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
Estimated time to pregnancy by age of woman
PER CYCLE RATE IS NOT APPROPRIATE FOR NATURAL HISTORY, NOR FOR TREATMENT

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