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

OutlineTerms: conceptionStages of pregnancy and lossEarly unrecognized pregnancy lossSpontaneous abortionEctopic pregnancyClinical implicationsPatient 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 commonGood 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 pregnancyConception (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 pregnancyConception (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 flowSymptomsCrM: 17+ days postpeakConfirmed by urine or serum HCG

Stages of pregnancy lossAfter conception, before implantation

Unknown levelsSome speculate as high as 50%+ of conceptions

After implantation, before clinical recognition12-22% of detected pregnancies

After recognition of pregnancy before 20 wksMiscarriage= spontaneous abortion5-15%+ of detected pregnancies

After 20 wksStillbirth; 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 inducedUnambiguous term for scientists and

cliniciansCan be understood readily by

patients

Postfertilization lossAfter conception, before implantation

Unknown percentage of all pregnancies

After implantation, before clinical recognition12-22% of detected pregnancies

After recognition of pregnancy before 20 wksMiscarriage= spontaneous abortion5-15%+ of detected pregnancies

After 20 wksStillbirth; 0.5% of detected pregnancies

Loss prior to implantation

Cannot be reliably measuredWild speculations exist about how much it

happens, up to 75%No reliable data to support inflated estimates

Loss prior to implantation

Likely to be commonGood studies are ethically difficultRates 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” variesUnsuspected; 6 weeks, no + urine, etc.May vary by intensity of surveillance

Early pregnancy lossAfter conception, before implantation

Unknown percentage of all pregnancies

After implantation, before clinical recognition12-22% of detected pregnancies

After recognition of pregnancy before 20 wksMiscarriage= spontaneous abortion5-15%+ of detected pregnancies

After 20 wksStillbirth; 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

Early Pregnancy Loss(22%)

Spontaneous Abortion (12-15%)

Pregnancy

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 Probability CP1-3 32%4-6 28% 7-9 17%10-14 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 studiedAge?Not drugs, smoking, alcohol

EPL as a risk factor?

EPL in preceding cycle associated with:

Event OR 95% CIConception 2.6 1.8 - 3.9CP 2.0 1.3 - 3.0EPL 2.4 1.4 - 4.2

But was NOT associated with:

SAB 1.1 0.4 - 3.3LBW 1.7 0.6 - 4.7PTD 1.4 0.4 - 4.7

Early Pregnancy Loss(22%)

Spontaneous Abortion (12-15%)

Pregnancy

Wilcox et al, NEJM 1988

SAB incidence

5-15%+Varies by age and populationVaries by level and timing of induced

abortion

SAB risk factors

Prior history of SAB (2 or more)AgeSubfertilitySmokingCocaineAlcoholNutritional deficienciesFever or external heat at critical windows

SAB risk factors?

Fertility treatmentMultiple prior induce abortionsDepressionEnvironmental exposuresCaffeine

Risk factors

Why are there different risk factors for early unrecognized pregnancy loss and spontaneous abortion?

Ectopic pregnancy

Also a type of pregnancy loss1-2% of detected pregnancies

Ectopic pregnancy risk factors

Prior tubal scarringSmokingPrior ectopic pregnancyOCP use, especially POPIUD 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, MDDepartment of Family and Preventive Medicine

University of Utah

Craig DeLisi, MDIn His Image Family Medicine Residency

Tulsa, Oklahoma

Research implications

Need to develop and validate markers for pregnancy prior to implantation.Normal fertilityInfertilityHormonal contraceptive use

Research Questions

Would stage of action of a birth control method influence women’s choices about using it?Stage 1: Before FertilizationStage 2: After Fertilization/Before ImplantationStage 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 Oklahoma30 in Utah

Methods

Questionnaire addressedHow 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 historyDemographics: age, race, education,

marital status, income, and degree of religiosity

Methods

Administered toWomen between ages 18-50 being seen

for any reasonWomen younger than 18 being seen for

maternity or family planning

Results

748/928 returned = 81% response rate

Eliminated: 17 patients over age 50108 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/Ethnicity74.8% Caucasian5.5% Hispanic4.2% African American3.2% American Indian3.1% Asian

DemographicsEducation

39.2% college degree39.2% some college14.6% high school or less

Income46.4% > $40,000/yr

Marital status58.4% married17.0% single in committed relationship16.5% single

Reproductive Intentions

28.6% currently pregnant48.1% may want to get pregnant

in future18.4% 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 affiliationBelieving life begins at fertilization

(Stage 2) or implantation (Stage 3)Being married Frequent attendance at worship

servicesHigh importance of faith in lifeClosely following church’s teaching

regarding birth control (exact teaching not specified)

Factors Not Related to Concern for Postfertilization Effects

AgeRaceIncomeEducationPrevious induced abortionsPlans for future pregnancyWhether 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 AnalysisHow 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.

ConclusionsA 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 conceptionA 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 populationNon-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.

AcknowledgementsRafael Mikolajczyk, MD

Walter Larimore, MD

Kirtly Parker Jones, MD