risk of recurrent pregnancy loss. introduction emotionally traumatic, similar to stillbirth or...
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RISK OF RECURRENT PREGNANCY LOSS
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INTRODUCTION
Emotionally traumatic, similar to stillbirth or neonatal death
Etiology is often unknown Primary or secondary
Live birth occurred at some time in secondary Better prognosis with secondary
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DEFINITION
≥ 3 consecutive losses of clinically recognized pregnancies < 20 week gestationEctopic, molar, and biochemical pregnancies not included
15 % experience sporadic loss of clinically recognized pregnancy
2 % experience 2 consecutive losses0.15 x 0.15 = 0.0225 = 2 %
0.4 to 1 % experience 3 consecutive losses 0.15 x 0.15 x 0.15 = 0.003 = 0.3 % observed frequency is
higher than expected by chance alone
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RISK FACTORS AND ETIOLOGY
Only in 50 %, the cause can be determined Etiological categories:
UterineImmunologicEndocrineGeneticThrombophilicEnvironmental
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UTERINE FACTORS
Acquired or congenital anomalies Congenital anomalies: 10 -15 % in ♀ with
RPL vs. 7 % in all ♀ Abnormal implantation:
↓ vascularity (septum)↑ inflammation (fibroid)↓ sensitivity to steroid hormones
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SEPTATE UTERUS
Most common Poorest outcome Miscarriage > 60 % Fetal survival with untreated cases 6 to 28 % The longer, the worse The mechanism
Not clearly understoodPoor blood supply poor implantation
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LEIOMYOMA
Submucous The mechanism
Their positionPoor endometrial receptivityDegeneration with increasing cytokine
production
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OTHER UTERINE CAUSES
Endometrial polypsRx: Polypectomy
Intrauterine adhesionsCurettage for pregnancy complications (4/52)Traumatize basalis layer granulation tissueInsufficient endometrium to support
fetoplacental growth Menstrual irregularities (hypomenorrhea,
amenorrhea), cyclic pelvic pain, infertility.
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OTHER UTERINE CAUSES
Cervical insufficiencyRecurrent mid-trimester loss
Other uterine anomaliesImpaired uterine distention
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IMMUNOLOGIC FACTORS
Antiphospholipid syndrome (APAS)5 - 15 % of ♀ with RPL may have APAS
Other immunological factorsNot well defined
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ENDOCRINE FACTORS
Luteal phase defectProgesterone is essential for implantation and
maintenance of pregnancy○ A defect in C.L. impaired progesterone
productionControversies:
○ Does this defect really exists?○ If it does, is related to miscarriage?○ No consensus on method of diagnosis○ No consensus on method of treatment
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ENDOCRINE FACTORS
Diabetes mellitusPoorly controlled early (and late) loss
○ No ↑ risk with well-controlled Mechanism
○ Hyperglycemia○ Maternal vascular disease○ Immunologic factors (possible)
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ENDOCRINE FACTORS
Insulin resistance No strong evidencePCOS
○ Miscarriage 20 - 40% vs. baseline rate 10 - 20%Mechanism is unknown
○ ↑ LH, Testosterone, and androstenedione adversely affect the endometrium
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ENDOCRINE FACTORS
Thyroid disease and antibodiesPoorly controlled hypo- or hyper-thyroidism
○ Infertility & pregnancy loss ↑ thyroid antibody, even if euthyroid.
○ No strong evidence
HyperprolactinemiaRx ↑ successful pregnancy (86 vs. 52%)BUT, need correct diagnosisAt what level to treat?
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GENETIC FACTORS
↑ RPL in 1st degree relatives of ♀ with unexplained RPLShared HLA types, coagulation defects, immune
dysfunction, other undefined heritable factors Chromosomal rearrangements
5 % of couples with RPL have major chromosomal defects (vs. 0.7 %)○ Balanced translocation or an inversion
Even if present, may not be the cause complete evaluation of RPL is indicated
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THROMBOPHILIA
Thrombosis on maternal side of the placenta impair placental perfusionLate fetal loss, IUGR, abruption, or PIH
Relationship with early loss is less clearlarge and contradictory literature May be restricted to specific defects not
completely defined, or presence of multiple defects
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MISCELLANEOUS Environmental chemicals & stress
Anesthetic gases (nitrous oxide), formaldehyde, pesticides, lead, mercury○ Sporadic spontaneous loss ○ No evidence of associations with RPL
Personal habits Obesity, smoking, alcohol, and caffeine
○ Association with RPL is unclearMay act in a dose-dependent fashion or synergistically to
↑ sporadic pregnancy loss Exercise
does not ↑ sporadic or RPL
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MISCELLANEOUS Male factor
Trend toward repeated miscarriages with abnormal sperm (< 4% normal forms, sperm chromosome aneuploidy) ○ ICSI
Paternal HLA sharing not risk factor for RPLAdvanced paternal age may be a risk factor for
miscarriage (at more advanced age than females) Infection
Listeria, Toxoplasma, CMV, and primary genital herpes
Cause sporadic loss, but not RPL
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MISCELLANEOUS
Decreased ovarian reserveQuality and quantity of oocytes decrease♀ with unexplained RPL have a higher D3 FSH
and E2 than ♀ with known cause Celiac disease
Untreated & even subclinical, associated with pregnancy loss, menstrual disorders, and infertilityTreatment prevent these problems
