conﬁdence interval (CI) 0.77–1.3], 0.97 (95% CI 0.91–1.04) and 0.96 (95% CI 0.54–1.7), respectively. In 27 studies that reported on BMI and the success of ART, the pooled ORs for overweight versus normal weight on live birth, ongoing and clinical pregnancy following ART were OR 0.90 (95% CI 0.82–1.0), 1.01 (95% CI 0.75–1.4) and OR 0.94 (95% CI 0.69–1.3), respectively.
CONCLUSIONS: Data on complications following ART are scarce and therefore a registration system should be implemented in order to gain more insight into this subject. In the available literature, there is no evidence of overweight or obesity increasing the risk of complications following ART. Furthermore, they only marginally reduce the success rates. Based on the currently available data, overweight and obesity in itself should not be a reason to withhold ART.
Souter I, Baltagi LM, Kuleta D, Meeker JD, Petrozza JC.
OBJECTIVE: To determine the fecundity of overweight and obese infertile women treated with gonadotropins and undergoing intrauterine insemination (IUI).
DESIGN: Retrospective study.
SETTING: Academic infertility clinic.
PATIENT(S): Four hundred seventy-seven women undergoing 1,189 ovulation induction (OI)/IUI cycles stratified by body mass index (BMI).
MAIN OUTCOME MEASURE(S): BMI groups were compared regarding the following: gonadotropin dose, duration of treatment, peak E(2), number of follicles (total, large, and medium size), E(2)/follicle, endometrial thickness, spontaneous abortion, and clinical and multiple pregnancy rates.
RESULT(S): There was a significant trend toward higher medication requirements and lower E(2) levels with increasing BMI. BMI was inversely associated with  the E(2) level per produced preovulatory follicle and  the number of medium-size follicles. Furthermore, BMI was inversely associated with the number of medium, large, and total follicles divided by total FSH dose, suggesting that women with a higher BMI develop a lower number of medium and/or large follicles at a given total FSH dose. BMI was positively associated with endometrial thickness, and endometrial thickness was positively associated with pregnancy. Mean number of cycles required to conceive, clinical pregnancy, and spontaneous abortion rates did not differ significantly among the different BMI categories.
CONCLUSION(S): Obese women require higher doses of medication and produce fewer follicles for a given dose, but once medication and response are adjusted to overcome the weight effect, the success of the treatment cycle is comparable to that of normal weight women.
Rittenberg V, Seshadri S, Sunkara SK, Sobaleva S, Oteng-Ntim E, El-Toukhy T.
An article published in the Reproductive BioMedicine Online journal (Impact Factor: 2.042) in 2011. It is a systematic review and meta-analysis of studies that evaluate the effect of raised BMI on treatment outcome following IVF/ICSI treatment. Overweight or obese women had significantly lower clinical pregnancy (that was defined as the observation of pregnancy sac on USG at least 4 weeks after embryo transfer) and lower live birth rates and significantly higher miscarriage rate. There weren´t big differences in subgroup analysis between overweight (BMl >25-29.9 kg/m^2) and obese (BMl>30 kg/m^) - in conclusion, raised BMI is associated with adverse pregnancy outcome in women undergoing IVF/ICSI treatment.
NOTE: this study was not able to adjust for important confounders such as patient age, cause and durative of infertility, ovarian stimulation protocol used and number and quality of embryos transferred, all of which varied among the included studies
There is conflicting evidence regarding the effect of raised body mass index (BMI) on the outcome of assisted reproductive technology. In particular, there is insufficient evidence to describe the effect of BMI on live birth rates. We carried out a systematic review and meta-analysis of studies to evaluate the effect of raised BMI on treatment outcome following IVF/ICSI treatment. Subgroup analysis on overweight and obese patients was performed. Literature searches were conducted on MEDLINE, EMBASE and the Web of Science from 1966 to 2010. Thirty-three studies including 47,967 treatment cycles were included. Results indicated that women who were overweight or obese (BMI⩾25) had significantly lower clinical pregnancy (RR=0.90, P<0.0001) and live birth rates (RR=0.84, P=0.0002) and significantly higher miscarriage rate (RR=1.31, P<0.0001) compared to women with a BMI < 25 following treatment. A subgroup analysis of overweight women (BMI⩾25–29.9) revealed lower clinical pregnancy (RR=0.91, P=0.0003) and live birth rates (RR=0.91, P=0.01) and higher miscarriage rate (RR=1.24, P<0.00001) compared to women with normal weight (BMI<25). In conclusion, raised BMI is associated with adverse pregnancy outcome in women undergoing IVF/ICSI treatment, including lower live birth rates. This effect is present in overweight as well as obese women.
