Transcript to the PowerPoint Slides

Early unrecognized pregnancy
loss and spontaneous abortion
Joseph B. Stanford, MD, MSPH, CFCMC
Professor
Family and Preventive Medicine, Obstetrics
and Gynecology, and Pediatrics
University of Utah
Outline
Terms: conception
Stages of pregnancy and loss
Early unrecognized pregnancy loss
Spontaneous abortion
Ectopic pregnancy
Clinical implications
Patient opinions
Conception- definition
“...fertilization of the oocyte by a
spermatozoon to form a viable zygote”.
-Stedman’s Medical Dictionary 3rd ed.
“...implantation of the blastocyst in the
endometrium; the formation of a viable
zygote”
-Dorlands Medical Dictionary 28th ed.
Changes in definition
 Conception redefined to mean implantation
 1965 and 1972 ACOG changed its definition of conception to “...the
implantation of the blastocyst. It is not synonymous with fertilization.”
 Pregnancy = begins with established implantation
 “...the state of a female after conception and until termination of the
gestation.”
 Why the change in definition of conception?
 In-vitro fertilization
 Contraception with effects after fertilization
Spinnato JA. Informed consent and the redefining of conception: a decision ill- conceived?
J Matern Fetal Med 1998; 7:264-8
Consequences of changed
definitions
 Abortion is interruption of pregnancy.
 Therefore abortion, by definition, does not happen
until after implantation.
 But this doesn’t change the moral issue of the
value of human life from the earliest stages.
In this presentation
Conception = fertilization
How often does postfertilization
loss occur naturally?
 There is an unknown natural rate of postfertilization loss.
 Cannot be measured reliably with hCG.
 Probably common
 Good studies are difficult to do ethically.
 Rates may vary among couples with various levels of
fertility.
 Ethical analogy: spontaneous abortion and elective
abortion (natural loss does not necessarily justify induced
loss)
Early stages of pregnancy
Milestones of pregnancy
Conception (2 weeks GA)
Implantation (2.5-4.0 weeks GA)
5-14 days post conception
Recognition of pregnancy (4-6+ weeks GA)
Detecting milestones of pregnancy
Conception (2 weeks GA)
Early pregnancy factor (chaperonin 10)???
Highly sensitive HCG???
Flushing the reproductive tract (unethical)
Implantation (2.5-4.0 weeks GA)
Positive urine or serum HCG
Recognition of pregnancy (4-6+ weeks GA)
Missed menstrual flow
Symptoms
CrM: 17+ days postpeak
Confirmed by urine or serum HCG
Stages of pregnancy loss
After conception, before implantation
Unknown levels
Some speculate as high as 50%+ of conceptions
After implantation, before clinical recognition
12-22% of detected pregnancies
After recognition of pregnancy before 20 wks
Miscarriage= spontaneous abortion
5-15%+ of detected pregnancies
After 20 wks
Stillbirth; 0.5% of detected pregnancies
Clear communication
We have introduced the term
“postfertilization loss,” now published in
several papers.
Any loss of human life after fertilization and
before clinically recognized pregnancy
Can be natural or induced
Unambiguous term for scientists and clinicians
Can be understood readily by patients
Postfertilization loss
After conception, before implantation
Unknown percentage of all pregnancies
After implantation, before clinical recognition
12-22% of detected pregnancies
After recognition of pregnancy before 20 wks
Miscarriage= spontaneous abortion
5-15%+ of detected pregnancies
After 20 wks
Stillbirth; 0.5% of detected pregnancies
Loss prior to implantation
Cannot be reliably measured
Wild speculations exist about how much it
happens, up to 75%
No reliable data to support inflated estimates
Loss prior to implantation
Likely to be common
Good studies are ethically difficult
Rates may vary among couples with various
levels of fertility.