No evidence that it causes RPL
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CANDIDATES FOR EVALUATION
Evaluate and Rx ≥ 2 or 3 consecutive losses Most have good prognosis for a successful
pregnancy, even when no Dx or Rx The minimum workup:
Complete medical, surgical, genetic, and family history
Physical examination
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HISTORY
GA & characteristics (anembryonic pregnancy, live embryo) of all previous pregnanciesRPL typically occurs at a similar GAMost common causes of RPL vary by trimester
○ Chromosomal & endocrine earlier than anatomic or immunological causes
Uterine instrumentation intrauterine adhesions Menstrual cycles regularity endocrine
dysfunction Galactorrhea, Headache, Visual disturbances
hyperprolactinemia
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HISTORY
Thyroid related symptoms Hx of congenital or karyotypic abnormalities
heritable Was cardiac activity detected? If not suggests
chromosomal abnormality Does F.Hx display patterns of disease consistent with
strong genetic influence? consanguinity Exposure to environmental toxins Hx venous thrombosis thrombophilia or APAS Information from previous laboratory, pathology, and
imaging studies
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PHYSICAL EXAMINATION
General physical Signs of endocrinopathy (hirsutism,
galactorrhea, thyroid) Pelvic organ abnormalities (uterine
malformation, cervical laceration)
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LABORATORY EVALUATION
Karyotype (Parental)Low yield & limited prognostic value only if
the other work-up was negative Karyotype (Embryonic)
Not really neededMay consider after 2nd lossIf abnormal karyotype + normal parents “bad
luck”
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UTERINE ASSESSMENT Sonohysterography (SIS)
More accurate than HSG Differentiate septate & bicornuate uterus
Hysterosalpingogram (HSG)Does not evaluate outer contourNot ideal for the cavity
HysteroscopyGold standard for Dx + Rx intrauterine lesionsCannot differentiate septate from bicornuateReserved for when no Dx is made
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UTERINE ASSESSMENT
UltrasoundPresence and location of uterine myomas Associated renal abnormalities
MRIDifferentiate septate from bicornuate
Hysteroscopy, laparoscopy, or MRI second-line tests when additional information is required
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APAS Dx: one lab & one clinical criteria are met Clinical criteria:
Venous or arterial thrmobosisRPL
Laboratory criteriaLupus anticoagulantAnticardiolipin antibody (IgG and IgM)
Medium or high titers of bothLow to mid positive can be due to viral illness
Repeat twice, 6-8 weeks apart
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THROMBOPHILIA
Contradictory literature Evaluate if loss > nine weeks + evidence of
placental infarction or maternal thrombosis
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THYROID
TSH +/- FT4 & FT3More important in ♀ with clinical manifestations
but even in asymptomatic Thyroid peroxidase antibody
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OVARIAN RESERVE
D3 FSH +/- D3 E2 in ♀ of any age or ¼ would be missed
Clomiphene challenge test
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NONE USEFUL TESTS
Routine cervical cultures for Chlamydia, Mycoplasma & vaginal evaluation for BV & toxoplasmosis serology
ANA Screening for DM Immune function (HLA typing, etc) Progesterone level (Single or multiple) Endometrial biopsy
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MANAGEMENT
Prognosis for successful future pregnancy is goodlive birth rates after normal and abnormal
diagnostic evaluations, 77 and 71 percent, respectively
Emotional support is important and enhance success
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PARENTAL KARYOTYPE ABNORMALITY
Refer for genetic counselingInformation for probability of a chromosomally
normal or abnormal conception May undergo prenatal genetic studies
AmniocentesisCVSIVF with PGD
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UTERINE ABNORMALITIES
Managed hysteroscopically Septum, adhesions, submucosal myoma
Cervical cerclage Second trimester loses
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MANAGEMENT Antiphospholipid syndrome
Aspirin & Heparin Suspected immunologic dysfunction
Several immunologic Rx advocatedNone effectiveSome are harmful
DMControlled at least 6/12 prior to conception
ThyroidHyper and Hypo thyroid should be controlledEuthyroid with ↑ peroxidase antibody may benefit
from treatment
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MANAGEMENT
Polycystic ovary syndrome No agreed upon protocolMetformin just as effective when stopped at
diagnosis of pregnancy or 12/52 gestation Hyperprolactinemia
Normal levels play important role in maintaining early pregnancy (in RPL)
Thrombophilia Anticoagulation if loss > 9/52
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UNEXPLAINED RPL
50% of RPL remain unexplained Prognosis is still good
>50 % live birth even without intervention
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UNEXPLAINED RPL
Lifestyle modification Eliminating use of tobacco, alcohol, and caffeine
& reduction in BMI (for obese women). Progesterone
Widely used but studies on its efficacy are lackingVaginally or IM
Human menopausal gonadotropinCorrecting LPD or creating thicker endometriumClinical experience supports the efficacy
IVF +/- PGDMixed resultsPromising
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UNEXPLAINED RPL
Useless interventions:hCGCC
Pregnancy issues Increased risk of :
○ IUGR○ PTD
No increased risk of:○ PIH○ GDM
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Thank you