Early unrecognized pregnancy loss and spontaneous abortion

1. 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

2. Outline • Terms: conception • Stages of pregnancy and loss • Early unrecognized pregnancy loss • Spontaneous abortion • Ectopic pregnancy • Clinical implications • Patient opinions

3. 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.

4. 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

5. 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.

6. In this presentation • Conception = fertilization

7. 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)

8. Early stages of pregnancy

9. 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)

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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)

16. 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

17. 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

18. 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

19. Pregnancy Early Pregnancy Loss (22%) Spontaneous Abortion (12-15%) No established methods exist for identifying preimplantation pregnancies or losses! Wilcox et al, NEJM 1988

20. 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

21. EPL Study Protocol: Immediately after stopping birth control: 1. Daily diary (intercourse, vaginal bleeding, medications, medical conditions 2. Daily first-morning urine collection

22. 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?

23. 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

24. Conception Rates, Wang et al., 2003 Among 518 women: Average probability of conceiving a clinical pregnancy per cycle over first twelve months = 30% CyclesProbability CP 1-3 32% 4-6 28% 7-9 17% 10-14 12% CP + EPL = total conception rate of 40% per cycle

25. Approximately 50% women became CP in first two cycles; > 90% by cycle 6

26. Early pregnancy loss • Risk factors for it? • Not well studied • Age? • Not drugs, smoking, alcohol • EPL as a risk factor?

27. EPL in preceding cycle associated with: Event OR 95% CI Conception 2.6 1.8 - 3.9 CP 2.0 1.3 - 3.0 EPL 2.4 1.4 - 4.2 But was NOT associated with: SAB 1.1 0.4 - 3.3 LBW 1.7 0.6 - 4.7 PTD 1.4 0.4 - 4.7

28. Pregnancy Early Pregnancy Loss (22%) Spontaneous Abortion (12-15%) Wilcox et al, NEJM 1988

29. SAB incidence • 5-15%+ • Varies by age and population • Varies by level and timing of induced abortion

30. SAB risk factors • Prior history of SAB (2 or more) • Age • Subfertility • Smoking • Cocaine • Alcohol • Nutritional deficiencies • Fever or external heat at critical windows

31. SAB risk factors? • Fertility treatment • Multiple prior induce abortions • Depression • Environmental exposures • Caffeine

32. Risk factors • Why are there different risk factors for early unrecognized pregnancy loss and spontaneous abortion?

33. Ectopic pregnancy • Also a type of pregnancy loss • 1-2% of detected pregnancies

34. Ectopic pregnancy risk factors • Prior tubal scarring • Smoking • Prior ectopic pregnancy • OCP use, especially POP • IUD use

35. Clinical implications • Earliest losses may be a positive prognostic factor. • Progesterone supplementation to prevent losses at all stages (?) • Assessment of earliest hormone profiles.

36. 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

37. Research implications • Need to develop and validate markers for pregnancy prior to implantation. • Normal fertility • Infertility • Hormonal contraceptive use

38. 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?

39. 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

40. 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

41. Methods • Administered to • Women between ages 18-50 being seen for any reason • Women younger than 18 being seen for maternity or family planning

42. 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

43. 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)

44. Demographics • Race/Ethnicity • 74.8% Caucasian • 5.5% Hispanic • 4.2% African American • 3.2% American Indian • 3.1% Asian

45. 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

46. Reproductive Intentions • 28.6% currently pregnant • 48.1% may want to get pregnant in future • 18.4% never want to get pregnant

47. Religion

48. Past Methods

49. Current and Future Methods

50. 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%