Dr. Sharda JainDirector: Global Institute of Gynaecoloy at Pushpanjali
Crosslay HospitalSecretary general: Delhi
Gynaecologist Forum
Recurrent Pregnancy Recurrent Pregnancy LossLoss
Learning ObjectivesLearning Objectives
Identify possible causes of Identify possible causes of early pregnancy lossearly pregnancy loss
Outline basic evaluation for Outline basic evaluation for recurrent pregnancy loss recurrent pregnancy loss (RPL)(RPL)
Review current treatment Review current treatment approaches for these approaches for these patientspatients
DefinitionDefinition Classical: 3 or more Classical: 3 or more
consecutive pregnancy consecutive pregnancy losses before 20 weeks losses before 20 weeks gestationgestation
Expanded: 2 or more Expanded: 2 or more consecutive lossesconsecutive losses Risk of further loss similar for 2 Risk of further loss similar for 2
versus 3 consecutive lossesversus 3 consecutive losses Initiation of evaluation Initiation of evaluation
appropriate after 2 losses based appropriate after 2 losses based on patient age and desireon patient age and desire
Hill Curr Prob Obstet Gynecol Fertil 1994;37:693-704
RecurrentRecurrent Loss Loss EpidemiologyEpidemiology
5% of couples attempting 5% of couples attempting pregnancy have 2 or more pregnancy have 2 or more consecutive lossesconsecutive losses
1% have 3 or more 1% have 3 or more consecutive lossesconsecutive losses
Most clinicians consider RPL Most clinicians consider RPL even if losses are not even if losses are not consecutiveconsecutive
Lee Semin Reprod Med 2000;18(4):433-40
SPAB SPAB Epidemiology Epidemiology
34% pregnancy loss in 34% pregnancy loss in prospective cohort of healthy prospective cohort of healthy womenwomen 22% unrecognized - detected by 22% unrecognized - detected by
assay onlyassay only 12 % clinically recognized12 % clinically recognized
Obstetrical history predictiveObstetrical history predictive prior success: 4-6 % chance of prior success: 4-6 % chance of
lossloss prior loss: 19-24%chance of lossprior loss: 19-24%chance of lossWilcox NEJM 1988;319:189-194
SPAB or RPL?SPAB or RPL?
A single SAB, unless a A single SAB, unless a successful pregnancy successful pregnancy intervenes, increases the risk intervenes, increases the risk for the next pregnancyfor the next pregnancy
Distinction between “sporadic” Distinction between “sporadic” and “recurrent” loss blurredand “recurrent” loss blurred
Effect of maternal age: SAB Effect of maternal age: SAB risk approaches 50% by age 40 risk approaches 50% by age 40 for both aneuploid and euploid for both aneuploid and euploid losseslosses
Cramer Semin Reprod Med 2000;18(4):331-9
Miscarriage Recurrence Miscarriage Recurrence RiskRisk
OutcomeOutcome Prior Prior LossesLosses
Recurrence Recurrence Risk %Risk %
LivebornLiveborn 00 1212
11 2424
22 2626
33 3232
44 2626
No No LiveLive BirthsBirths
11 1919
22 3535
33 4747
44 5454Warburton D, Fraser FC: Am J Human Genet 16:1, 1964
PCOS & Pregnancy LossPCOS & Pregnancy Loss
Pregnancy loss ↑ with PCOSPregnancy loss ↑ with PCOS Franks S, Ann Int Med 93, Jacobs HS BRJOBGYN 93
GnRH-a ↓ miscarriage in PCOS GnRH-a ↓ miscarriage in PCOS womenwomen
Homburg R, et al: Fertil Steril 59:527, 1993
RSA patients with ↑ LH, DHEAS or RSA patients with ↑ LH, DHEAS or T more likely to miscarryT more likely to miscarry
Tulpalla M, et al: BrJOBGYN 100:348, 1993
GnRH-a ↓ miscarriages in RSA GnRH-a ↓ miscarriages in RSA patients with PCOS compared to patients with PCOS compared to clomid (10% vs 55%)clomid (10% vs 55%)
Johnson P, et al: BMJ 300:154, 1990
Metformin Reduces Metformin Reduces Pregnancy Loss in PCOSPregnancy Loss in PCOS
Retrospective study of PCOS Retrospective study of PCOS women who became pregnantwomen who became pregnant Group 1: metformin during Group 1: metformin during
pregnancy (n=101)pregnancy (n=101) Group 2: control (n=31)Group 2: control (n=31)
