J.D.F. Habbema

Antral follicle counts by transvaginal ultrasonography are related to age in women with proven natural fertility

OBJECTIVE To investigate the relation between reproductive age and ultrasound (US)-based follicle counts and the reproducibility of follicle counts in regularly cycling women with proven fertility. DESIGN Prospective observational study. SETTING Tertiary fertility center. PATIENT(S) Healthy female volunteers with proven fertility, recruited by advertisement in local newspapers. INTERVENTION(S) The number of antral follicles sized 2-10 mm and ovarian volume were estimated by transvaginal US in the early follicular phase of the menstrual cycle in 162 women. A subgroup of 81 women underwent transvaginal US at several times in three subsequent cycles. MAIN OUTCOME MEASURE(S) Antral follicle count and total ovarian volume. RESULT(S) Women aged 25-46 years (n = 162) were studied. The relation of age with the US indices was computed after natural log transformation. Antral follicle count showed the clearest correlation with age (R = -0.67). A biphasic linear model gave the best fit to the data. Before the age of 37 years, the antral follicle count showed a mean yearly decline of 4.8%, compared with 11.7% thereafter. The reproducibility of the antral follicle count in two subsequent cycles was moderate. CONCLUSION(S) The number of small antral follicles in both ovaries as measured by US is clearly related to reproductive age and could well reflect the size of the remaining primordial follicle pool.

Delaying childbearing: effect of age on fecundity and outcome of pregnancy.

OBJECTIVES--To study the age of the start of the fall (critical age) in fecundity; the probability of a pregnancy leading to a healthy baby taking into account the age of the woman; and, combining these results, to determine the age dependent probability of getting a healthy baby. DESIGN--Cohort study of all women who had entered a donor insemination programme. SETTING--Two fertility clinics serving a large part of The Netherlands. SUBJECTS--Of 1637 women attending for artificial insemination 751 fulfilled the selection criteria, being married to an azoospermic husband and nulliparous and never having received donor insemination before. MAIN OUTCOME MEASURES--The number of cycles before pregnancy (a positive pregnancy test result) or stopping treatment; and result of the pregnancy (successful outcome). RESULTS--Of the 751 women, 555 became pregnant and 461 had healthy babies. The fall in fecundity was estimated to start at around 31 years (critical age); after 12 cycles the probability of pregnancy in a woman aged greater than 31 was 0.54 compared with 0.74 in a woman aged 20.31. After 24 cycles this difference had decreased (probability of conception 0.75 in women greater than 31 and 0.85 in women 20.31). The probability of having a healthy baby also decreased--by 3.5% a year after the age of 30. Combining both these age effects, the chance of a woman aged 35 having a healthy baby was about half that of a woman aged 25. CONCLUSION--After the age of 31 the probability of conception falls rapidly, but this can be partly compensated for by continuing insemination for more cycles. In addition, the probability of an adverse pregnancy outcome starts to increase at about the same age.

Age-dependent decrease in embryo implantation rate after in vitro fertilization

OBJECTIVE To investigate the relation between the implantation rate per embryo after replacement in IVF-ET in relation to female age. DESIGN Retrospective study using linear and biphasic models in a multivariate analysis. SETTING Academic tertiary care institution. INTERVENTION(S) In vitro fertilization-ET and determination of gestational sacs at 6 to 7 weeks of pregnancy buy ultrasound. MAIN OUTCOME MEASURE(S) Implantation rate as defined by the number of gestational sacs per embryo replaced. RESULT(S) Womans age and embryo morphology were strongly related to the implantation rate, indication for IVF-ET and cycle rank number also were related significantly but less strongly. A linear model was built describing the decrease in implantation rate with age, resulting in a decrease of approximately 7%. A biphasic model was tested also and performed significantly better, resulting in a yearly decrease of > 20% after 37 years of age. CONCLUSION(S) The most important independent factors related to the ability of embryos to implant are female age and embryo morphology. The best way to describe the relation with female age is biphasic model with a discontinuity at approximately 37 years of age.

