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PubMed2003

Characteristics of the best prognostic evidence: an example on prediction of outcome after clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility.

The standard first-line treatment for normogonadotropic anovulatory infertile patients [referred to as World Health Organization group 2 (WHO 2)] is ovulation induction using clomiphene citrate (CC) in incremental doses. Twenty to 25% of women show clomiphene-resistant anovulation (CRA), that is, they remain anovulatory even after multiple attempts with increased doses of CC. About 50% of the ovulatory CC patients conceive within six CC-induced cycles. Given the heterogeneous nature of the group, the individual prognosis (i.e., the chance of success) will vary considerably between patients. In the event an individual prognosis of each patient would be available before the start of the treatment, the overall efficiency of ovulation induction could be improved. Prognostic evidence at an individual level should use multiple patient variables, including results from previous treatments (if any). When variables are interdependent, a statistical model can be used to relate individual characteristics with the predicted outcome. Such a model will provide estimates of prognosis for individualized patient profiles, allowing new patients to profit from the experience of the cohort of previous patients used to build the model. This paper discusses the prediction of time to pregnancy following induction of ovulation with CC. This prediction was broken down in two steps, leading to two separate prognostic models. The first model predicts an intermediate outcome, the chance that the patient will be CRA (i.e., no ovulation in response to CC medication); the second model predicts the final outcome (time until pregnancy) in women who do ovulate. The CRA model was based on a prospective cohort study of 201 patients with normogonadotropic oligoamenorrheic infertility, 45 of whom were CRA (22%). It contained four predictor variables all related to the diagnosis of PCOS within the group of WHO 2: Increased free androgen index (FAI; hyperandrogenemia), elevated body mass index (BMI; obesity), greater mean ovarian volume (as an ultrasound feature of polycystic ovaries), and amenorrhea were all predictive for CRA. The second model was based on the non-CRA patients and contained two prognostic variables: increased age and oligomenorrhea were predictive for longer time to pregnancy after first ovulation with CC. Using the example of the prediction of time to pregnancy following induction of ovulation with CC, we present and discuss characteristics of good prognostic evidence for clinical use, focusing on study design, statistical analysis, evaluation, and presentation of results.

Amenorrhea↗
PubMed1995

Total ovarian volume before human chorionic gonadotrophin administration for ovulation induction may predict the hyperstimulation syndrome.

Total ovarian volumes were measured before the administration of HCG in 42 women undergoing treatment for infertility by in-vitro fertilization (IVF) and embryo transfer and considered to have an exaggerated response to stimulation ( > 20 follicles). Seven women who subsequently developed moderate or severe ovarian hyperstimulation syndrome (OHSS) (n = 7; group 1) were compared with 35 matched controls (five matched controls per case; n = 35; group 2) of similar age, number of follicles and duration of infertility who underwent follicular stimulation, oocyte recovery, in-vitro fertilization and embryo transfer during the same period but did not develop moderate or severe OHSS. The mean age, duration of infertility and total number of follicles were similar but the mean total ovarian volume was significantly higher in the group of women who developed moderate or severe OHSS compared with controls (271.00 +/- 87.00 versus 157.30 +/- 54.20 ml; P < 0.01). We conclude that total ovarian volume measured before HCG administration is higher in women who develop moderate or severe OHSS compared with controls and may therefore be used as an additional parameter in the preventative strategy for the ovarian hyperstimulation syndrome.

Adult↗
PubMed1985

Outcome of successive cycles of ovulation induction in the same individual.

Because of the failure to conceive after the first cycle of in vitro fertilization (IVF), many couples often undergo repeated attempts. However, choosing the best stimulation protocol in successive cycles of IVF in the same individual is hindered by the lack of information regarding outcome in successive cycles following utilization of the same or different stimulation protocols. Examination of repeated cycles of the same stimulation protocol in 33 women demonstrated that comparing women with an initial "A" estradiol (E2) pattern (daily E2 levels that continued to rise throughout the stimulation) and those with non-A E2 patterns (failure to have continually rising E2 levels throughout the stimulation), the former were significantly less likely to have a subsequent passed cycle (P = 0.007) and tended to be more likely to have a subsequent A cycle (P = 0.079). Changing the stimulation protocol resulted in a different E2 pattern in 15 of 20 subsequent cycles. Thus, it is suggested that after a cycle with an acceptable E2 pattern, successive cycles be performed with the same stimulation protocol. However, after an initial unacceptable E2 pattern, it may be more efficacious to utilize an alternate stimulation protocol.