Early loss rate 12.9% vs Early loss rate 12.9% vs 41.9% 41.9% (p=0.001)(p=0.001)
Prior SPAB: 15.7% vs 58.3% Prior SPAB: 15.7% vs 58.3% (p=0.005)(p=0.005)Jakubowicz DJ, et al: abstract P2-427, Endocrine Society, 2001Jakubowicz DJ, et al: abstract P2-427, Endocrine Society, 2001
Etiology Etiology Anatomic Anatomic FactorsFactors
10-15% recurrent 110-15% recurrent 1stst trimester trimester losses have congenital losses have congenital anomalyanomaly
Variations of the double Variations of the double uterus the most commonuterus the most common
Septate loss rates 25-90% - Septate loss rates 25-90% - usually amenable to resectionusually amenable to resection
Bicornuate loss rates 40% - Bicornuate loss rates 40% - uncertain benefit of surgeryuncertain benefit of surgery
Propst & Hill Semin Reprod Med 2000;18(4):341-50
Etiology Etiology Anatomic Anatomic FactorsFactors
Unicornuate uteri 50% lossUnicornuate uteri 50% loss Uterus didelphys 40% lossUterus didelphys 40% loss DES exposure - many have DES exposure - many have
abnormal uterine structureabnormal uterine structure Cervical incompetenceCervical incompetence Intrauterine synechiaeIntrauterine synechiae
Etiology Etiology Anatomic Anatomic FactorsFactors
Unclear relationship between Unclear relationship between uterine leiomyomata and RPLuterine leiomyomata and RPL Large submucosal fibroids distort Large submucosal fibroids distort
the cavity or occupy a large the cavity or occupy a large subendometrial areasubendometrial area
? Mechanism(s) - mechanical ? Mechanism(s) - mechanical constriction or inadequate constriction or inadequate placentation resulting from poorly placentation resulting from poorly vascularized endometriumvascularized endometrium
Acquired Uterine DefectsAcquired Uterine Defects
Etiology Etiology InfectionInfection
No infectious agent has been No infectious agent has been proven to cause recurrent proven to cause recurrent pregnancy losspregnancy loss ? Colonization with ? Colonization with Ureaplasma Ureaplasma
urealyticum urealyticum leading to empiric leading to empiric antibioticsantibiotics
Certain infections have been Certain infections have been associated with spontaneous associated with spontaneous lossloss Toxoplasma gondiiToxoplasma gondii, rubella, HSV, , rubella, HSV,
CMV, measles, coxsackieCMV, measles, coxsackie
Lee Semin Reprod Med 2000;18(4):433-40
Etiology Etiology Genetic FactorsGenetic Factors
Trisomy (50%) #16 all lethal 1/3 of all
trisomies #21 Down Syndrome
usually due to meiotic non-disjunction 80% maternatal
Monsomy X (20%) 45X Turner Syndrome
most common Triploidy (15%)
90% from father Tetraploidy (5%) Mosaicism (2%)
% Chromosomal % Chromosomal Abnormal by Abnormal by
Gestational AgeGestational Age
% abnormal% abnormal Gestational Gestational ageage
6060 1212
4545 1616
1212 2020
66 2424
~1~1 4040
Etiology Etiology Genetic Genetic FactorsFactors
Parental abnormalities in Parental abnormalities in 3-5% of couples with 3-5% of couples with recurrent lossrecurrent loss
Balanced translocation Balanced translocation most commonmost common Reciprocal (60%) or Reciprocal (60%) or
Robertsonian (40%)Robertsonian (40%) 25-50% risk of pregnancy 25-50% risk of pregnancy
lossloss May eventually produce May eventually produce
normal offspringnormal offspring
Etiology Etiology Genetic Genetic FactorsFactors
Etiology Etiology Genetic Genetic FactorsFactors
Homologous Homologous Robertsonian Robertsonian translocationtranslocation 1/2500 couples1/2500 couples precludes successful precludes successful
reproductionreproduction Heterozygous may lead Heterozygous may lead
to partial monosomy or to partial monosomy or trisomy; “milder” trisomy; “milder” phenotypical phenotypical expressionexpression
Ward Semin Reprod Med 2000;18(4):425-32
Etiology Etiology Genetic Genetic FactorsFactors
