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LECTURE 3.a.
Female and Male Infertility
3
Different definitions of infertilityTime trends and geographic variations in infertilityEtiology and treatment of male and female factor infertilityAdverse effects of infertility treatment
Lecture Objectives
4
Inability to achieve a recognized pregnancy after trying to conceive for:– > 1 year (U.S. ACOG) or – > 2 years (WHO)
Primary infertility: no prior pregnancy
Secondary infertility: Prior pregnancy by woman or man
Infecundity: Inability to achieve a live birth
Definitions of infertility
5
Definition Prevalence (%)Ever waited > 24 months 20.6Tried for > 24 months 12.5Consulted a physician 9.6Diagnosed infertility 6.1
Prevalence of infertility depends on the specificity of the question asked
Prevalence of Infertility Depends on the question
6
Primary infertility: Absence of a live birth at specific ages (e.g. > age 30) in non-contracepting population
Secondary infertility: Absence of a live birth > 5 years in persons with prior births
Demographic Definitions
7
1965 1982 1988 1995
All 13.3 13.9 13.7 11.9
Primary 2.2 5.8 6.0 5.7
Secondary 11.1 8.1 7.7 6.2
Definition: Inability to conceive >1 year, within past 3 years. NSFG 1965 – 1995.
Source: Chandra. Infertil Repro Clin North Amer 1994;5:283.
U.S. Married Women Aged 15 – 44 years
Prevalence of Infertility in U.S. 1965 - 1995
8
1965 1982 1988 1995
Number(millions)
3.0 2.4 2.3 2.1
Excludes sterilized couples. Source: NSFG 1995.
Numbers of Infertile Women in US
9
Demographic:– Delay in marriage (1968 24.9 vs 2002
25.1 yrs)– Delay in first birth 1968 21.4 vs 2002
25.1 yrs– Delayed childbearing →
shifts first births
to later ages when fertility is lower
Biologic: – Possible effects of STDs and PID?
U.S. trends in primary infertility
10
Decrease in Secondary Infertility
– Decrease in family size since 1960’s
– More couples adopt sterilization to terminate reproduction and do not recognize secondary infertility
U.S. Trends in secondary infertility
11
12
Most data come from demographic sources– Proportions childless age 25-34– Proportions with no birth in past 5 years
Range of primary infertility, 3-20+%
Regional variation: Historic “Infertility Belt”in central Africa– Cameroon, Congo, Uganda
Developing Country trends
13
Infertility in Africa decreased in recent decades– Difficult to determine trends from
surveys due to selective inclusion of currently married women (e.g. infertile women may often be divorced)
– Variation in survey samples over time
Trends in Developing Countries
14
Papua New Guinea– Tabar infertility 45% in 1940’s decreased to
18.5% in one generation following use of penicillin for presumptive therapy
Zaire– Equater province infertility 42% in1955,
decreased to 9.7% in 1975
Source: WHO Technical Report 1975; No. 582
Trends in Developing Countries
15
Etiologic studies require invasive procedures and clinical evaluation
Variability between clinics– Type of service (general, specialization)– Triage (selective referral)– Costs and socioeconomic barriers– Lack of standardization
Female cause ∼ 50-60%
Male cause ∼ 40-50%
Etiology of Infertility
16
Tubal oculsion due to Pelvic Inflammatory Diseases (PID)– Industrialized countries 33%– Africa 75%
Ovulatory disorders– ∼
30%
EndometriosisHIVToxic exposures:– smoking, glycol ethers, nitrous oxide,
pesticides
Etiology of Infertility in Women
17
Pelvic Inflammatory Disease and Infertility
1. Cervical infection (C. trachomatis and/or N. gonorrhoeae)
18
Pelvic Inflammatory Disease and Infertility
2. Alteration of cervicovaginal microenvironment, increased pH
19
Pelvic Inflammatory Disease and Infertility
3. Overgrowth of vaginal and anaerobic flora, resulting in BV.
20
Pelvic Inflammatory Disease and Infertility
4. Progressive ascent of original cervical pathogen and/or BV anaerobes into the endometrium, fallopian tubes, and the peritoneal cavity.
21
1. Cervix2. Uterine Cavity3. Fallopian Tubes4. Abdominal Cavity
Sequence of Extension
22
Endocervicitis: May be asymptomatic; vaginal discharge, cervical inflammation, or infection; local tendernessEndosalpingitis: Constant bilateral lower quadrant abdominal pain aggravated by body motion. Tenderness in one or both adnexal areas. Abscess formation may occur.Endometriosis: Menstrual irregularityPeritonitis: Nausea, emesis, abdominal distention, rigidity, tenderness. Pelvic or abdominal cavity abscess formation may follow.