Ethical analogy: spontaneous abortion and
elective abortion (natural loss does not
necessarily justify induced loss)
Early Pregnancy Loss
Loss of pregnancy prior to clinically
recognized pregnancy
Note that use of the term is variable in
literature with respect to whether
unrecognized, and whether after
conception or fertilization
Definition of “clinically unrecognized”
varies
Unsuspected; 6 weeks, no + urine, etc.
May vary by intensity of surveillance
Early pregnancy loss
After conception, before implantation
Unknown percentage of all pregnancies
After implantation, before clinical recognition
12-22% of detected pregnancies
After recognition of pregnancy before 20 wks
Miscarriage= spontaneous abortion
5-15%+ of detected pregnancies
After 20 wks
Stillbirth; 0.5% of detected pregnancies
Detection of Early Pregnancy
• Home pregnancy test kits
• Measure hCG (indicative of
implantation)
• Positive around 4-5 weeks GA
• Ultrasound
• Visualization of ruptured follicle
• Implanted blastocyst at 3 weeks GA
• Embryonic heart beat at 5 weeks GA
Pregnancy
Early Pregnancy Loss Spontaneous Abortion
(22%)
(12-15%)
No established methods exist for identifying
preimplantation pregnancies or losses!
Wilcox et al, NEJM 1988
EPL Study
Prospective study of occupational cohort
(N=518) women employed at textile plant
in China (Wang et al., Fertil Steril 2003)
Eligibility criteria:
• Full-time employment
• Newly married
• 20-34 years of age
• Had obtained permission to have a child
EPL Study
Protocol: Immediately after stopping birth
control:
1. Daily diary (intercourse, vaginal
bleeding, medications, medical conditions
2. Daily first-morning urine collection
Defining EPL versus SAB
SAB: loss of pregnancy lasting at least 6
weeks’ gestational age, and less than 28
weeks
EPL: pregnancy detected only by HCG in
urine
Presumably mutually exclusive?
518 women
618 identified conceptions (urine HCG)
152 (25%) EPL
49 (8%) SAB
13 (2%) other preg. outcomes
404 (65%) live births
or ongoing pregnancy
Conception Rates, Wang et al., 2003
Among 518 women:
Average probability of conceiving a clinical
pregnancy per cycle over first twelve months = 30%
Cycles
1-3
4-6
7-9
10-14
Probability CP
32%
28%
17%
12%
CP + EPL = total conception rate of 40% per cycle
Approximately 50% women became CP in first two cycles; > 90% by cycle 6
Early pregnancy loss
Risk factors for it?
Not well studied
Age?
Not drugs, smoking, alcohol
EPL as a risk factor?
EPL in preceding cycle associated with:
Event
Conception
CP
EPL
OR
2.6
2.0
2.4
95% CI
1.8 - 3.9
1.3 - 3.0
1.4 - 4.2
But was NOT associated with:
SAB
LBW
PTD
1.1
1.7
1.4
0.4 - 3.3
0.6 - 4.7
0.4 - 4.7
Pregnancy
Early Pregnancy Loss Spontaneous Abortion
(22%)
(12-15%)
Wilcox et al, NEJM 1988
SAB incidence
5-15%+
Varies by age and population
Varies by level and timing of induced
abortion
SAB risk factors
Prior history of SAB (2 or more)
Age
Subfertility
Smoking
Cocaine
Alcohol
Nutritional deficiencies
Fever or external heat at critical windows
SAB risk factors?
Fertility treatment
Multiple prior induce abortions
Depression
Environmental exposures
Caffeine
Risk factors
Why are there different risk factors for
early unrecognized pregnancy loss and
spontaneous abortion?
Ectopic pregnancy
Also a type of pregnancy loss
1-2% of detected pregnancies
Ectopic pregnancy risk factors
Prior tubal scarring
Smoking
Prior ectopic pregnancy
OCP use, especially POP
IUD use
Clinical implications
Earliest losses may be a positive
prognostic factor.
Progesterone supplementation to prevent
losses at all stages (?)
Assessment of earliest hormone profiles.
