Presentation on theme: "Infertility Treatment: Public Health and Primary Care Perspectives"— Presentation transcript:
1 Infertility Treatment: Public Health and Primary Care Perspectives Joseph B. Stanford, MD, MSPHDivision of Epidemiology, Statistics,and Prevention ResearchNational Institute of Child Healthand Human DevelopmentDepartment of Health and Human Services2005/11/171
2 Outline Definition Incidence and Prevalence Public Health Issues Primary Care IssuesEvaluation and Treatment OptionsEffectivenessResearch Suggestions(Clinical case study)
3 Definition: infertility Inability to conceive despite 1 year of intercourse without contraception.“Trying”?Cycles “at risk”?Excludes incomplete or sporadic use of contraceptionPrimary: no previous pregnancySecondary: previous pregnancySyndrome, not diagnosis!
4 Related (confused) terms InfertilitySubfertilitySterilityInfertility + recurrent miscarriage = subfecundity (epidemiology)Or visa versa (demography)
5 Definition: infertility What about spontaneous abortion?Most definitions of infertility do not include recurrent miscarriageAssociation between infertility and miscarriageFrom clinical and public health standpoints, the pertinent issue is inability to have a live birth.
6 Definition: infertility WHO recommends 2 yearsOngoing discussion in the literature about optimal definition- multidimensional?Time, (presumed) etiology, prognosisInfertility plus impaired fecunditySome are suggesting a new definition: 6 months of adequately timed intercourse.Within 6-day fecund window prior to and including ovulation.
7 Dunson, Colombo et al, Obstet Gynecol 2004 Estimated time to pregnancy by age of womanPER CYCLE RATE IS NOT APPROPRIATE FOR NATURAL HISTORY, NOR FOR TREATMENT
8 Couple HeterogeneityNormal fertility/infertility not a dichotomous state
10 Etiology of Infertility Wide variation in diagnostic evaluationStrong trend towards minimal evaluation!Issue of cause versus association of diagnostic abnormalitiese.g., male factorMultiple factors are commonPrioritization, classification?Independent, or reflect underlying process?e.g., limited cervical mucus and ovarian dysfunction
11 Incidence Incidence German study (2004): 10.4% 1 year trying and “at risk”Population basis: unknown
12 Prevalence: Ascertainment One (two) year(s) sexually active without contraceptionOne (two) year(s) tryingConsulted physicianPhysician diagnosed problemSelf-report of difficulty conceiving
13 Prevalence Marchbanks: 6-33% lifetime prevalence USA age-adjusted, n=4754, early 1980sLarsen: 6-12% point prevalenceNorthern Tanzania, n=1125, 2003Developed countries: 5-21%1970s-80s
16 Public Health Issues Delaying of initial childbearing Reduction in fecundityOver 35: immediate evaluation and treatmentTime pressure and sense of crisisMay extend to younger ages
17 Public Health IssuesTreatment 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
18 Infertility: Lifestyle risk factors AlcoholTobaccoUp to 13% attributable riskAlso impairs ART treatmentCaffeineMarijuana, CocaineOdds ratios 1.2 to 2.0
20 Infertility as a Risk Factor WomanDiabetes, cardiovascular (PCOS)Pelvic pain and GI problems (endometriosis)Endometrial, ovarian, breast cancer (hormonal)PregnancyMiscarriagePrematurity, pre-ecclampsia, gestational diabetesMan (?)Child
21 Public Health Issues Access to care Providers Insurance coverage Approximately 400 ART centers USA (2000)Approximately 100,000 ART procedures7.9 million women with fertility problems19,750 women per center0.013 procedures per woman
22 Public Health Issues Rapid development and adoption of new treatments Beyond initial indicationsAlthough 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
23 Public Health IssuesCostIVF over $12,000 per cycle (average)
24 Public Health Issues Multiple gestation Multiple gestation- iatrogenic Twins increased 50% fromHigher older multiples increased 4x fromEstimated 70% due to ART and ovulation inductionPressure to maximize per-cycle success incentivizes multiple embryo transfers in ART and superovulation in ovulation induction without ART
25 Public Health IssuesAdverse outcomes of ART, independent of multiple gestationLow birth weightPrematurityPerinatal mortalityBirth defects (9% versus 4%)Aneuploidy (1-2%)Angelman’s syndrome (rare, but increased)Others?
