Infertility Treatment: Public Health and Primary Care Perspectives Joseph B. Stanford, MD, MSPH Division of Epidemiology, Statistics, and Prevention Research National Institute of Child Health and Human Development Department of Health and Human Services 2005/11/17 1

Outline Definition Incidence and Prevalence Public Health Issues Primary Care Issues Evaluation and Treatment Options Effectiveness Research Suggestions (Clinical case study)

Definition: infertility Inability to conceive despite 1 year of intercourse without contraception. “Trying”? Cycles “at risk”? Excludes incomplete or sporadic use of contraception Primary: no previous pregnancy Secondary: previous pregnancy Syndrome, not diagnosis!

Related (confused) terms Infertility Subfertility Sterility Infertility + recurrent miscarriage = subfecundity (epidemiology) Or visa versa (demography)

Definition: infertility What about spontaneous abortion? Most definitions of infertility do not include recurrent miscarriage Association between infertility and miscarriage From clinical and public health standpoints, the pertinent issue is inability to have a live birth.

Definition: infertility WHO recommends 2 years Ongoing discussion in the literature about optimal definition- multidimensional? Time, (presumed) etiology, prognosis Infertility plus impaired fecundity Some are suggesting a new definition: 6 months of adequately timed intercourse. Within 6-day fecund window prior to and including ovulation.

Dunson, Colombo et al, Obstet Gynecol 2004 Estimated time to pregnancy by age of woman PER CYCLE RATE IS NOT APPROPRIATE FOR NATURAL HISTORY, NOR FOR TREATMENT

Couple Heterogeneity Normal fertility/infertility not a dichotomous state

Etiology of Infertility Male Factors 30-50% Ovarian Causes 30-70% PCOS 15-30% Age, Diminished Reserve ? Anatomic Obstruction 20-30% Endometriosis 5-75% Mucus Factors 5-80% Coital Issues 5-10% Luteal Phase Defects 10-55% Lifestyle issues 10-40% Unexplained 10-30%

Etiology of Infertility Wide variation in diagnostic evaluation Strong trend towards minimal evaluation! Issue of cause versus association of diagnostic abnormalities e.g., male factor Multiple factors are common Prioritization, classification? Independent, or reflect underlying process? e.g., limited cervical mucus and ovarian dysfunction

Incidence Incidence German study (2004): 10.4% 1 year trying and “at risk” Population basis: unknown

Prevalence: Ascertainment One (two) year(s) sexually active without contraception One (two) year(s) trying Consulted physician Physician diagnosed problem Self-report of difficulty conceiving

Prevalence Marchbanks: 6-33% lifetime prevalence USA age-adjusted, n=4754, early 1980s Larsen: 6-12% point prevalence Northern Tanzania, n=1125, 2003 Developed countries: 5-21% 1970s-80s

Prevalence- NSFG, USA 1982 1988 1995 2002 12-month infertility 8.5 7.9 7.1 7.4 Impaired fecundity 10.8 10.7 12.9 15.1

Public Health Issues Delaying of initial childbearing Reduction in fecundity Over 35: immediate evaluation and treatment Time pressure and sense of crisis May extend to younger ages

Public Health Issues Treatment of age-related infertility is a race against a biologic time clock, rather than treatment of an underlying disorder. “Except for oocyte donation, [treatments for age-related infertility] are intended to accelerate the time to conception rather than directly affect oocyte or embryo quality.” ASRM 2004, emphasis added

Infertility: Lifestyle risk factors Alcohol Tobacco Up to 13% attributable risk Also impairs ART treatment Caffeine Marijuana, Cocaine Odds ratios 1.2 to 2.0

Infertility: Risk factors Sexually transmitted infection Chlamydia 20-90% sensitivity for tubal occlusion Pelvic inflammatory disease Overweight Ovulatory infertility (RR 2-3) PCOS Underweight Ovulatory infertility (RR 1.5-4.5)

Infertility as a Risk Factor Woman Diabetes, cardiovascular (PCOS) Pelvic pain and GI problems (endometriosis) Endometrial, ovarian, breast cancer (hormonal) Pregnancy Miscarriage Prematurity, pre-ecclampsia, gestational diabetes Man (?) Child