Cost-effectiveness of 'immediate IVF' versus 'delayed IVF': A prospective study

STUDY QUESTION How does the cost-effectiveness (CE) of immediate IVF compared with postponing IVF for 1 year, depend on prognostic characteristics of the couple? SUMMARY ANSWER The CE ratio, i.e. the incremental costs of immediate versus delayed IVF per extra live birth, is the highest (range of €15 000 to >€60 000) for couples with unexplained infertility and for them depends strongly on female age and the duration of infertility, whilst being lowest for endometriosis (range 8000-23 000) and, for such patients, only slightly dependent on female age and duration of infertility. WHAT IS KNOWN ALREADY A few countries have guidelines for indications of IVF, using the diagnostic category, female age and duration of infertility. The CE of these guidelines is unknown and the evidence base exists only for bilateral tubal occlusion, not for the other diagnostic categories. STUDY DESIGN, SIZE, DURATION A modelling approach was applied, based on the literature and data from a prospective cohort study among couples eligible for IVF or ICSI treatment, registered in a national waiting list in The Netherlands between January 2002 and December 2003. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 5962 couples was included. Chances of natural ongoing pregnancy were estimated from the waiting list observations and chances of ongoing pregnancy after IVF from follow-up data of couples with primary infertility that began treatment. Prognostic characteristics considered were female age, duration of infertility and diagnostic category. Costs of IVF were assessed from a societal perspective and determined on a representative sample of patients. A cost-effectiveness comparison was made between two scenarios: (I) wait one more year and then undergo IVF for 1 year and (II) immediate IVF during 1 year, and try to conceive naturally in the following year. Comparisons were made for strata determined by the prognostic factors. The final outcome was a live birth. MAIN RESULTS AND THE ROLE OF CHANCE The gain in live birth rate of the immediate IVF scenario versus postponed IVF increased with female age, and was independent from diagnostic category or duration of infertility. By contrast, the corresponding increase in costs primarily depended on diagnostic category and duration of infertility. The lowest CE ratio was just below €10 000 per live birth for endometriosis from age 34 onwards at 1 year duration. The highest CE ratio reached €56 000 per live birth for unexplained infertility at age 30 and 3 years duration, dropping to values below € 30 000 per live birth from age 32 onwards. It reached values below €20 000 per live birth with 3 years duration at age 34 and older. The CE ratio was in between for the three other diagnostic categories (i.e. Male infertility, Hormonal and Immunological/Cervical). LIMITATIONS, REASONS FOR CAUTION We applied estimates of chances with IVF, excluding frozen embryos, for which we had no data. Therefore, we do not know the effect of frozen embryo transfers on the CE. WIDER IMPLICATIONS OF THE FINDINGS The duration of infertility at which IVF becomes cost-effective depends, firstly, on the level of societys willingness to pay for one extra live birth, and secondly, given a certain level of willingness to pay, on the womans age and the diagnostic category. In current guidelines, the chances of a natural conception should always be taken into account before deciding whether to start IVF treatment and at which time. STUDY FUNDING/COMPETING INTEREST(S) Supported by Netherlands Organisation for Health Research and Development (ZonMW, grant 945-12-013). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none.

Prognostic significance of pretreatment variables in patients with invasive cervical cancer

In 119 consecutive patients with invasive cervical cancer 92 variables of potential significance in predicting recurrence were determined before treatment. In 49 patients recurrent disease was diagnosed during follow-up after therapy. The investigated variables include: clinical data, routinely performed hematological and biochemical tests, histopathological data, oncofetal antigens, placental and pregnancy associated substances, serum levels of acute phase reactants, complement components, immunoglobulins and circulating immune complexes, and assays measuring the general immune competence of the patient. Thirty-three of the variables appeared to give statistically significant differences between values of future recurrence and non-recurrence patients. Further selection was carried out by stepwise forward discriminant analysis. This selection resulted in a prognosis rule using a subset of 7 variables. Carcino-embryonic antigen and the complement component C3PA appeared to be the most powerful variables. Although the stage of disease was the third most important single variable, it did not add prognostic information, once CEA and C3PA were used. By applying the prognosis rule a probabilistic prediction is obtained for each patient. In about 60% of the future recurrences and 40% of the future non-recurrence patients, these predictions reached a high level of accuracy. It was argued that the prediction of non-recurrence does not warrant to change the treatment protocol at present. Whether the prediction of recurrence is clinically useful remains to be clarified.