2005/11/17

Infertility Treatment:Infertility Treatment:Public Health and Primary Public Health and Primary

Care Perspectives 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

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

Definition: infertilityDefinition: 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) Related (confused) termsterms

Infertility Subfertility Sterility

Infertility + recurrent miscarriage = subfecundity (epidemiology) Or visa versa (demography)

Definition: infertilityDefinition: 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: infertilityDefinition: 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

Couple Heterogeneity

Etiology of Etiology of InfertilityInfertility

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 Etiology of InfertilityInfertility

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

IncidenceIncidence

Incidence German study (2004): 10.4%

1 year trying and “at risk” Population basis: unknown

Prevalence: AscertainmentPrevalence: Ascertainment

One (two) year(s) sexually active without contraception

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

PrevalencePrevalence

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, USAPrevalence- 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 IssuesPublic 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 IssuesPublic 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 Infertility: Lifestyle risk factorsrisk factors

Alcohol Tobacco

Up to 13% attributable risk Also impairs ART treatment

Caffeine Marijuana, Cocaine Odds ratios 1.2 to 2.0

Infertility: Risk Infertility: Risk factorsfactors

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 Infertility as a Risk FactorFactor

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 IssuesPublic Health Issues Access to care

Insurance coverage Providers

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

Public Health IssuesPublic 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 IssuesPublic 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 IssuesPublic Health Issues What are optimal evaluation and treatment

strategies for infertility? Is ART currently over-used or under-used?

Primary Care IssuesPrimary 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 Levels of care for infertilityinfertility

Prevention Primary detection, basic medical evaluation, and management

Secondary full medical evaluation and management

Tertiary medical management

A rational and complete A rational and complete approach to infertility approach to infertility needs to address it at needs to address it at the levels of public the levels of public

prevention and primary prevention and primary care as much as at the care as much as at the tertiary care level.tertiary care level.

Evaluation and Treatment Evaluation and Treatment OptionsOptions

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 Infertility Treatment OptionsOptions

Assisted Reproductive Technology Artificial insemination (partner or donor)

Super-ovulation, usually with artificial insemination

In vitro fertilization Intracytoplasmic sperm injection (ICSI)

Infertility Treatment Infertility Treatment OptionsOptions

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 Natural Procreative TechnologyTechnology (NPT) (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:Creighton Model NaPro Tracking:Vaginal discharge biomarkersVaginal discharge biomarkersCreighton Model NaPro Tracking:Creighton Model NaPro Tracking:Vaginal discharge biomarkersVaginal 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

Estrogen/Progesterone Estrogen/Progesterone curvescurves

Type E and G mucus at Type E and G mucus at cervixcervix

Fertility Charting of Fertility Charting of Vaginal Discharge (Creighton Vaginal Discharge (Creighton Model NaProTracking)Model NaProTracking)

What are the best days to What are the best days to conceive?conceive?

Probability of Clinical Pregnancy

Creighton Model NaPro Creighton Model NaPro Tracking is optimal for Tracking is optimal for timing intercourse to timing intercourse to achieve pregnancy.achieve pregnancy.

AND it provides key information to guide

diagnostics and adjust therapy.

NaProTracking makes the NaProTracking makes the couple an equal couple an equal

participant in their own participant in their own fertility evaluation and fertility evaluation and

treatment.treatment.

They are as much an expert in their own fertility as is

the doctor.

NPT 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 ProtocolNPT 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 Illustrative CrM cycles in infertilityin infertility

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

01020304050607080

unexplainedendometriosis

low progestlow estroganovulationabnl mucusabnl spermtubal obstrpelvic adh

other

ARTNPT

Twelve Twelve effectiveeffective cycles 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 HistoryCase History

Case #1Case #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 #1Case #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 #1Case #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 #1Case #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 #1Case #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 #1Case #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

EffectivenessEffectiveness

OutcomesOutcomes

Positive Pregnancy: “chemical” or “clinical” Live birth

Negative Multiple birth rates

Prematurity Neonatal and childhood morbidity

Cost effectiveness

Comparison of Comparison of approachesapproaches

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)

SelectionSelection

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 Natural history of infertilityinfertility

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 Natural history of infertilityinfertility

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!

CohortCohort 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 U.S. National Registry of ART Clinicsof 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 StudyUU Cohort StudyPeterson, Hatasaka, Jones, Poulson, Carrell, UrryPeterson, 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 StudyUU 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 IVFVery 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 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 1996Stolwijk 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 Effectiveness in infertilityinfertility 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.

Irish NPT StudyIrish NPT Study

Over 1239 couples 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 StudyIrish 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 StudyIrish NPT Study

No prior IVF crude LT 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 morbidityNPT neonatal morbidity

Preterm birth rate <6% Low birth rate <8%

NPT TwinsNPT Twins 4.1 %, compared with 28% IVF (HFEA)

Less prematurity, low birth weight, morbidity, mortality and cost

CommentsComments

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 SuggestionsResearch 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 pointsTake 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.

Take home pointsTake 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.

Take home pointsTake 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.

AcknowledgmentsAcknowledgments

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