Public Health Issues Access to care Providers Insurance coverage Approximately 400 ART centers USA (2000) Approximately 100,000 ART procedures 7.9 million women with fertility problems 19,750 women per center 0.013 procedures per woman

Public Health Issues Rapid development and adoption of new treatments Beyond initial indications Although the rapid and widespread introduction of IVF, ICSI, and related technologies into the clinic has been technology-driven rather than evidence-based, ART has become the gold standard with which other treatments are compared…ART has become widely used without comprehensive assessment of its efficacy and safety. JL Evers, Lancet, 2002

Public Health Issues Cost IVF over $12,000 per cycle (average)

Public Health Issues Multiple gestation Multiple gestation- iatrogenic Twins increased 50% from 1980-2001 Higher older multiples increased 4x from 1980-2001 Estimated 70% due to ART and ovulation induction Pressure to maximize per-cycle success incentivizes multiple embryo transfers in ART and superovulation in ovulation induction without ART

Public Health Issues Adverse outcomes of ART, independent of multiple gestation Low birth weight Prematurity Perinatal mortality Birth defects (9% versus 4%) Aneuploidy (1-2%) Angelman’s syndrome (rare, but increased) Others?

Public Health Issues What are optimal evaluation and treatment strategies for infertility? Is ART currently over-used or under-used?

Primary Care Issues Common problem Couples problem- both woman and man Chronic condition Chronic versus acute disease management model Lifestyle and preconception issues Psychosocial dimensions Cultural, ethical, and cost issues Importance of patient preferences and values

Levels of care for infertility Prevention Primary detection, basic medical evaluation, and management Secondary full medical evaluation and management Tertiary medical management

A rational and complete approach to infertility needs to address it at the levels of public prevention and primary care as much as at the tertiary care level.

Evaluation and Treatment Options Assisted Reproductive Technology (ART) Bypass one or more parts of the natural process and perform it in the lab, “in vitro” Natural Procreative Technology (NPT) Restore or establish natural reproductive function fertilization occurs in vivo from sexual intercourse

Infertility Treatment Options Assisted Reproductive Technology Artificial insemination (partner or donor) Super-ovulation, usually with artificial insemination In vitro fertilization Intracytoplasmic sperm injection (ICSI)

Infertility Treatment Options Restore or establish natural reproductive function Disease-specific treatment eg, treat polycystic ovarian disease, thyroid disease, correct anatomical abnormalities Ovulation induction, correction of follicular and luteal hormonal/functional deficiencies Fertility tracking Systematic approach: NPT

Natural Procreative Technology (NPT) A systematic approach to normalize and optimize reproductive function in women and men. Components Health education: Creighton NaPro Tracking Biomarkers: vaginal bleeding and mucus discharge Medical evaluation and management Surgical correction of anatomic abnormalities, if indicated

www.naprotechnology.com

Creighton Model NaPro Tracking: Vaginal discharge biomarkers Highly correlated with ovulation Changes precede ovulation Maximizes time available for intercourse to try to conceive Gives information about sperm survival Easily observed by women 3

Estrogen/Progesterone curves

Type E and G mucus at cervix

Fertility Charting of Vaginal Discharge (Creighton Model NaProTracking)

What are the best days to conceive?

Probability of Clinical Pregnancy

Creighton Model NaPro Tracking is optimal for timing intercourse to achieve pregnancy. AND it provides key information to guide diagnostics and adjust therapy.

They are as much an expert in their own fertility as is the doctor. NaProTracking makes the couple an equal participant in their own fertility evaluation and treatment. They are as much an expert in their own fertility as is the doctor.

NPT Use NaPro Tracking to time diagnostic tests accurately hormone levels, endometrial biopsy follicular ultrasound Use NaPro Tracking to time treatments to improve ovulatory function and cervical mucus production, and to monitor and adjust treatment. Goal is to facilitate in vivo conception over 12 effective cycles.