Speculation about single Speculation about single gene mutations gene mutations Blastocyst formationBlastocyst formation ImplantationImplantation Morphogenesis of vital organsMorphogenesis of vital organs
Etiology Etiology Genetic Genetic FactorsFactors
Skewed X inactivationSkewed X inactivation Preferential inactivation(>90%) Preferential inactivation(>90%)
of one of the X allelesof one of the X alleles May be lethal to a male offspringMay be lethal to a male offspring May result in X-autosome May result in X-autosome
translocationstranslocations Trisomy mosaicism in the Trisomy mosaicism in the
germlinegermline
Etiology Etiology Genetic Genetic FactorsFactors
Advanced maternal ageAdvanced maternal age Impact on risk for pregnancy loss Impact on risk for pregnancy loss
cannotcannot be over-emphasized be over-emphasized Increased rates of maternally-Increased rates of maternally-
derived trisomiesderived trisomies Probable “natural selection” of Probable “natural selection” of
better quality oocytes earlier in better quality oocytes earlier in reproductive lifereproductive life
Oocytes recruited later in life Oocytes recruited later in life more likely to be abnormal or more likely to be abnormal or experience meiotic errorexperience meiotic error
Lobo, R. A. N Engl J Med 2005;353:64-73
Decline in the Number of Oocytes from Birth to Menopause
Heffner, L. J. N Engl J Med 2004;351:1927-1929
Fertility and Miscarriage Rates as a Function of Maternal Age
EtiologyEtiology ThrombophiliaThrombophilia
Pregnancy is a Pregnancy is a hypercoagulable statehypercoagulable state
Women with heritable or Women with heritable or acquired thrombophilic acquired thrombophilic disorders have significantly disorders have significantly increased risks of pregnancy increased risks of pregnancy lossloss
Kutteh Semin Reprod Med 2006;24(1):54-65
EtiologyEtiology ThrombophiliaThrombophilia Venous Venous
Most common inherited:Most common inherited: Heterozygous Factor V Leiden Heterozygous Factor V Leiden
(G1691A)(G1691A) Factor II-prothrombin mutation Factor II-prothrombin mutation
(G20210A)(G20210A) Hyperhomocysteinemia (MTHFR Hyperhomocysteinemia (MTHFR
C677T and A1298C)C677T and A1298C)
EtiologyEtiology ThrombophiliaThrombophilia Venous Venous
Most common acquired:Most common acquired: Anti-phospholipid antibodies Anti-phospholipid antibodies
(APAs)(APAs) Activated Protein C resistanceActivated Protein C resistance Hyperhomocysteinemia (MTHFR Hyperhomocysteinemia (MTHFR
C677T and A1298C)C677T and A1298C) Other possible abnormalitiesOther possible abnormalities
Anti-thrombin deficiencyAnti-thrombin deficiency Protein C or S deficiencyProtein C or S deficiency Elevated Factor VIIIElevated Factor VIII
EtiologyEtiology ThrombophiliaThrombophilia Arterial Arterial
HyperhomocysteinemiaHyperhomocysteinemia APAsAPAs Lupus anticoagulantLupus anticoagulant
EtiologyEtiology ThrombophiliaThrombophilia
Factor V LeidenFactor V Leiden Abnormal factor V resistant to Abnormal factor V resistant to
anticoagulant effects of activated anticoagulant effects of activated protein Cprotein C
Majority of patients resistant to Majority of patients resistant to activated protein C will be activated protein C will be heterozygous for Factor V Leidenheterozygous for Factor V Leiden
Present in 3-8% of the White Present in 3-8% of the White populationpopulation
Rare in Blacks, Asians, Native Rare in Blacks, Asians, Native AmericansAmericans
EtiologyEtiology ThrombophiliaThrombophilia
Factor V LeidenFactor V Leiden Autosomal dominantAutosomal dominant Acquired activated protein C Acquired activated protein C
resistance in pregnancy, OCP use resistance in pregnancy, OCP use and in presence of APAsand in presence of APAs
Heterozygotes: 7X increase Heterozygotes: 7X increase lifetime risk thrombosis; 15X lifetime risk thrombosis; 15X increase during pregnancy or increase during pregnancy or OCP useOCP use