Clinical Features
23
05
101520253035404550
0 1 2 3+
Number of PID Episodes
Perc
ent
Percent of women with tubal factor infertility following PID, by number of episodes
Source: Westrom LV. Sex Trans Dis 1994;24(2 Suppl):S32-37.
Tubal Factor Infertility & PID
24
Pelvic Inflammatory Disease Hospitalizations of Women 15 to 44 years United
States, 1980–2003
Note: The relative standard error for these estimates of the total number of acute and chronic PID cases ranges from 6% to 18%. Data available through 2003.
SOURCE: National Hospital Discharge Survey (National Center for Health Statistics, CDC)
Hospitalizations (in thousands)
Acute, Unspec.Chronic
0
40
80
120
160
200
1980 82 84 86 88 90 92 94 96 98 2000 02
25
Pelvic Inflammatory Disease Initial Visits to Physicians’ Offices
Women 15-44 : US, 1980-2004
Note: The relative standard error for these estimates ranges from 19% to 30%.
Visits (in thousands)
0
100
200
300
400
500
1980 82 84 86 88 90 92 94 96 98 2000 02 04
SOURCE: National Disease and Therapeutic Index (IMS Health)
26
Ectopic Pregnancy Hospitalizations of Women 15 to 44 United
States, 1980–2003Hospitalizations (in thousands)
0
20
40
60
80
100
1980 82 84 86 88 90 92 94 96 98 2000 02
Note: Some variations in 1981 and 1988 estimates may be due to changes in sampling procedures. The relative standard error for these estimates ranges from 8% to 12%. Data
available through 2003.
SOURCE: National Hospital Discharge Survey (National Center for Health Statistics, CDC)
27
Risks of subfertility > 1 year– Mother smoker
• RR = 1.5 (1.2-2.0)
– Father smoker, mother non-smoker (passive smoking)• RR = 1.2 (1.0-1.4)
Source: Hull et al. Fertil Steril 2000;74:725
Smoking and Subfertility
28
Microchip Manufacturing: Female Workers Exposure to Ethylene Glycol Ethers (EGE)
EGE Exposure
Subfertility (Inability to conceive > 1year)
(%) RR (CI)
None 9.2 1.0
Low 13.3 1.5 (0.7-3.1)
Medium 13.3 1.8 (0.8-4.3)
High 27.3 4.6 (1.6-13.3)
Source: Correa A, et al. Ethylene glycol ethers and risks of spontaneous abortion and subfertility. Am J Epidemiol 1996;143:707-17
29
Tubal Oculsion– Assisted Reproductive Technologies
(ART)• In vitro fertilization (IVF)• Gamete intrafallopian transfer (GIFT)• Zygote intrafallopian transfer (ZIFT)
– Tubal surgery
Treatment of Female Infertility
30
In vitro fertilization (IVF)
United States: 1 in 80-100 births now IVF conceptions; 100,000 IVF cycles; 48,000 births
(1) Once mature, the eggs are suctioned from the ovaries and (2) placed in a laboratory culture dish with the man's sperm for fertilization. (3) The dish is then placed in an incubator. (4) About 2 days later, 3 to 5 embryos are transferred to the woman's uterus.
Public Domain
31
Live births per embryo transfer, by age of mother and age of donor
Figure 2. Van Vorhiss BJ. Clinical practice. In vitro fertilization. NEJM 2007 Jan 25;356(4):379-86. Copyright © 2007 Massachusetts Medical Society. All Rights Reserved.
32
Preconception genetic diagnoses
One or two balstomeres are removed from the embryoChromosome identification and evaluation by fluorescence in situ hybridization (FISH)Current techniques allow evaluation of up to 10 chromosomes in a single cell
33
Ovulation Disorders– Ovulation induction by Clomid, GnRH
Endometriosis– Drug treatment (Danazol)– Surgery
Treatment of Female Infertility
34
Prognosis varies with:– Age– Primary vs. secondary infertility– Duration of infertility– Type and severity of pathology– Single vs. multiple causes– Male, female, or both affected– Smoking, caffeine, nutrition
Prognosis of Infertility
35
Delivery Rates with IVF
No male factorAge Delivery %<35 35.735-39 33.540+ 10.3
Male factor infertilityAge Delivery %<35 35.135-39 33.540+ 12.8
ASRM/SART Registry Fertil Steril 2002;77:18-31
36
Live births per embryo transfer ~50%Pregnancy loss ~ 18%Multiple births per delivery – 31% twins– 3% triplets or more
– (normal conception, 1% multiple gestations)
Source: Society for Assisted Reprod Technol. Fertil Steril 2000;74:641.