Nafiye Yilmaz, M.D., Sevtap Kilic, M.D., Ph.D., Mine Kanat-Pektas, M.D., Cavidan Gulerman, M.D., and Leyla Mollamahmutoglu, M.D.
OBJECTIVE: Obesity is an important factor that might reduce fecundity. In order to determine the underlying physiological mechanisms and risk factors, the obesity-fecundity association is investigated in relation to parity, menstrual cycle regularity, smoking habits, and age.
METHODS: This was a retrospective cohort study of 22,840 women who gave birth between January 2006 and January 2007 in the Dr Zekai Tahir Burak Women's Health Research and Education Hospital. Age, parity, prepregnancy body mass index (BMI) values, time to pregnancy data related to smoking, and reproductive, medical, and gynecological history were obtained from the medical records.
RESULTS: Fecundity was reduced for overweight and obese women compared with optimal weight women, and this reduction was more evident for obese primiparous women. Fecundity remained reduced for overweight and obese women with normal menstrual cycles. Obese and overweight women were found to smoke significantly more than the optimal weight group.
CONCLUSIONS: Obesity was found to be associated with reduced fecundity for all weight-adjusted groups of women and persisted for women with regular cycles. Weight loss should be encouraged initially during the treatment of infertile overweight and obese women.
Augood C, Duckitt K, Templeton AA.
Meta-analysis of 12 observational studies with an objective to determine whether there is an association between smoking and female infertility. It was published in The human reproduction journal (impact factor 4,475) in 1998.
The high prevalence of smoking among women in their reproductive years continues to be a matter of concern. The negative effects of smoking on general health are well known, but smoking may also affect fertility. The objective of the present study was to perform a systematic review of the literature to determine whether there is an association between smoking and risk of infertility in women of reproductive age, and to assess the size of this effect. In the 12 studies used for this meta-analysis, the overall value of the odds ratio (OR) for risk of infertility in women smokers versus non-smokers was 1.60 [95% confidence interval (CI) 1.34-1.91]. Studies of subfertile women undergoing in-vitro fertilization (IVF) treatment also show a reduction in fecundity among women smokers. A meta-analysis of nine studies found an OR of 0.66 (95% CI 0.49-0.88) for pregnancies per number of IVF-treated cycles in smokers versus non-smokers. Despite the potential limitations of meta-analyses of observational studies, the evidence presented in this review is compelling because of the consistency of effect across different study designs, sample size and types of outcome. However, continued reassurance is needed that the calculated overall effect is not in fact due to confounding variables.
Justine Shuhui Loh, Abha Maheshwar
An article published in the year 2011 in The Human Reproduction Journal (impact factor 4,475). It is a systematic review of studies that describes the role of AMH as a marker. According to the authors of the study, definite evidence of use of AMH is currently availaible only for the prediction of poor/over response in an IVF setting. For the other utilization described in literature (predicting the age of menopause, screening for polycistic ovaries etc.) , relevant data in studies weren´t shown or designs of studies weren´t ideal. Nevertheless, the potential of using AMH is promising.
Several studies have demonstrated that anti-Müllerian hormone (AMH) is a better marker of ovarian reserve than age, basal FSH, estradiol and inhibin. AMH is very good in (i) predicting both over- and poor-response in the controlled ovarian stimulation environment, (ii) determining the most appropriate stimulation regimen and (iii) pre-treatment counselling for couples to make an appropriate and informed choice. Recent reports are exploring the use of AMH in various other indications, including (i) predicting long-term fertility and guiding how long a woman can delay childbearing without facing the risk of reduced ovarian reserve, (ii) predicting the age of menopause, (iii) prediction of ovarian ageing in women prior to or following chemotherapy, (iv) prediction of long-term fertility following ovarian surgery and (v) screening for polycystic ovaries. However, widespread use of AMH for indications not proved by evidence-based medicine can lead to either false reassurance or distress, leading to unnecessary medical interventions . It also has huge implications for costs. We evaluated the evidence basis for using AMH for various indications to decide how justified it is to promote AMH as a crystal ball, until more evidence is available.