Homozygotes: 50-100X increase Homozygotes: 50-100X increase lifetime risk thrombosislifetime risk thrombosis
EtiologyEtiology ThrombophiliaThrombophilia
Prothrombin G20210A Prothrombin G20210A MutationMutation Higher plasma prothrombin Higher plasma prothrombin
concentrations, augmented concentrations, augmented thrombin generationthrombin generation
Heterozygotes: 2-3% WhitesHeterozygotes: 2-3% Whites Conflicting prevalence studies Conflicting prevalence studies
among RPLamong RPL Recent critical review suggests Recent critical review suggests
an associationan association
EtiologyEtiology ThrombophiliaThrombophilia
Hyperhomocysteinemia Hyperhomocysteinemia polymorphismspolymorphisms C677T thermolabile MTHFRC677T thermolabile MTHFR
Heterozygous 10-20% Whites• Normal or slightly elevated
homocysteine• Increased homocysteine when
combined with B vitamin deficiencies
Homozygous 10% Whites• Significantly increased
homocysteine
EtiologyEtiology ThrombophiliaThrombophilia
Hyperhomocysteinemia Hyperhomocysteinemia polymorphismspolymorphisms A1298C often occurs with A1298C often occurs with
thermolabile C677Tthermolabile C677T 33% frequency in Dutch
population Combined heterozygosity
results in hyperhomocysteinemia and decreased plasma folate levels
EtiologyEtiology ThrombophiliaThrombophilia
Hyperhomocysteinemia Hyperhomocysteinemia polymorphismspolymorphisms Significant association between Significant association between
hyperhomocysteinemia and RPLhyperhomocysteinemia and RPL ? Mechanism: interference in ? Mechanism: interference in
embryonic development through embryonic development through defective chorionic villous defective chorionic villous vascularizationvascularization
Known association with later Known association with later pregnancy-related complicationspregnancy-related complications
EtiologyEtiology ThrombophiliaThrombophilia
Anti-thrombin DeficiencyAnti-thrombin Deficiency Physiologic inhibitor of coagulationPhysiologic inhibitor of coagulation
Type I: quantitative; decreased antigen and function; caused by gene deletions, nucleotide changes
Type II: qualitative; normal antigen levels, decreased function; caused by point mutations with single amino acid changes leading to a dysfunctional protein
EtiologyEtiology ThrombophiliaThrombophilia
Anti-thrombin DeficiencyAnti-thrombin Deficiency Autosomal dominantAutosomal dominant Prevalence Type I heterozygous Prevalence Type I heterozygous
carriers: 1/2000 – 1/5000carriers: 1/2000 – 1/5000 Prevalence Type II heterozygous Prevalence Type II heterozygous
carriers: 3/1000carriers: 3/1000 Most thrombogenic of inherited Most thrombogenic of inherited
thrombophilia: 20-50% lifetime thrombophilia: 20-50% lifetime riskrisk
Associated increased risk Associated increased risk stillbirth and fetal lossstillbirth and fetal loss
EtiologyEtiology ThrombophiliaThrombophilia
Protein C DeficiencyProtein C Deficiency Down-regulates coagulation Down-regulates coagulation
cascade; deficiencies lead to cascade; deficiencies lead to unregulated fibrin formationunregulated fibrin formation
Autosomal dominant: > 160 Autosomal dominant: > 160 mutationsmutations
Type I: quantitativeType I: quantitative Type II: decreased functionType II: decreased function Associated with 2Associated with 2ndnd trimester trimester
losseslosses
EtiologyEtiology ThrombophiliaThrombophilia
Protein S DeficiencyProtein S Deficiency Principal cofactor of activated Protein C; Principal cofactor of activated Protein C;
mimics C deficiency: questionable mimics C deficiency: questionable association with pregnancy lossassociation with pregnancy loss
Autosomal dominant: > 160 mutations: Autosomal dominant: > 160 mutations: prevalence 0.15-0.8% general prevalence 0.15-0.8% general population; acquired forms in multiple population; acquired forms in multiple disease statesdisease states