Bradley NEJM 2007;356:379
Outcomes of IVF: U.S.
37Copyright ©2005 BMJ Publishing Group Ltd.
Kallen, B. et al. BMJ 2005;331:382-383. All Rights Reserved.
Percentage of twins after in vitro fertilisation by year of birth in Europe
38
IVF Pregnancy Outcomes (Shevell Obstet Gybecol 2005;106:1039)
Odds of adverse outcomes IVF vs no ART– Preeclampsia OR 2.7 (1.7-4.4)– Preterm labor OR 1.5 (1.0-2.2)– Placental abruption OR 2.4 (1.1-5.2)– Placenta previa OR 6.0 (3.4-10.7)– Cesarean section OR 2.3 (1.8-2.9)
39
Low Birth Weight and ART (US) Schieve NEJM 2002;346:731-7
– N = 42,463 ART vs 3,389,098 natural conceptions
– Risk of low birth weight with ART RR = 2.6 (2.4-2.7)
– Very low birth weight (<1500 gm) RR = 1.8 (1.7-2.0)
– 4.3% of very low birth weight attributable to ART
40
Birth Defects and ARTN = 837 IVF; 301 ICSI; 4000 natural conceptionsAll Major Defects:– IVF = 9.0%, ICSI = 8.6%, natural = 4.2%– IVF RR = 2.0 (1.5-2.9); ICSI RR = 2.0 (1.3-
3.2)– Musculoskeletal defects: IVF = 3.3%, ICSI =
3.3%, natural = 1.1%– Chromosomal defects: IVF = 0.7%, ICSI =
1.0%, Natural = 0.2%VLBW: IVF = 4%, ICSI = 1%, natural= 1.0%
– Hansen NEJM 2002;346:725-30
41
Ovulation induction $1500-5000
Artificial insemination $1000-2000
IVF woman’s own eggs $12,500-25,000
IVF donor eggs $20,000-35,000
Costs of in vitro Fertilization
42
Insurance Coverage and IVF: USA 2001
IVF primarily privately funded– 3 states full coverage– 5 states partial coverage – 37 states no coverage
IVF per 1000 women– Full coverage 3.8/1000– Partial coverage 1.8/1000– No coverage 1.4/1000Jain NEJM 2002;347:661
IVF procedures 1996 = 64,036 vs 2001 = 107,587
43
Women with recurrent EPLs have no recognized pregnancy and report delayed conception. If delay >1 year classified as infertile.Increased SABs in women with infertility may reflect a common mechanism of damage to ovum and fetus such as toxic exposures.– e.g., Glycol ethers increase SAB (RR=
2.8) and infertility (RR = 4.6)
Infertility and Pregnancy Loss
44
Early Pregnancy Loss (EPL)– No Infertility history EPL = 21.1%– Infertility history EPL = 69.7%
Spontaneous Abortion (SAB)– No Infertility history SAB = 14%– Infertility history SAB = 23%
Women with delays in conception have higher rates of EPLs and SABs
Infertility and Pregnancy Loss
45
Microchip Manufacturing: Female Workers Exposure to Ethylene Glycol Ethers (EGE)
EGE Exposure
Spontaneous Abortion
Subfertility
(%) RR (CI) (%) RR (CI)
None 14.8 1.0 9.2 1.0
Low 16.0 1.0 (0.6-0.7)
13.3 1.5 (0.7-3.1)
Medium 18.9 1.4 (0.8-2.6)
13.3 1.8 (0.8-4.3)
High 33.3 2.8 (1.4-5.6)
27.3 4.6 (1.6-13.3)
46
Infertility increases with ageSABs increase with ageDue to ovum deterioration with age
IVF with donation of an ovum from young women to an older recipient increases pregnancy rates and decreases SABs
Infertility, SABs, and Age
47
Male Infertility
GNU Free Documentation License
48
Varicoele ∼ 20-40% (importance?)