Chorionic Gonadotropin↗
PubMed1991

Ovulation induction with human menopausal gonadotropins--a changing scene.

The aim of human menopausal gonadotropin treatment (hMG), to simulate normal follicular development by injecting FSH and LH and induce follicular rupture with hCG, is rarely met. Multiple follicular development occurs because hypothalamic-pituitary feedback is bypassed. This, exacerbated by the long half-life of hCG, causes the principal complications of hMG therapy--multiple pregnancy and hyperstimulation. The initial use of hMG in pituitary deficiency has been widened to include failure to respond to clomiphene, polycystic ovaries, 'unexplained infertility' and in vitro fertilization. Reported pregnancy rates, incidence of hyperstimulation and of multiple pregnancy vary widely. We reviewed the results of hMG therapy from 1977 to 1989 in 260 consecutive women with clomiphene-resistant infertility. Conception and live birth rates after six treatment cycles were 45.7% and 43.3%, respectively and were influenced by the cause of infertility, age, weight and sperm parameters. The miscarriage rate was 18.6% and multiple pregnancy rate 19.3%. The conception rate fell during the 12-year period in all groups except those with regular anovulatory cycles. Over this period, age, weight and male subfertility increased in patients referred to us. hMG is an effective and safe treatment for women with clomiphene-resistant infertility and patent tubes.

Adult↗
PubMed2005

Ovulation induction, assisted conception and childhood cancer.

Rapid advances have been made in the treatment of infertility over the last 30 years following the introduction of in vitro fertilisation and intracytoplasmic sperm injection. Whilst effects of assisted reproductive technology (ART) on birth outcomes are well documented little is known about effects on child health after the neonatal period. Childhood cancer is one area warranting further examination. The hypothesis that cancer in children may be initiated during early fetal development means that events leading up to and around conception may be important. Whilst the few large-scale epidemiological studies that have looked at childhood cancer incidence following ART have failed to find any significant increased risk, some case-control studies have reported an increased risk of specific cancers. However, it is important not to over interpret these findings as the reason for the infertility may be the predisposing factor, rather than the procedure itself. Recent recommendations by the UK's National Health Service to offer intra-uterine insemination and one free treatment cycle for infertile couples will result in increasing numbers of children born following ART. More detailed investigations that include larger numbers plus sufficient follow-up periods and information on the underlying causes of the infertility are needed since long term outcomes for these children, in particular the risk of developing cancer, remain largely unknown.

Adult↗
PubMedDate not supplied

Males with subnormal hypo-osmotic swelling test scores have lower pregnancy rates than those with normal scores when ovulation induction and timed intercourse is used as a treatment for mild problems with sperm count, motility, or morphology.

This study was designed to evaluate the effectiveness and clinical usefulness of the hypo-osmotic swelling (HOS) test in predicting successful conception in couples in which men with mild male-factor infertility criteria were undergoing a timed vaginal inter-course protocol. One hundred couples, in which mild male infertility was the only abnormality, were included in the study. Semen was analyzed according to standard World Health Organization (WHO) criteria and subjected to the HOS test. Patients were divided into 2 groups: group 1 (n=39) with normal HOS test and group 2 (n=61) with abnormal HOS test. All women underwent three consecutive cycles of follicular growth ultrasound monitoring and timed intercourse. Ten couples were exclude from the study. Ten clinical pregnancies were achieved in group 1 with a pregnancy rate per patient and per cycle of 28.5% and 9.5%, respectively. In group 2, 6 pregnancies were achieved, with a pregnancy rate per patient and per cycle of 10.9% and 3.6%, respectively. Both pregnancy rates per patients and per cycle was significantly higher (P <.05) in group 1 than in group 2. The HOS test may be considered an easy and reliable test in identifying among subfertile men those who have a greater possibility of causing pregnancy.

Adult↗
PubMed1993

Fibrinolytic parameters in women undergoing ovulation induction.