Type I: quantitativeType I: quantitative Type II: decreased functionType II: decreased function Type III: low free protein, normal Type III: low free protein, normal
antigen, reduced activityantigen, reduced activity
EtiologyEtiology Luteal Phase Luteal Phase DefectDefect
Luteal phase defect is a Luteal phase defect is a controversial cause of RPLcontroversial cause of RPL Studies proving LPD as a Studies proving LPD as a
cause of RPL lackingcause of RPL lacking No convincing studies showing No convincing studies showing
LPD treatment improves LPD treatment improves pregnancy outcomepregnancy outcome
Lee Semin Reprod Med 2000;18(4):433-40 80% of women with low 80% of women with low
midluteal progesterone midluteal progesterone proceed to termproceed to term
20% of fertile women have 20% of fertile women have abnormal endometrial biopsiesabnormal endometrial biopsies
P4 drops after meals & P4 drops after meals & standingstanding
Etiology Etiology Endocrine Endocrine FactorsFactors
Poorly controlled diabetesPoorly controlled diabetes Overt hyperthyroidismOvert hyperthyroidism Overt hypothyroidismOvert hypothyroidism No evidence that No evidence that
asymptomatic systemic asymptomatic systemic endocrinologic or metabolic endocrinologic or metabolic disorders are a cause of RPLdisorders are a cause of RPL
EtiologyEtiology Autoimmune Autoimmune FactorsFactors
Certain autoimmune diseases Certain autoimmune diseases are associated with are associated with pregnancy losspregnancy loss Systemic lupus erythematosisSystemic lupus erythematosis
1st trimester loss: 10% risk 2nd and 3rd trimester loss: 6%
Anti-phospholipid syndromeAnti-phospholipid syndrome 2nd trimester loss: 38%
Fausett & Branch Semin Reprod Med 2000;18(4):379-392
EtiologyEtiology Autoimmune Autoimmune FactorsFactors
Anti-phospholipid antibodies Anti-phospholipid antibodies (aPL)(aPL) autoantibodies recognizing autoantibodies recognizing
various combinations of various combinations of phospholipids, phospholipid-phospholipids, phospholipid-binding proteins, or bothbinding proteins, or both
Anti-phospholipid syndrome Anti-phospholipid syndrome (APS) - clinical association (APS) - clinical association between aPL and syndrome between aPL and syndrome of hypercoagulabilityof hypercoagulability
Levine NEJM 2002;346:752-63
EtiologyEtiology Autoimmune Autoimmune FactorsFactors
APS diagnostic criteria:APS diagnostic criteria: Clinical featuresClinical features
Vascular thrombosis or Loss of fetus at or after 10
weeks or Preterm delivery at or before
34 weeks or 3 or more consecutive SAB
before 10 weeks
EtiologyEtiology Autoimmune Autoimmune FactorsFactors
APS diagnostic criteria:APS diagnostic criteria: Laboratory featuresLaboratory features
Anti-cardiolipin (aCL) antibodies: IgG or IgM at moderate or high levels on 2 or more occasions at least 6 weeks apart
Lupus anticoagulant (LA) antibodies: detected on 2 or more occasions at least 6 weeks apart
EtiologyEtiology Autoimmune Autoimmune FactorsFactors
Other anti-phospholipid Other anti-phospholipid antibodiesantibodies Anti-phosphatidylserine: nearly Anti-phosphatidylserine: nearly
always associated with APS, always associated with APS, highly correlated to cardiolipin highly correlated to cardiolipin bindingbinding
Other antibodies have less Other antibodies have less correlationcorrelation
No consistency among reported studies
No independence from aCL
Fausett Semin Reprod Med 2000;18(4):379-92
EtiologyEtiology Autoimmune Autoimmune FactorsFactors
Low levels of aPL are not Low levels of aPL are not associated with RPLassociated with RPL
Assays for non-aCL aPL are Assays for non-aCL aPL are not standardizednot standardized
Studies thus far are Studies thus far are contradictorycontradictory
EtiologyEtiology Autoimmune Autoimmune FactorsFactors