Patients’ attitudes about
postfertilization actions of birth control
Joseph B. Stanford, MD, CNFPMC
Daniel Jones, MD
Mark Christian, MD
Department of Family and Preventive Medicine
University of Utah
Craig DeLisi, MD
In His Image Family Medicine Residency
Tulsa, Oklahoma
Research implications
Need to develop and validate markers for
pregnancy prior to implantation.
Normal fertility
Infertility
Hormonal contraceptive use
Research Questions
Would stage of action of a birth control
method influence women’s choices about
using it?
Stage 1: Before Fertilization
Stage 2: After Fertilization/Before Implantation
Stage 3: After Implantation
Do women’s views correlate with
demographic and personal characteristics?
Methods
Developed 4 page, 37 item, written
questionnaire to address use, attitudes, and
knowledge of birth control of women of
childbearing age
IRB approval obtained (University of Utah)
Pilot questionnaires administered and used
to revise the questionnaire
25 in Oklahoma
30 in Utah
Methods
Questionnaire addressed
How mechanism of action at Stage 1, 2, or 3
would affect women’s choice to use a method
Perceived mechanism of action of 11 forms of
birth control or family planning
Reproductive and contraceptive history
Demographics: age, race, education, marital
status, income, and degree of religiosity
Methods
Administered to
Women between ages 18-50 being seen for any
reason
Women younger than 18 being seen for maternity or
family planning
Results
748/928 returned = 81% response rate
Eliminated:
17 patients over age 50
108 patients with condition that would prevent them
from becoming pregnant
618 questionnaires adequate for analysis
Responses by Site
Family Medical Care of Tulsa (500)
Salt Lake City, UT (428)
University of Utah OBGYN Clinic (207)
Sugarhouse Family Medicine Clinic (113)
Oquirrh View Community Health Center (30)
2 private OBGYN clinics (78)
Demographics
Race/Ethnicity
74.8% Caucasian
5.5% Hispanic
4.2% African American
3.2% American Indian
3.1% Asian
Demographics
 Education
39.2% college degree
39.2% some college
14.6% high school or less
 Income
46.4% > $40,000/yr
 Marital status
58.4% married
17.0% single in committed relationship
16.5% single
Reproductive Intentions
28.6% currently pregnant
48.1% may want to get pregnant in future
18.4% never want to get pregnant
Religion
Past Methods
Current and Future Methods
Do Women Care? – Stage 2
“Would you consider using a birth control
method that works at Stage 2?”
No = 53.4%
Yes = 19.9%
Unsure = 22.8%
Do Women Care? – Stage 2
 “If you were using a birth control method, and you
learned that it sometimes works at Stage 2, how would
this affect your choice about using it?
48.6% (61.3% of respondents) - “If there was even a
remote possibility of it working at Stage 2, I would
stop using it.” (High Concern)
17.6% - Would stop depending on how often it
worked at Stage 2 (Intermediate Concern)
13.0% - Would not stop regardless of frequency
(Low Concern)
Do Women Care? – Stage 3
“Would you consider using a birth control
method that works at Stage 3?”
No = 73.9%
Yes = 6.3%
Unsure = 13.8%
Do Women Care? – Stage 3
 “If you were using a birth control method, and you
learned that it sometimes works at Stage 3, how would
this affect your choice about using it?
69.4% (78.6% of respondents) - “If there was even a
remote possibility of it working at Stage 3, I would
stop using it.” (High Concern)
6.1% - Would stop depending on how often it
worked at Stage 3 (Intermediate Concern)
9.7% - Would not stop regardless of frequency (Low
Concern)
Informed?
Do women want to be informed?