26 Public Health IssuesWhat are optimal evaluation and treatment strategies for infertility?Is ART currently over-used or under-used?
27 Primary Care Issues Common problem Couples problem- both woman and man Chronic conditionChronic versus acute disease management modelLifestyle and preconception issuesPsychosocial dimensionsCultural, ethical, and cost issuesImportance of patient preferences and values
28 Levels of care for infertility PreventionPrimary detection, basic medical evaluation, and managementSecondary full medical evaluation and managementTertiary medical management
29 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.
31 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 functionfertilization occurs in vivo from sexual intercourse
32 Infertility Treatment Options Assisted Reproductive TechnologyArtificial insemination (partner or donor)Super-ovulation, usually with artificial inseminationIn vitro fertilizationIntracytoplasmic sperm injection (ICSI)
34 Natural Procreative Technology (NPT) A systematic approach to normalize and optimize reproductive function in women and men.ComponentsHealth education: Creighton NaPro TrackingBiomarkers: vaginal bleeding and mucus dischargeMedical evaluation and managementSurgical correction of anatomic abnormalities, if indicated
36 Creighton Model NaPro Tracking: Vaginal discharge biomarkers Highly correlated with ovulationChanges precede ovulationMaximizes time available for intercourse to try to conceiveGives information about sperm survivalEasily observed by women3
42 Creighton Model NaPro Tracking is optimal for timing intercourse to achieve pregnancy. AND it provides key information to guide diagnostics and adjust therapy.
43 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.
44 NPT Use NaPro Tracking to time diagnostic tests accurately hormone levels, endometrial biopsyfollicular ultrasoundUse 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.
45 NPT Infertility Protocol Initial Medical ConsultationNaProTracking for 2 cyclesBlood Tests & Seminal fluid analysisMedical Review - 3rd or 4th cycleBasic Anatomic Evaluation+/- Ultrasound Follicle TrackingConsider Diagnostic Laparoscopy - 6th cycle12 effective cycles of medical treatment
48 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 appropriatelyOther medical/surgical issues identified and addressed (CrM chart)
50 Case #1 26 y/o P0010, previous SAB in 2 years’ trying BMI 18.2, healthy habits, no comorbid conditionsUsual cycles daysHusband good healthNo STDs or GYN surgeriesNormal exam
51 Case #1 Previous evaluations Normal FSH and LH Low progesterone level on “day 21”Normal semen analysis and HSGPrevious treatments6 cycles of clomid, hCG injections, AIHS, luteal PGResulted in one pregnancy with SABIVF was recommended as next step
52 Case #1 Recommended: CrM NaPro Tracking optimal timing of intercourse Vitamin B6 to enhance mucus productionTimed hormonal evaluation, based on chartingFasting serum insulin and glucoseFollicular ultrasound series
53 Case #1 Results NaPro Tracking- limited mucus pattern Good timing of intercourseSevere PG and E2 deficiency in luteal phaseFasting serum insulin- normalFollicular ultrasound series- slightly small follicle prior to rupture, no PCO on US
54 Case #1RecommendedSupport of luteal phase with postpeak hCG injections, 2000 Units IM on peak +3, 5, 7, 9Continue vitamin B6Continue fertility-focused intercourseReassess after 2 cycles of hCG support
55 Case #1ResultsOn second cycle of postpeak hCG injections, she conceivedAt 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
58 Outcomes Positive Negative Cost effectiveness Pregnancy: “chemical” or “clinical”Live birthNegativeMultiple birth ratesPrematurityNeonatal and childhood morbidityCost effectiveness
59 Comparison of approaches Per cycleMultiple unmeasured confounders of selectionAssumes per cycle probability same in early and late cyclesInherent bias towards intense, invasive, costly approaches (generally ART)CohortMore realistic comparison of treatments of different types, including NFP-based and ARTRCT ideal, but rare (except within method)
60 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.
