Transcript Infertility

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
All patients
Last preg ab
Only ab
Last preg nl
All preg nl
Primigravida
Multigravida
SAB risk (%)
12
19
24
5
4
5
14
Age and Risk of SAB
(Knudsen et al.,
1991)
n=19,737
Age
20-29
30-34
35-39
40+
SAB risk (%)
11.3 (10.9-11.8)
9.7 (9.2-12.7)
11.5 (10.6-12.6)
21.4 (19.2-23.7)
42.2 (35.1-47.4)
Number of Previous SABs
and Risk of SAB (Knudsen et al., 1991)
Previous SABs
0
1
Because of
2
this, ACOG
advises W/U
3
After 2
4
SAB risk (%)
10.7 (10.3-11.2)
15.9 (15.4-16.4)
25.1 (23.4-27)
45.0 (39.8-50.4)
54.3 (43.7-64.4)
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


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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
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)
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
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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)

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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
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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

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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)

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Three or more SABs occurs in 0.51.0% of couples (Alberman, 1988)
In most women, no cause can be
identified (Harger et al., 1983)
Chromosomal
Abnormalities & RSA
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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)
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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

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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
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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
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Hysterosalpingogram
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Very sensitive for Mullerian
abnormalities
Hysterosonogram

More sensitive for myomas and polyps
(Goldberg et al., 1997; Keltz et al., 1997)
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MRI
Hysteroscopy/ Laparoscopy
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Gold standard
Uterine Factor & RSA:
Evaluation
Hysterosalpingogram (HSG)
Uterine Factor & RSA:
Evaluation
Hysterosalpingogram (HSG)
Septated Uterus
Bicornuate Uterus
Intrauterine
Adhesions
Polyps
Uterine Factor & RSA:
Evaluation
Hysterosonogram (HSN)
Polyps
Intrauterine Adhesions
Uterine Factor & RSA:
Treatment
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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
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ACOG: “mixed results” for septum
repair; association of RSA with
polyps and myomas controversial
IVF with gestational surrogacy
Infectious Agents & RSA

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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

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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)

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Routine thromboprophylaxis during
pregnancy cannot be recommended for
women with thrombophilic
abnormalities
If used, get hematologic consultation
Antiphospholipid Antibody
Syndrome & RSA: Evaluation
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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
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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
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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
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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
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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)
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Controversial: Metformin  SAB risk
(Glueck et al., 2001; Jakubowicz et al., 2002; Heard et al., 2002)
Endocrine Disorders & RSA:
Luteal Phase Defect
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No difference in P4 levels in RSA pts
going to term with next pregnancy
versus having another abortion
(Ogasawara et al., 1997)
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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

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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
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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
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McDonald cerclage (1963)
Shirodkar operation (1955)
Modified Shirodkar cerclage
(Caspi et al.,
1990)
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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 Medicine
Montefiore Institute for Reproductive Medicine &
Health
Hartsdale, NY
(914) 997-1060