NPT Infertility Protocol Initial Medical Consultation NaProTracking for 2 cycles Blood Tests & Seminal fluid analysis Medical Review - 3rd or 4th cycle Basic Anatomic Evaluation +/- Ultrasound Follicle Tracking Consider Diagnostic Laparoscopy - 6th cycle 12 effective cycles of medical treatment

Illustrative CrM cycles in infertility

Irish clinic diagnoses ART vs. NPT (n=95)

Twelve effective cycles Adequate mucus flow (CrM chart) Repeated intercourse during days with mucus flow (fertile days) (CrM chart) Optimal progesterone and estradiol levels on 7th day after peak (CrM chart) Attention to manage stress appropriately Other medical/surgical issues identified and addressed (CrM chart)

Case History

Case #1 26 y/o P0010, previous SAB in 2 years’ trying BMI 18.2, healthy habits, no comorbid conditions Usual cycles 40-45 days Husband good health No STDs or GYN surgeries Normal exam

Case #1 Previous evaluations Normal FSH and LH Low progesterone level on “day 21” Normal semen analysis and HSG Previous treatments 6 cycles of clomid, hCG injections, AIHS, luteal PG Resulted in one pregnancy with SAB IVF was recommended as next step

Case #1 Recommended: CrM NaPro Tracking optimal timing of intercourse Vitamin B6 to enhance mucus production Timed hormonal evaluation, based on charting Fasting serum insulin and glucose Follicular ultrasound series

Case #1 Results NaPro Tracking- limited mucus pattern Good timing of intercourse Severe PG and E2 deficiency in luteal phase Fasting serum insulin- normal Follicular ultrasound series- slightly small follicle prior to rupture, no PCO on US

Case #1 Recommended Support of luteal phase with postpeak hCG injections, 2000 Units IM on peak +3, 5, 7, 9 Continue vitamin B6 Continue fertility-focused intercourse Reassess after 2 cycles of hCG support

Case #1 Results On second cycle of postpeak hCG injections, she conceived At 5 weeks EGA, she felt like she was going to miscarry. The progesterone level was very low. Progesterone was given IM twice a week and tapered as her levels returned to normal. She delivered a healthy baby girl at 39.5 wks EGA

Effectiveness

Outcomes Positive Negative Cost effectiveness Pregnancy: “chemical” or “clinical” Live birth Negative Multiple birth rates Prematurity Neonatal and childhood morbidity Cost effectiveness

Comparison of approaches Per cycle Multiple unmeasured confounders of selection Assumes per cycle probability same in early and late cycles Inherent bias towards intense, invasive, costly approaches (generally ART) Cohort More realistic comparison of treatments of different types, including NFP-based and ART RCT ideal, but rare (except within method)

Selection Those who present for treatment. Those whom the clinic agrees to treat. Age, diagnosis, and morbidity mix can greatly affect a clinic’s success rates.

Natural history of infertility 2198 couples seen at 11 academic infertility clinics in Canada 1984-87 873 never treated; 1325 delayed treatment Life table analysis of probability of conception leading to live birth at 12 months without treatment: 14.3% A mean per cycle pregnancy rate of 1.2% Other studies: 10-20% over 1 year

Natural history of infertility Age Female…and male Primary versus secondary Diagnosis Most favorable: unexplained Least favorable: azospermia, tubal obstruction Length of time infertile or attempting per cycle assumption does not hold!

Cohort Crude rates- include in denominator those who drop out of treatment who may have gotten pregnant with treatment Lifetables- assume that those dropping out of treatment have same prognosis with treatment as those continuing treatment Time unit? Treatment cycles versus chronological time ART is intensive and cycle-based Restorative approaches (like NPT) are not

U.S. National Registry of ART Clinics All data in terms of treatment cycles Unknown number of women, cycles per woman, or centers per woman 74,957 cycles with fresh nondonor eggs 64,280 retrievals, 60,299 transfers, 23,042 pregnancies, 19,042 live births 38% pregnancy per transfer 25% live birth per cycle of treatment

UU Cohort Study Peterson, Hatasaka, Jones, Poulson, Carrell, Urry Nonrandomized study UU patients 1990-1991 Mean age about 33 years Mean duration trying about 4 years From UU patients 1990-91 3 groups Ovulation induction/artificial insemination, up to 4 cycles (27) In vitro vertilization (1 cycle) (19) No treatment (21)

UU Cohort Study crude LT OI/AI at 1 cycle .09 .09 OI/AI at 2 cycles .26 .30 OI/AI at 3 cycles .30 .41 OI/AI at 4 cycles .32 .53 IVF .26 .26 Observation .14 .14

Very few RCTs of IVF For unexplained infertility No difference between 1 cycle IVF and 6 months no treatment (1 small trial) No difference between IVF and IUI (1 trial) “The effectiveness of IVF relative to other treatment options for unexplained infertility remains unproven. Adverse events and the costs associated with the interventions compared have not been adequately assessed. ” Pandian Z, Bhattacharya S, Nikolaou D, Vale L, Templeton A.. In vitro fertilisation for unexplained subfertility (Cochrane Review). In: The Cochrane Library , Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd.