Factors Significantly Related to Concern
for Postfertilization Effects
 Claiming any religious affiliation
 Believing life begins at fertilization (Stage 2) or
implantation (Stage 3)
 Being married
 Frequent attendance at worship services
 High importance of faith in life
 Closely following church’s teaching regarding
birth control (exact teaching not specified)
Factors Not Related to Concern for
Postfertilization Effects
 Age
 Race
 Income
 Education
 Previous induced abortions
 Plans for future pregnancy
 Whether or not want to be informed (Stage 2)
Levels of Concern
High – would stop using method no matter
how often it worked at Stage (2 or 3)
Intermediate – would stop using method if
worked in that way for various frequencies
(from 0.1% to 50%)
Low – would not stop using method no matter
how often worked at Stage (2 or 3)
Religion and Stage 2 Concerns
Religion and Stage 3 Concerns
Faith Importance and Stage 2
“My faith is the most important thing in my
life.”
Faith Importance and Stage 3
“My faith is the most important thing in my
life.”
Marital Status and Stage 2
Marital Status and Stage 3
Personal Opinion of When Life
Begins and Stage 2
Personal Opinion of When Life
Begins and Stage 3
Further Analysis
How well are the issues understood?
 Of original 618, eliminated 182 who were not
consistent in their responses about Stage 2 or 3
effects  436
 Of these, selected 271 who answered questions
about established mechanisms of action of birth
control correctly (condoms, abortion, abstinence,
and sterilization)
 Re-analyzed both groups (431 and 271) to see if
different than original analysis  no difference in
results already shown
Example Open Responses
 “In your own opinion, when does human life begin?”
 “birth control is for before the fact; any "birth control" after the egg is
fertilized is called abortion and that is murder”
 “after delivery when baby takes in breath of life”
 "choices" are made before conception. After conception your "choice"
involves taken good care of your baby.
 “when fetal heart tones are heard”
 “when the fetus is viable on its own, though I'd never want to consider
abortion after a certain time period. When I can perceive it as a human
or when I thought it could "feel" pain, etc.”
 “at conception, Jesus was the Christ at conception”
 “when you have sex”
 Similar responses indicating before fertilization were common
 “human life….well mine ends if I get stuck with a child.”
Example Open Responses
 “What are the most important ethical issues to consider in
choosing a method of birth control (if any)?”
 “I believe life begins at conception and it is not up to me to end it.”
 “I want freedom to choose what I want. I don't want someone else's
religious beliefs affecting me.”
 “The thought of being pregnant and yet the birth control I take terminates
the process without warning is heart breaking”
 “Never wanting to cause the death of my child accidentally, ignorantly or
otherwise.”
 “If you wait until the fetus could survive outside the womb - then ethics are
involved - before that time I do not feel birth control should be an ethical
decision”
 “What effect it has on your relationship with the Lord”
 “I'm not sure, my mother makes me use it.”
Questions of Bias
 In reviewing this study with colleagues, the question has arisen of
whether the questionnaire pushed patients one way or another on
this issue.
 This is the reason that we did not ask about concerns for specific methods
of birth control.
 The questionnaire was reviewed in detail by colleagues on “both sides” of
the issue about respect for early human life.
 Some patients wrote comments suggesting that we were trying to push a
“pro-choice” agenda, and others wrote comments suggesting that we were
trying to push a “pro-life” agenda, suggesting that perhaps we got as close
to a neutral stance as possible.
Conclusions
 A very high proportion of women of child-bearing
age seen in OBGYN and family medicine clinics
have a level of concern for postfertilization effects
that would affect their decision regarding birth
control.
Particularly true if they are married, religious, or believe
life begins at conception
 A majority of women (75%) want these discussion to
occur, regardless of whether it would affect their
decision or not.
 The majority have not sufficiently discussed the
mechanism of action of their birth control with their
provider.
Limitations of Study
 More religious segment of population?
 67% Christian (including 21% LDS)
Perhaps more religious than US population
Non-religious did show a much lower concern for
postfertilization effects
 Some minorities underrepresented
Black/African American (4.2%)
Hispanic (5.5%)
 Women may not have directly considered their
own specific method that might contradict their
concerns.
Acknowledgements
Rafael Mikolajczyk, MD
Walter Larimore, MD
Kirtly Parker Jones, MD