61 Natural history of infertility 2198 couples seen at 11 academic infertility clinics in Canada873 never treated; 1325 delayed treatmentLife 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
62 Natural history of infertility AgeFemale…and malePrimary versus secondaryDiagnosisMost favorable: unexplainedLeast favorable: azospermia, tubal obstructionLength of time infertile or attemptingper cycle assumption does not hold!
63 CohortCrude rates- include in denominator those who drop out of treatment who may have gotten pregnant with treatmentLifetables- assume that those dropping out of treatment have same prognosis with treatment as those continuing treatmentTime unit?Treatment cycles versus chronological timeART is intensive and cycle-basedRestorative approaches (like NPT) are not
64 U.S. National Registry of ART Clinics All data in terms of treatment cyclesUnknown number of women, cycles per woman, or centers per woman74,957 cycles with fresh nondonor eggs64,280 retrievals, 60,299 transfers, 23,042 pregnancies, 19,042 live births38% pregnancy per transfer25% live birth per cycle of treatment
65 UU Cohort Study Peterson, Hatasaka, Jones, Poulson, Carrell, Urry Nonrandomized study UU patientsMean age about 33 yearsMean duration trying about 4 yearsFrom UU patients3 groupsOvulation induction/artificial insemination, up to 4 cycles (27)In vitro vertilization (1 cycle) (19)No treatment (21)
66 UU Cohort Study crude LT OI/AI at 1 cycle .09 .09 OI/AI at 2 cyclesOI/AI at 3 cyclesOI/AI at 4 cyclesIVFObservation
67 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, Chichester, UK: John Wiley & Sons, Ltd.
68 Other Cohort DataA few studies have reported cumulative lifetables based on cycles of treatmentTan 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%
69 Stolwijk et al 1996 Estimated adjusted life table rates Assigned those discontinuing to a good prognosis or a poor prognosisCrude rate 29.5Traditional life table 56.0Adjusted life table 34.4
70 Effectiveness in infertility Per cycle success rates are not appropriate for NPTCan be misleading for any infertility treatmentCohort-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.
71 Irish NPT Study Over 1239 couples Average Female age 36.1 yrs. Entered treatment Feb through Jan. 2002Average Female age 36.1 yrs.Average time trying to conceive 5.2 yrs.28.6% with history of unsuccessful IVF
72 Irish NPT Study Crude live birth rate 25.5 Lifetable live birth rate 46.3Lifetable is at 24 months, which corresponds roughly to 12 effective cycles.
73 Irish NPT Study No prior IVF crude LT Prior failed IVF Age <= 37 yrsAge >=38 yrsPrior failed IVFAge <= 37 yrsAge >=38 yrs
76 NPT Twins 4.1 %, compared with 28% IVF (HFEA) Less prematurity, low birth weight, morbidity, mortality and cost
77 CommentsNPT cohort pregnancy rates (crude and lifetable) similar to IVF cohort studies.Crude rates underestimate success; lifetable rates overestimateNPT takes more time than IVF, but is far less costly, and has much lower rates of prematurity and neonatal morbidity.
78 Research SuggestionsPopulation-based cohorts for incidence and longitudinal outcomes of infertility, with and without treatmentClinic-based cohort for factors associated success with NPT treatmentRandomized trial of NPT treatment
80 Take home pointsInfertility 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
81 Take home pointsInfertility 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
82 Take home pointsResearch 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
83 Acknowledgments Dr. Phil C. Boyle, Ireland Dr. Tracey Parnell, Canada Dr. Thomas W. Hilgers, USADr. Estella Parrott, RSB, CPR, NICHDDrs. Germaine Buck Louis, Mark Klebanoff, and DESPR, NICHD