Infections (e.g. mumps, STD orchitis & epididymitis, HIV)
Undescended testis
Toxins (e.g. DPCP, glycol ethers)
Etiology of Male Infertility
49
Varicocelectomy– 7 Randomized trials no benefit– Pregnancy RR = 1.04 (0.7-1.4)– Evers & Collins Lancet 2003;361:1849
Artificial insemination by donor or self
Hormone supplements
Intracytoplasmic sperm injection (ICSI)
Treatment of Male Infertility
Male fertility and time trends in semen quality
51
Male fertility and age, effect of endocrine status
Secular trends in semen quality
Testicular development and testicular cancer as a marker of adverse effects
Possible effects of environmental factors including environmental estrogens, endocrine disruptors hypothesis
Factors influencing male fertility
52
Sexual activity declines with age
Testosterone decline with age
Semen quality and age
Difficult to estimate male fertility with age, independent of female age-specific fertility– Correlation of partner’s age– Only women become pregnant
Ireland and Bangladesh data suggest decline in male fertility > age 50
Male Fertility and Age
53
0
100
200
300
400
500
600
700
20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79
Age groups
Num
ber
of s
exua
l eve
nts
per
5 ye
ars
Male Sexual Activity and Age
Any sexual activity
Sexual intercourse
54
0
2
4
6
8
10
12
20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59
Age (years)
Plas
ma
Test
oste
rone
(mg/
ml)
95th
75th
Median
25th
5th
Data Source: Simon D, et al. The influence of aging on plasma sex hormones in men: the Telecom Study. Am J Epidemiol 1992;135;783-91.
Testosterone Level and Age
55
Birth rates by male age married to women aged 20-29, Ireland 1911
Birth per 1000 by male age
425 411
356
293
0
50
100
150
200
250
300
350
400
450
1 2 3 4
male age
Birt
h/10
00
~40 ~45 ~50 60~
56
Requires sample from masturbation
Assessed by:– Semen volume (normal 5 mL)– Sperm count (normal > 20 million/mL)– Motility (>40%)– Morphology (50% typical forms)
Assessment of Semen
57
Variation in semen quality
– Between laboratories and regionally
– Season (lower in hot months)– Age (lower with age)
– Recent ejaculation (decreased if < 3 days)
Problems in assessment of Semen
58
Semen Quality and Age
Young (<39)Volume 5.3 mLCount 325 millMotility 32.8%Abnormal morphology 11.0%
Chromosomal abnormalities 11.9%
Older men (> 59)Volume 2.3 mLCount 208 millMotility 23.8%AbnormalMorphology 12.8%
Chromosmal abnormalities4.8%
Sartorelli, Fertil Steril 2001;76:1119-23
59
40
50
60
J F M A M J J A S O N DCalendar Months
30
40
50
60
7050
60
70
80
50
60
70
80
60708090
J F M A M J J A S O N DCalendar Month
7080
90100
110
90
100
110
120
120130140150160170
Data Source: Levine et al. Male factors contributing to the seasonality of human reproduction. Ann NY Acad Sci 1994;709:29-45.
Sperm concentration, millions/mlMacLeod
Levine (Calgary)
Spira
SL Pol
Tjoa
Levine (New Orleans)
Mortimer
Politoff
Seasonal Variation in Sperm Count
60
Meta-analysis and some longitudinal studies suggest declines in sperm counts of “normal”males over time– Is this evidence for male reproductive
damage?
Are these trends real?– Consistency between studies– Selection effects– Definition of “normal”– Adjustment for recency of intercourse, age
and season
Time Trends in Semen Quality
61
From Carlsen E, et al. Evidence for decreasing quality of semen during past 50 years. BMJ 1992;305:609-613. Copyright © 1992 BMJ. All Rights Reserved.
Trends in Sperm Count over Time
62
“Environmental Estrogen Hypothesis”Environmental estrogens may act as hormonal disruptors:– Diet (fat, phytoestrogens)– Synthetic hormones– Estrogenic chemicals (e.g. pesticides,
organochlorine and benzene derivatives)– Solvents– Fungicide causing azoospermia (DBCP)
Hormonal Disruptors hypothesis
63
0
50
100
150
200
250
300
350
1950-54
1955-59
1960-64
1965
Birth Cohort
Sper
m C
once
ntra
tion
(x 1
06 / m
L)
**
**0
1
2
3
4
5
6
7
8
1950-54
1955-59
1960-64
1965
Bi r t h Cohor t
Sem
en V
olum
e (m
L)
**
*
*
* * *
*
Data Source: Rasmussen et al. No evidence for decreasing semen quality in four birth cohorts of 1,055 Danish men born between 1950 and 1970 Fertil Steril 1997:68(6):1061.
Concentration of Sperm by Birth Cohort
64
Studies inconsistent
Variations in definitions of “normal” (WHO definition decreased from 60 to 20 million/mL over time)
Selection of “normal” men varies between studies (e.g. sperm donors, vasectomy cases)
Problems with Time Trends in Semen Quality
65
Lack of control for time since last ejaculation, season, and age
Variation in laboratory methods, and inter-observer variation in sperm counts
Confounding between regions
Problems with Time Trends in Semen