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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