Other auto-antibodies NOT Other auto-antibodies NOT associated with RPLassociated with RPL Anti-nuclear antibodies may be Anti-nuclear antibodies may be
more common among women more common among women with RPL but their presence or with RPL but their presence or absence do not predict absence do not predict subsequent pregnancy outcomesubsequent pregnancy outcome
EtiologyEtiology Autoimmune Autoimmune FactorsFactors
Other auto-antibodies NOT Other auto-antibodies NOT associated with RPLassociated with RPL Anti-thyrogobulin and anti-Anti-thyrogobulin and anti-
thyroid peroxidase are markers of thyroid peroxidase are markers of increased risk for pregnancy loss increased risk for pregnancy loss if identified early in pregnancyif identified early in pregnancy
Some small studies suggest a Some small studies suggest a slight association in RPL; other slight association in RPL; other larger studies do notlarger studies do not
Subsequent pregnancy outcomes Subsequent pregnancy outcomes not affectednot affected
EtiologyEtiology Alloimmune Alloimmune FactorsFactors
Immune response to non-self Immune response to non-self components of pregnancycomponents of pregnancy Cytotoxic antibodiesCytotoxic antibodies Absence of maternal blocking Absence of maternal blocking
antibodiesantibodies Inappropriate sharing of HLAInappropriate sharing of HLA Disturbances in natural killer cell Disturbances in natural killer cell
function and distributionfunction and distribution
Porter Semin Reprod Med 2000;18(4):393-400
EtiologyEtiology Alloimmune Alloimmune FactorsFactors
Cytotoxic antibodiesCytotoxic antibodies Maternal response to paternal Maternal response to paternal
antigensantigens Present in normal pregnanciesPresent in normal pregnancies More common in fertile couples More common in fertile couples
than those with RPLthan those with RPL No bearing on subsequent No bearing on subsequent
pregnancy outcomepregnancy outcome
EtiologyEtiology Alloimmune Alloimmune FactorsFactors
Blocking antibodiesBlocking antibodies Theory: maternal anti-fetal Theory: maternal anti-fetal
antibodies block maternal cell-antibodies block maternal cell-mediated response; if absent, mediated response; if absent, then fetal rejection occursthen fetal rejection occurs
EtiologyEtiology Alloimmune Alloimmune FactorsFactors
Blocking antibodiesBlocking antibodies Not present in normal Not present in normal
pregnancies, yet are often pregnancies, yet are often present in RPLpresent in RPL
Detected by the non-specific Detected by the non-specific mixed lymphocyte response mixed lymphocyte response assayassay
EtiologyEtiology Alloimmune Alloimmune FactorsFactors
Blocking antibodiesBlocking antibodies Animal model: B-cell deficient Animal model: B-cell deficient
(agammaglobulinemic) mice have (agammaglobulinemic) mice have normal pregnancy outcomesnormal pregnancy outcomes
Human agammaglobulinemics Human agammaglobulinemics have successful pregnancieshave successful pregnancies
Presence or absence not Presence or absence not predictive of subsequent outcomepredictive of subsequent outcome
EtiologyEtiology Alloimmune Alloimmune FactorsFactors
Parental HLA sharingParental HLA sharing Theory: if parents are Theory: if parents are
antigenically similar, mother is antigenically similar, mother is less likely to develop blocking less likely to develop blocking antibodiesantibodies
Studies contradictory: some show Studies contradictory: some show increased sharing in HLA-B and increased sharing in HLA-B and HLA-DR lociHLA-DR loci
Most show no associationsMost show no associations
EtiologyEtiology Alloimmune Alloimmune FactorsFactors
Natural killer cellsNatural killer cells Theory: CD56+ NK-like cells Theory: CD56+ NK-like cells
secrete a transforming growth secrete a transforming growth factor-factor--like substance crucial to -like substance crucial to the maintenance of pregnancythe maintenance of pregnancy
