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

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

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)

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

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)

Previous Pregnancy & SAB Risk (Regan et al., 1989)

n=407 SAB risk (%)All patients 12Last preg ab 19Only ab 24Last preg nl 5All preg nl 4Primigravida 5Multigravida 14

Age and Risk of SAB (Knudsen et al., 1991)

n=19,737 SAB risk (%)11.3 (10.9-11.8)

Age20-29 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)

Number of Previous SABs and Risk of SAB (Knudsen et al., 1991)

Previous SABs SAB 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 ofthis, ACOG

advises W/UAfter 2

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%

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,XNot associated with advances in parental age

15% are triploidy; 10% are tetraploidy; 5% are structural

NondisjunctionMost common

chromosomal mechanismof aneuploidy

Most commonlymaternal in origin &

most commonlyoccurs during Meiosis IIf paternally derived,

nondisjunctionin M1=M2

(e.g. Trisomy 21)

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

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

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

Chronic Diseases & SABs

Chronic wasting diseases (e.g. tuberculosis or carcinomatosis) seldom cause SAB

Celiac sprue has been reported to cause SAB (Sher, 1994)

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)

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)

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)

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)

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)

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)

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%

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

Balanced Translocations

Balanced Translocations:No loss/gain of chromosomal

material. No gene disruption

Robertsonian Translocations

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

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

Uterine Factor & RSA: Evaluation

Hysterosalpingogram (HSG)

Uterine Factor & RSA: Evaluation

Hysterosalpingogram (HSG)

Bicornuate Uterus

Septated Uterus Intrauterine Adhesions Polyps

Uterine Factor & RSA: Evaluation

Hysterosonogram (HSN)

Polyps Intrauterine Adhesions

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)

Uterine Factor & RSA: Treatment

ACOG: “mixed results” for septum repair; association of RSA with polyps and myomas controversial

IVF with gestational surrogacy

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”

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)

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)

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

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

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

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)

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

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)

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”

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

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)

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?)

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

Pregnancy Loss

Gregory Zapantis, M.D.Assistant Professor

Albert Einstein College of MedicineMontefiore Institute for Reproductive Medicine &

HealthHartsdale, NY

(914) 997-1060