OBJECTIVE: The purpose of this study was to evaluate the effect of elevated levels of circulating estradiol on the clotting and fibrinolytic system in patients undergoing controlled ovarian hyperstimulation. STUDY DESIGN: Fifty-two patients undergoing controlled ovarian hyperstimulation with human menopausal gonadotropins or urofollotropin were asked to participate. Blood for hemostasis parameters was obtained on the days that patients returned for estradiol sampling. Sample days were identified as cycle days 1 to 5 (baseline), 6 to 9, and 10 to 14. Each factor was analyzed by repeated-measures analysis of variance and correlation analysis. RESULTS: A significant decline was observed for tissue plasminogen activator antigen and plasminogen activator inhibitor type 1 activity from baseline to cycle days 10 to 14. As serum estradiol levels increased throughout each phase (maximum mean estradiol 739.8 pg/ml), a significant linear decrease was observed for both tissue plasminogen activator antigen and plasminogen activator inhibitor type 1 activity, whereas thrombin-antithrombin III complexes did not change significantly. A significant positive correlation was also observed for plasminogen activator inhibitor activity and tissue plasminogen activator antigen level over all cycle days examined. CONCLUSION: Down-regulation of the fibrinolytic system was observed as estradiol levels increased. However, thrombin formation did not change, thus suggesting that elevated circulating estradiol alone does not predispose to a thromboembolic event.

Adult↗
PubMed1995

Effect of ovulation induction on uterine blood flow and oestradiol and progesterone concentrations in early pregnancy.

To determine if oestradiol and progesterone concentrations are related to uterine blood flow in early pregnancy, we measured these hormones at the time of vaginal Doppler ultrasound before and after the beginning of intervillous circulation in spontaneous pregnancy (group I), after clomiphene citrate administration (group II), and after clomiphene citrate plus human menopausal gonadotrophin (HMG) administration (group III). Despite large increases of oestradiol concentration in group II (60%) and III (300%) and of progesterone in groups II (100%) and III (300%), compared with group I, increases in blood flow were modest during the first 9 weeks of gestation. Uterine artery flow volume increased by 20% in group II and 33% in group III (P < or = 0.02); average velocity increased by 37% in group III (P < or = 0.003) compared with groups I and II; vessel diameter increased by 15% in groups II (P < 0.025) and III (P < 0.001) compared with group I; and the uterine artery resistance index decreased by 3 to 5% in group III (P = 0.004) compared with groups I and II. Serum oestradiol and progesterone concentrations were unrelated to the uterine artery resistance index or volume by an analysis of covariance. We conclude that uterine artery blood flow is significantly increased during early pregnancy following HMG administration, and that the increase is unrelated to increases in oestradiol and progesterone concentrations.

Blood Flow Velocity↗
PubMed1997

Early prediction of ovarian multifollicular response during ovulation induction in patients with polycystic ovary syndrome.

OBJECTIVE: To examine the association between the midfollicular FSH-LH ratio and the number of follicles, and the multifollicular ovarian response to gonadotropin stimulation in patients with polycystic ovary syndrome (PCOS) with normal basal LH and FSH levels. SUBJECT(S): Eighteen patients who had an abandoned treatment cycle because of multifollicular ovarian response. For comparison, all other completed treatment cycles in the same group of patients were used. MAIN OUTCOME MEASURE(S): The dose of hMG or FSH, daily effective dose, day 8 serum FSH and LH concentration, day 8 number of follicles > or = 8 mm, E2 and number of follicles on hCG day or day of cycle was abandoned. RESULT(S): In the abandoned cycles, day 8 serum LH concentrations were significantly lower and day 8 number of follicles and FSH-LH ratios were significantly higher compared with the completed cycles. A high predictive power (> 90%) for multifollicular response was established by using a set of two criteria: a FSH-LH ratio > or = 1.6 and the number follicles > or = 7 as the cutoff point. CONCLUSION(S): When aiming for a monofollicular response in women with PCOS and normal basal FSH and LH levels, cycles with high midfollicular FSH-LH ratios (> or = 1.6) and a high number of follicles (> or = 7) are those prone to develop a multifollicular ovarian response.

Adult↗
PubMed1987

Pulsatile intravenous gonadotropin-releasing hormone for ovulation-induction in infertile women. II. Analysis of follicular and luteal phase responses.

