Pregnancy Loss

1. Pregnancy Loss Gregory Zapantis, M.D. Assistant Professor Department of Obstetrics, Gynecology & Women’s Health, Division of Reproductive Endocrinology & Infertility Albert Einstein College of Medicine

2. Pregnancy Loss • Abortion: Termination of pregnancy before the fetus is sufficiently developed to survive • Pregnancy loss before 20 weeks GA; fetus weighing less than 500 g

3. Pregnancy Loss: Types • Threatened Abortion: Vaginal bleeding when a viable embryo or fetus is suspected (first 20 wks GA) • Embryonic Demise/ Missed Abortion: Intrauterine embryo with no heart beat (CRL > 4mm) • Blighted Ovum (Anembryonic Pregnancy): Gestational sac without embryonic development at a gestational age or sac size in which such development expected (> 5-6 wks, sac diameter 10-18mm)

4. Pregnancy Loss: Types • Incomplete Abortion: Any of the above with an incomplete expulsion of the products of conception • Complete Abortion: Any of the above with resultant complete expulsion of the products of conception

5. Pregnancy Loss • More than 80% of SABs occur before 12 weeks GA, then decrease rapidly (Harlap and Shiono, 1980) • Based on sensitive uCG assay: SAB rate 31% (22% before expected menses; 9% after) (Wilcox et al., 1988) • Maternal age and previous pregnancy history (and paternal age) influence the risk of spontaneous abortion (Wilson et al., 1986)

6. Previous Pregnancy & SAB Risk (Regan et al., 1989) n=407SAB risk (%) All patients 12 Last preg ab 19 Only ab 24 Last preg nl 5 All preg nl 4 Primigravida 5 Multigravida 14

7. Age and Risk of SAB (Knudsen et al., 1991) n=19,737SAB risk (%) 11.3 (10.9-11.8) Age 20-29 9.7 (9.2-12.7) 30-34 11.5 (10.6-12.6) 35-39 21.4 (19.2-23.7) 40+ 42.2 (35.1-47.4)

8. Number of Previous SABs and Risk of SAB (Knudsen et al., 1991) Previous SABsSAB risk (%) 0 10.7 (10.3-11.2) 1 15.9 (15.4-16.4) 2 25.1 (23.4-27) 3 45.0 (39.8-50.4) 4 54.3 (43.7-64.4) Because of this, ACOG advises W/U After 2

9. Risk of SAB with Fetal Heart Motion (Stenchever et al., 2001) • Fetal heart motion, 5-6 weeks: 6-8%. At 8 weeks: 2% • Fetal heart motion with vaginal bleeding: 15% • Fetal heart motion with a history of recurrent spontaneous abortions: 20-30%

10. Chromosomal Abnormalities & SABs: Aneuploidy • Occur in 50-85% of SABs • How many more due to undetectable causes? (Lanesa and Hogge, 2000) • 50-67% are trisomies • Trisomies 16 and 22 (also 13,18,21) most common • Due to isolated nondisjunction, maternal or paternal balanced translocation, or balanced chromosomal inversion • 7-15% are 45,X Not associated with advances in parental age • 15% are triploidy; 10% are tetraploidy; 5% are structural

11. Nondisjunction Most common chromosomal mechanism of aneuploidy Most commonly maternal in origin & most commonly occurs during Meiosis I If paternally derived, nondisjunction in M1=M2 (e.g. Trisomy 21)

12. Chromosomal Abnormalities & SABs: Euploidy • Later SABs than for aneuploid: ¾ of losses by 13 weeks vs. 8 weeks for aneuploid (Kajii et al., 1980) • Increase dramatically after maternal age of 35 years (Stein et al., 1980) • Reasons unknown; possibly genetic abnormality (e.g. isolated mutation), or maternal or paternal factors

13. Chromosomal Abnormalities & SABs • Better pregnancy term rate after aneuploid loss (68%) (19 pts) than after euploid loss (41%) (39 pts) (Jivraj et al., 2001) • Benefit to karyotype abortus? ACOG does not recommend routine testing

14. Infections & SABs • SABs have been independently associated with maternal HIV-1 antibody, maternal syphilis seroreactivity, group B Strep vaginal colonization, HSV genital infection in the first half of pregnancy (Temmerman, 1992) • ? Toxoplasma, Mycoplasma, Ureaplasma

15. Chronic Diseases & SABs • Chronic wasting diseases (e.g. tuberculosis or carcinomatosis) seldom cause SAB • Celiac sprue has been reported to cause SAB (Sher, 1994)

