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Infertility Treatment: Public Health and Primary Care Perspectives

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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, 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

2 Outline Definition Incidence and Prevalence Public Health Issues
Primary Care Issues Evaluation and Treatment Options Effectiveness Research 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 contraception Primary: no previous pregnancy Secondary: previous pregnancy Syndrome, not diagnosis!

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

5 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.

6 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.

7 Dunson, Colombo et al, Obstet Gynecol 2004

8 Couple Heterogeneity Normal fertility/infertility not a dichotomous state

9 Etiology of Infertility
Male Factors % Ovarian Causes % PCOS % Age, Diminished Reserve ? Anatomic Obstruction 20-30% Endometriosis % Mucus Factors % Coital Issues % Luteal Phase Defects % Lifestyle issues % Unexplained %

10 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

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 contraception One (two) year(s) trying Consulted physician Physician diagnosed problem Self-report of difficulty conceiving

13 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

14 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


16 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

17 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

18 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

19 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 )

20 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

21 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

22 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

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

24 Public Health Issues Multiple gestation Multiple gestation- iatrogenic
Twins increased 50% from Higher older multiples increased 4x from 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

25 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?

26 Public Health Issues What 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 condition Chronic versus acute disease management model Lifestyle and preconception issues Psychosocial dimensions Cultural, ethical, and cost issues Importance of patient preferences and values

28 Levels of care for infertility
Prevention Primary detection, basic medical evaluation, and management Secondary full medical evaluation and management Tertiary 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 function fertilization occurs in vivo from sexual intercourse

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

33 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

34 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


36 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

37 Estrogen/Progesterone curves

38 Type E and G mucus at cervix

39 Fertility Charting of Vaginal Discharge (Creighton Model NaProTracking)

40 What are the best days to conceive?

41 Probability of Clinical Pregnancy

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 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.

45 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

46 Illustrative CrM cycles in infertility

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

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 appropriately Other medical/surgical issues identified and addressed (CrM chart)

49 Case History

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

51 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

52 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

53 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

54 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

55 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


57 Effectiveness

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

59 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)

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 Canada 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

62 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!

63 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

64 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

65 UU Cohort Study Peterson, Hatasaka, Jones, Poulson, Carrell, Urry
Nonrandomized study UU patients Mean age about 33 years Mean duration trying about 4 years From UU patients 3 groups Ovulation 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 cycles OI/AI at 3 cycles OI/AI at 4 cycles IVF Observation

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 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%

69 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

70 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.

71 Irish NPT Study Over 1239 couples Average Female age 36.1 yrs.
Entered treatment Feb through Jan. 2002 Average 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 46.3 Lifetable 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 yrs Age >=38 yrs Prior failed IVF Age <= 37 yrs Age >=38 yrs

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


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

77 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.

78 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


80 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

81 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

82 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

83 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


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