Pulsatile intravenous gonadotropin releasing hormone (IV-GnRH) was used in 36 infertile patients with primary amenorrhea (n = 5), secondary amenorrhea due to hypothalamic chronic anovulation (HCA) (n = 22), hyperprolactinemia (n = 1) or polycystic ovary syndrome (PCOS) (n = 5), and oligomenorrhea (n = 3), using several dosage and timing regimens. Early follicular phase responses showed four patterns: type 1 consisted of a delayed follicle-stimulating hormone (FSH) peak and was seen with severe hypothalamic suppression (n = 4); type 2 consisted of a brisk and dominant FSH peak on the first day of treatment, and occurred with mild to moderate hypothalamic suppression (n = 19); type 3, which consisted of an FSH peak accompanied by an immediate and exaggerated luteinizing hormone (LH) rise, occurred with mild PCOS and some cases of HCA (n = 5); and type 4, in which LH levels were high to begin with and neither FSH nor LH levels rose with GnRH, occurred with severe PCOS (n = 2). Exaggerated estradiol responses within 24 hours of therapy were seen in eight cycles: in four cases no ovarian abnormality was apparent; in three cases a dominant follicle was already present; and in one case ovarian hyperstimulation was diagnosed ultrasonographically. With standard human chorionic gonadotropin luteal phase support, luteal phase defects were rare with HCA but common with PCOS.

Estradiol↗
PubMed2002

Clinical and endocrine effects of ovulation induction with FSH and hCG supplementation in low responders in the midfollicular phase. A pilot study.

OBJECTIVE: To assess the endocrine and clinical effects of luteinizing hormone (LH) activity supplementation administered in the midfollicular phase during controlled ovarian hyperstimulation to poor responders who were candidates for in vitro fertilization (IVF)--embryo transfer. STUDY DESIGN: Prospective, controlled, nonrandomized trial with historical controls. Twenty-five IVF patients who had shown a poor response to standard, long-protocol GnRH-a and FSH only in a preceding cycle (cycle A), were stimulated in the next cycle after six months with hCG supplementation (50 I.U. subcutaneously daily) starting on day 7 during standard, long-protocol GnRH-a and FSH (cycle B). The comparative analysis of clinical effects (duration of stimulation, total highly purified (HP)-FSH dose, number of oocytes retrieved and pregnancy rate) and endocrine responses (serum E2, follicular E2 and androstenedione levels) were determined between cycles A and B. RESULTS: Maximum serum E2 levels and clinical pregnancy rate were higher in cycle B, with hCG supplementation. Also, the follicular E2 and androstenedione levels were higher in cycle B. No differences were noted between cycles as regards the duration of stimulation, total HP-FSH dose and number of oocytes retrieved. CONCLUSION: LH activity supplementation in the midfollicular phase yields favorable pregnancy results in low responders. This may be due to enhanced release of follicular precursors for greater synthesis of E2.

Chorionic Gonadotropin↗
PubMed2006

HMG versus rFSH for ovulation induction in developing countries: a cost-effectiveness analysis based on the results of a recent meta-analysis.

Both cost and effectiveness should be considered conjointly to aid judgments about drug choice. Therefore, based on the results of a recent published meta-analysis, a Markov model was developed to conduct a cost-effectiveness analysis for estimation of the cost of an ongoing pregnancy in IVF/intracytoplasmic sperm injection (ICSI) cycles. In addition, Monte Carlo micro-simulation was used to examine the potential impact of assumptions and other uncertainties represented in the model. The results of the study reveal that the estimated average cost of an ongoing pregnancy is 13,946 Egyptian pounds (EGP), and 18,721 EGP for a human menopausal gonadotrophin (HMG) and rFSH cycle respectively. On performing a sensitivity analysis on cycle costs, it was demonstrated that the rFSH price should be 0.61 EGP/IU to be as cost-effective as HMG at the price of 0.64 EGP/IU (i.e. around 60% reduction in its current price). The difference in cost between HMG and rFSH in over 100,000 cycles would result in an additional 4565 ongoing pregnancies if HMG was used. Therefore, HMG was clearly more cost-effective than rFSH. The decision to adopt a more expensive, cost-ineffective treatment could result in a lower number of cycles of IVF/ICSI treatment undertaken, especially in the case of most developing countries.

Cost-Benefit Analysis↗
PubMed2003

Use of recombinant human chorionic gonadotropin in ovulation induction.