16. Drug Use & Environmental Factors & SAB risk • Smoking ≥14 cigarettes a day increases SAB risk by 1.7X (Stenchever et al., 2001) • Alcohol use: 2X SAB risk if used twice weekly; 3X SAB risk if used daily (Stenchever et al., 2001) • Caffeine use: >4 cups, slight  risk (Armstrong et al., 1992)

17. Drug Use & Environmental Factors & SAB risk • Radiation: No increased risk for congenital malformations and SABs from ionizing radiation at doses < 5 rads (Brent, 1989) • No proven risk 0-8 wks or > 25 wks; harmful range greatest 8-15 wks (Committee on Biological Effects, 1990)

18. Drug Use & Environmental Factors & SAB risk • Anesthetic gases implicated in SABs: controversial (Axelsson et al., 1982) • Arsenic, lead, formaldehyde, benzene and ethylene oxide may cause abortions (Barlow and Sullivan, 1982)

19. Aging Gametes & SAB risk • Increased SAB risk if IUI occurred 4 days before or 3 days after ovulation by BBT temperature shift (Guerrero and Rojas, 1975)

20. Recurrent Spontaneous Abortion (RSA) • Three or more SABs occurs in 0.5-1.0% of couples (Alberman, 1988) • In most women, no cause can be identified (Harger et al., 1983)

21. Chromosomal Abnormalities & RSA • Occur less likely in SABs from women < age 36 with RSA history (Stephenson et al., 2002) • Higher genetic abnormalities in preimplantation genetic studies than in control IVF patients (Simon et al., 1998) • Significantly higher preterm delivery (13%), SGA (13%), perinatal loss (2.5%), and CS birth (36%) than controls (U.K. study of 162 pregnancies) (Wolf, 1996)

22. Chromosomal Abnormalities & RSA (Stenchever et al., 2001) • In couples with RSA, prevalence of a structural chromosomal abnormality in either parent: 3-5% • Abnormalities 2X more frequent in female partner • 50% are balanced translocations • 25% are Robertsonian translocations • With translocation, subsequent SAB rate: 80%

23. Chromosomal Abnormalities & RSA • More common in couples with previous malformed or mentally retarded children • However, ACOG states presence of phenotypically normal offspring does not exclude parental chromosomal abnormalities

24. Balanced Translocations Balanced Translocations: No loss/gain of chromosomal material. No gene disruption

25. Robertsonian Translocations

26. Chromosomal Abnormalities & RSA • Genetic counseling • Donor eggs (Remohi et al., 1996) ; donor sperm (Rubio, 1999) ; donor embryos • ACOG recommends preimplantation genetic diagnosis (PGD) if parental structural defect is determined

27. Uterine Factor & RSA: Evaluation • Hysterosalpingogram • Very sensitive for Mullerian abnormalities • Hysterosonogram • More sensitive for myomas and polyps (Goldberg et al., 1997; Keltz et al., 1997) • MRI • Hysteroscopy/ Laparoscopy • Gold standard

28. Uterine Factor & RSA: Evaluation Hysterosalpingogram (HSG)

29. Uterine Factor & RSA: Evaluation Hysterosalpingogram (HSG) Intrauterine Adhesions Septated Uterus Polyps Bicornuate Uterus

30. Uterine Factor & RSA: Evaluation Hysterosonogram (HSN) Polyps Intrauterine Adhesions

31. Uterine Factor & RSA: Treatment • Myomas, polyps, intrauterine adhesions usually removed hysteroscopically • Pre-op Lupron, lamineria, PGE1 analogue (e.g. misoprostol) • Outcomes comparable to abdominal procedures (Basko, 1997) • Septum repair: improved delivery rates; lower abortion rates (uncontrolled series, Hickok, 2000)

32. Uterine Factor & RSA: Treatment • ACOG: “mixed results” for septum repair; association of RSA with polyps and myomas controversial • IVF with gestational surrogacy

33. Infectious Agents & RSA • Listeria, ureaplasma, toxoplasmosis, viruses (e.g. rubella, HSV, CMV, Coxsackievirus, measles) have been associated with RSA in past • ACOG: “none are convincingly associated with RSA”

34. Thrombophilia & RSA: Evaluation • ACOG Practice Bulletin: Testing for heritable thrombophilias in RSA not recommended; lack of evidence of association of thrombophilia with RSA, and lack of RCTs showing efficacy of antithrombotic therapy (ACOG Practice Bulletin, 2001) • Association between congenital or acquired thrombophilia and RSA vs. controls; strongest for 2nd, 3rd trimesters (Prestron et al., 1996)