Other Cohort Data A few studies have reported cumulative lifetables based on cycles of treatment Tan et al 1994 (5 IVF cycles) Crude rate 31% Life table 69% Guzick et al 1986 (6 IVF cycles) Crude rate 27% Life table 60%

Stolwijk et al 1996 Estimated adjusted life table rates Assigned those discontinuing to a good prognosis or a poor prognosis Crude rate 29.5 Traditional life table 56.0 Adjusted life table 34.4

Effectiveness in infertility Per cycle success rates are not appropriate for NPT Can be misleading for any infertility treatment Cohort-based measures are appropriate. Crude rates will underestimate effectiveness. Traditional life tables will overestimate effectiveness to an unknown extent. How about infertility? First I note some important issues in comparing CrM approaches to conventional approaches, such as assisted reproductive techniques, such as in vitro fertilization. The usual way of measuring success with IVF is on a per cycle basis. This is an inappropriate way to measure success rates for CrM. I argue that it is biased and inappropriate for IVF as well. The most appropriate measures are cohort-based measures, both for CrM and other infertility treatments. Of the cohort-based measures, crude rates will underestimated effectiveness, because of drop outs. Traditional life tables will overestimate effectiveness, also because of dropouts. However, this kind of overestimation will probably happen more for IVF than it will for CrM.

Irish NPT Study Over 1239 couples Average Female age 36.1 yrs. Entered treatment Feb. 1998 through Jan. 2002 Average Female age 36.1 yrs. Average time trying to conceive 5.2 yrs. 28.6% with history of unsuccessful IVF

Irish NPT Study Crude live birth rate 25.5 Lifetable live birth rate 46.3 Lifetable is at 24 months, which corresponds roughly to 12 effective cycles.

Irish NPT Study No prior IVF crude LT Prior failed IVF Age <= 37 yrs 32.0 53.6 Age >=38 yrs 20.3 43.8 Prior failed IVF Age <= 37 yrs 21.6 38.8 Age >=38 yrs 15.1 25.3

NPT neonatal morbidity Preterm birth rate <6% Low birth rate <8%

NPT Twins 4.1 %, compared with 28% IVF (HFEA) Less prematurity, low birth weight, morbidity, mortality and cost

Comments NPT cohort pregnancy rates (crude and lifetable) similar to IVF cohort studies. Crude rates underestimate success; lifetable rates overestimate NPT takes more time than IVF, but is far less costly, and has much lower rates of prematurity and neonatal morbidity.

Research Suggestions Population-based cohorts for incidence and longitudinal outcomes of infertility, with and without treatment Clinic-based cohort for factors associated success with NPT treatment Randomized trial of NPT treatment

Take home points Infertility is a health syndrome that can, and should be addressed in the realm of public health and primary care, integrated with specialty care. Infertility should be investigated within the broader context of the health of women, men, and offspring. 2

Take home points Infertility should be treated as a chronic health condition, rather than as an acute health condition. Infertility should be addressed in a rational, stepped-care approach that integrates prevention, primary, secondary, and tertiary care, respecting patient preferences. An “all or nothing” approach should be discouraged. 2

Take home points Research on infertility should address a balanced spectrum of prevention, incidence, diagnosis, treatment, and outcomes. Natural procreative technology offers one possibility for an integrated diagnostic and treatment strategy in primary care. 2

Acknowledgments Dr. Phil C. Boyle, Ireland Dr. Tracey Parnell, Canada Dr. Thomas W. Hilgers, USA Dr. Estella Parrott, RSB, CPR, NICHD Drs. Germaine Buck Louis, Mark Klebanoff, and DESPR, NICHD