To review the use of hCG and to describe the clinical benefit of recombinant hCG (r-hCG) based on the published results of prospective, randomized studies. Review of published articles. Tertiary infertility care center.None.None. Oocyte number and quality, luteal phase progesterone, pregnancy and OHSS rate, and local tolerability. The published data consistently show that single doses of 250 microg r-hCG and 5,000 IU urinary (u)-hCG produce similar clinical outcomes when used in infertility treatment cycles for timed intercourse, IUI, and IVF in terms of the number of oocytes retrieved, number of mature oocytes harvested, and fertilization and pregnancy rates attained. Single doses of 10,000 IU u-hCG also gave results comparable to single doses of 250 microg r-hCG. P levels in the midluteal phase were significantly higher with the use of r-hCG compared with u-hCG, and local injection site adverse effects were significantly less frequent, demonstrating the higher purity of the recombinant product. A single 500-microg dose of r-hCG led to a higher rate of ovarian hyperstimulation syndrome compared with a 250-microg dose, with no significant improvement in pregnancy rates.A single dose of 250 microg r-hCG was at least as effective as single doses of 5,000 or 10,000 IU u-hCG but offered the advantages associated with use of a recombinant product: local injection site adverse effects were significantly less frequent with r-hCG than with u-hCG.

Chorionic Gonadotropin↗
PubMed1999

Poor responders to ovulation induction: is proceeding to in-vitro fertilization worthwhile?

A 'poor response' in the context of in-vitro fertilization (IVF) can be defined as failure to produce an adequate number of mature follicles, and/or a peak oestradiol concentration less than a defined minimum. The cut-off points implied in this definition vary between different centres. Many opt to cancel the IVF cycle when their defined minimum concentrations are not reached despite the lack of evidence of improved outcome in subsequent cycles. Patients attending the Oxford Fertility Unit who are 'poor responders' have always been given the option of continuing with treatment. The first cycles of IVF in 124 patients, with normal day 3 follicle stimulating hormone (FSH), who produced less than five follicles within a 2 year period were studied. The patients were divided into three groups according to the number of follicles produced: A (one or two follicles; n = 33), B (three follicles; n = 33) and C (four follicles; n = 58). The three groups were similar in age, day 3 FSH, total gonadotrophin dose, duration of stimulation, peak oestradiol concentration, oocyte yield, fertilization rate and the clinical pregnancy rate. However, group A had a significantly higher oestradiol concentration per follicle (P < 0.001). The clinical pregnancy rate/cycle in the three groups was comparable to our overall rate in the study period (25.5%). This paper suggests that poor responders with a normal day 3 FSH may still achieve a pregnancy rate similar to that of normal responders.

Adult↗
PubMed2005

Oral ovulation induction agents combined with low-dose gonadotropin injections and intrauterine insemination: cost- and clinical effectiveness.

OBJECTIVE: To compare the efficacy and cost-effectiveness of different induction protocols involving gonadotropins with intrauterine insemination (IUI). STUDY DESIGN: We performed a retrospective chart review of 648 IUI cycles. Some patients had gonadotropin injections alone before human chorionic gonadotropin (hCG) and IUI (human menopausal gonadotropin protocol); others were given oral medications, then gonadotropins before hCG and IUI (combination protocol). Outcomes included pregnancy rates, multiple birth rates, endometrial thickness, number of ovarian follicles, injection days, ampules of gonadotropins and cost. RESULTS: The combination protocol was more cost-effective. In first cycles, pregnancy rates, multiple birth rates, number of large follicles produced and cancellation rates were similar. The combination group had fewer days of injections and fewer ampules used. When all cycles were analyzed, the multiple birth rate was lower in the combination group. Comparing the different oral medications in the combination protocols, letrozole yielded higher pregnancy rates than tamoxifen or clomiphene. Multiple birth rates were similar for all oral medications. CONCLUSION: Combination protocols are less costly and equally effective, with potentially fewer multiple births than with gonadotropins alone. Letrozole may be more effective than clomiphene and tamoxifen in a combination protocol.

Administration, Oral↗
PubMed1994

Simplification of IVF: minimal monitoring and the use of subcutaneous highly purified FSH administration for ovulation induction.