35. Thrombophilia & RSA: Evaluation • Maternal intervillous blood flow begins after 8 weeks • Studies support and refute: factor V Leiden mutation, prothrombin G20210A mutation, MTHFR C677T mutation, Protein C or S, and Antithrombin III deficiency (Regan et al., 1990)

36. Thrombophilia & RSA: Treatment • Small, nonrandomized trials: low-dose heparin and aspirin increase the live birth rate in thrombophilic women with either early or late pregnancy loss (Brenner et al., 2000; Grandone et al., 2002) • Routine thromboprophylaxis during pregnancy cannot be recommended for women with thrombophilic abnormalities • If used, get hematologic consultation

37. Antiphospholipid Antibody Syndrome & RSA: Evaluation • Lupus anticoagulant (LA) and/or anticardiolipin antibody (aCL) present in 15% of RSA vs. 2% controls (Stenchever et al., 2001; Li, 1998) • ACOG: One or both present on 2 occasions, > 6 weeks apart • IgG isotype of aCL most relevant; repeated IgM positive can be used to make diagnosis • If LA negative, aCL < 20 units of uncertain significance

38. Antiphospholipid Antibody Syndrome & RSA: Treatment • Low dose heparin (5000 IU SQ BID) as effective as higher dose (Kutteh and Ermel, 1996) and better than asa alone (Kutteh, 1996) • RCT: prednisone and asa- no effect on subsequent delivery rates, more prematurity, premature rupture of membranes (Laskin et al., 1997) • ACOG: term rates 70-75% Hep/asa

39. Antiphospholipid Antibody Syndrome & RSA: Treatment • Observational study (Rai et al., 2000) : No difference in term baby rates in early losses (805 women; asa 68%, no tx 65%) • Improved with late losses (250 women; asa 65%, no tx 49%) • IV IgG treatment for RSA not effective (Stephenson et al., 1998)

40. Alloimmune Disorders & RSA • Hypothesis: Maternal immune response abnormality to semiallogeneic fetal “graft” linked to RSA • No good data to support this (23) (e.g. HLA typing) (Speroff et al., 1999) • Paternal leukocyte (mononuclear cell) transfusion not effective; may increase SAB risk (Ober et al., 1999) —ACOG concurs

41. Endocrine Disorders & RSA • Hypothyroidism, no  risk; but, antithyroid antibodies marker for SAB risk (Stenchever et al., 2001) • DM under control: no  risk of SAB (25) •  fasting insulin (>20 UmL) in women with RSA (Craig et al., 2002) • 2X  risk in anovulatory PCOS women (Stenchever et al., 2001; Barnes, 1997) • Controversial: Metformin  SAB risk (Glueck et al., 2001; Jakubowicz et al., 2002; Heard et al., 2002)

42. Endocrine Disorders & RSA: Luteal Phase Defect • No difference in P4 levels in RSA pts going to term with next pregnancy versus having another abortion (Ogasawara et al., 1997) • No difference in out of phase specimens for patients with infertility, normal fertility and RSA (Peters et al., 1992) • ACOG: association between LPD and RSA is “speculative”

43. Unexplained RSA • 3 prospective, non-randomized trials found “tender loving care” significantly decreased the risk of subsequent abortion in women with RSA (Stenchever et al., 2001; Clifford et al., 1997) • Weekly U/S 5-12 weeks; reassurance if viability and normal growth seen; easy nurse and physician access

44. Incompetent Cervix • Painless cervical dilation in second trimester, and spontaneously ruptured membranes • Etiology: previous cervical trauma (D&C, conization, cauterization), abnormal cervical development (e.g. in utero DES exposure)

45. Incompetent Cervix: Pre-op Evaluation • Surgical treatment to reinforce weak cervix with purse string suture • U/S to exclude major fetal anomalies • Cultures for GC, CT, group B Strep • Delay until after 14 weeks • No consensus on how late (24-26 weeks?)

46. Incompetent Cervix: Treatment • McDonald cerclage (1963) • Shirodkar operation (1955) • Modified Shirodkar cerclage (Caspi et al., 1990) • Less trauma & blood loss vs. Shirodkar • 85-90% success rate • Reserved for previous McDonald failures

47. Pregnancy Loss Gregory Zapantis, M.D. Assistant Professor Albert Einstein College of Medicine Montefiore Institute for Reproductive Medicine & Health Hartsdale, NY (914) 997-1060