During the past few years much effort has been put into simplifying the clinical management of in-vitro fertilization/embryo transfer cycles. One important step was the introduction of transvaginal ultrasound-guided oocyte collection, as previously described. This study describes further simplifications of the clinical management of ovarian stimulation. During the period 1st January 1991 to 31st August 1993, three major simplification steps were introduced. All cycles were down-regulated with a gonadotrophin-releasing hormone (GnRH) agonist according to a long protocol permitting fairly precise programming of the oocyte collection. During period I (n = 329 cycles), closer monitoring by several pelvic ultrasound scans and serum oestradiol was used for monitoring the ovarian stimulation. During period II (n = 230 cycles), only one ultrasound scan was used for monitoring the ovarian cycle; oocyte collections during weekends were avoided. During period III (n = 386 cycles), further simplification of the clinical management was introduced by using a highly purified follicle stimulating hormone (FSH) (Fertinorm/Metrodin HP), which was self-administered s.c. for ovarian stimulation. The take-home baby rates per started cycle for periods I, II and III were 16.4, 32.6 and 31.3% respectively. These figures indicate that when using long down-regulation with a GnRH agonist, simplification of the monitoring of the ovarian stimulation is possible without decreasing the pregnancy rate. Furthermore, the use of a highly purified FSH, self-administered s.c., greatly simplified treatment without compromising cycle outcome or increasing the risk of developing an ovarian hyperstimulation syndrome.

Adult↗
PubMed1984

One ovary or two: differences in ovulation induction, estradiol levels, and follicular development in a program for in vitro fertilization.

The choice of clomiphene citrate (CC) and human menopausal gonadotropin (hMG) protocols for stimulation of ovarian follicular maturation has traditionally not been made with regard to the anatomic status of the pelvis. To evaluate whether hormone production and/or follicular development vary based on the number of ovaries and/or the method of stimulation, 117 cycles were reviewed. Forty-five women received CC, 29 with two ovaries and 16 with one ovary. Seventy-two women received hMG, 50 with two ovaries and 22 with one ovary. Among women receiving CC, those with two ovaries tended to have higher initial estradiol levels and a greater number of large (greater than or equal to 15 mm) follicles. Among women receiving hMG, those with two ovaries tended to have higher estradiol levels, but the number of large follicles (greater than or equal to 15 mm) was similar. With either stimulation protocol, women with two ovaries developed a higher total number of follicles than women with one ovary. The total number of follicles in women with one ovary was similar for hMG and CC stimulations. The number of oocytes recovered at laparoscopy was greater in women with two ovaries who received hMG in comparison with CC, but did not significantly vary between women with one or two ovaries who received CC nor between women with one or two ovaries who received hMG. The number of oocytes was also similar for the women with one ovary regardless of stimulation protocol.

Castration↗
PubMed2004

Ovulation induction with urinary FSH or recombinant FSH in polycystic ovary syndrome patients: a prospective randomized analysis of cost-effectiveness.

The aim of this prospective, randomized trial was to compare the clinical results and the cost-effectiveness of urinary FSH (uFSH) and recombinant FSH (rFSH) in ovarian stimulation for intrauterine insemination (IUI) cycles in polycystic ovary syndrome (PCOS) patients. One-hundred and seventy PCOS infertile patients undergoing IUI were enrolled, and protocols of ovarian stimulation with uFSH or rFSH were randomly assigned. The total number of cycles performed was 379 (182 and 197, respectively). The main outcome measures were the number of mature follicles, the days of stimulation, the number of ampoules and IU used per cycle, the biochemical/clinical pregnancy rates, the number of multiple pregnancies and the cost-effectiveness. No statistically significant differences were found in the follicular development, length of stimulation, pregnancy rates, delivery rates and multiple pregnancies between the two groups. In the uFSH group, the cost per cycle remained significantly lower (218.51 +/- 88.69 versus 312.22 +/- 118.12; P < 0.0001), even though a significantly higher number of IU of gonadotrophins were used (809.3 +/- 271.9 versus 589.1 +/- 244.7; P < 0.0001). The cost-effectiveness (i. e. within a group, the total cost of all cycles divided by no. of clinical pregnancies) was 1729.08 in the uFSH group and 3075.37 in the rFSH group. In conclusion, uFSH and rFSH demonstrated the same effectiveness in ovarian stimulation in IUI cycles in PCOS patients. The urinary preparation is more cost-effective due to the difference of its cost per IU.

Adult↗