Present in endometria and early Present in endometria and early gestational decidua of women gestational decidua of women with RPLwith RPL
EtiologyEtiology Alloimmune Alloimmune FactorsFactors
Natural killer cellsNatural killer cells Murine models show activation of Murine models show activation of
NK cells increases the rate of NK cells increases the rate of abortion; depletion of NK cells abortion; depletion of NK cells has opposite effecthas opposite effect
Human studies show no Human studies show no association of testing and association of testing and successful pregnancysuccessful pregnancy
EtiologyEtiology Alloimmune Alloimmune FactorsFactors
T helper (Th1) T helper (Th1) immunodystrophismimmunodystrophism Theory: aberrant or inappropriate Theory: aberrant or inappropriate
Th1 stimulation may result in Th1 stimulation may result in overproduction of cytokines that overproduction of cytokines that have deleterious effect on have deleterious effect on conceptusconceptus
Dichotomous Th1 versus Th2 Dichotomous Th1 versus Th2 cytokine profile associated with cytokine profile associated with human pregnancy loss and human pregnancy loss and successsuccessHill Semin Reprod Med 2000;18(4):401-405
EtiologyEtiology Male Male FactorFactor
No significant difference in semen No significant difference in semen parameters among men whose partners parameters among men whose partners have RPL compared to WHO standards and have RPL compared to WHO standards and men fathering successful pregnanciesmen fathering successful pregnancies
No difference in incidence of anti-sperm No difference in incidence of anti-sperm antibodiesantibodies
Aside from cytogenetic abnormalities,Aside from cytogenetic abnormalities, male male factor contribution to RPL unknownfactor contribution to RPL unknown
Hill ASRM 2002 Course 6 p.56 DNA Fragmentation may result in early DNA Fragmentation may result in early
embryo lossembryo lossHum Reprod. 2006 Nov;21(11):2876-81; Check JH: Arch Androl. 2005 Mar-Apr;51(2):121-4
EtiologyEtiology Male Male FactorFactor
RPL males have higher RPL males have higher incidence of sperm incidence of sperm aneuploidy:aneuploidy: Oligoasthenoteratospermia 35-Oligoasthenoteratospermia 35-
74%74% Fertile donor sperm 4-7%Fertile donor sperm 4-7%
Etiology - Etiology - Environmental FactorsEnvironmental Factors
Confirmed Confirmed associationassociation Ionizing irradiationIonizing irradiation Organic solventsOrganic solvents AlcoholAlcohol MercuryMercury LeadLead
Gardella & Hill Semin Reprod Med 2000;18(4):407-424
Suspected Suspected associationassociation Caffeine (> 300 Caffeine (> 300
mg/day)mg/day) Hyperthermia/feverHyperthermia/fever Cigarette smokingCigarette smoking
Unknown associationUnknown association PesticidesPesticides
Etiology - Etiology - Environmental FactorsEnvironmental Factors
Diagnostic x-Diagnostic x-raysrays
Air travelAir travel Microwave Microwave
ovensovens Diagnostic Diagnostic
ultrasoundsultrasounds ElectromagnetiElectromagneti
c fieldsc fields Video display Video display
terminalsterminals AspartameAspartame
ChocolateChocolate Drinking waterDrinking water BGHBGH PhytoestrogenPhytoestrogen
ss PhthalatesPhthalates HerbicidesHerbicides Hair dyesHair dyes Nail polishNail polish SaccharinSaccharin
Etiology - IdiopathicEtiology - Idiopathic
More than 50% of couples More than 50% of couples with RPL have no explanation with RPL have no explanation despite extensive despite extensive evaluation(s)evaluation(s)
Informative and sympathetic Informative and sympathetic counseling appears to play counseling appears to play an important rolean important role 70% live birth rates reported in 70% live birth rates reported in
couples with unexplained RPL couples with unexplained RPL who undertake an untreated who undertake an untreated subsequent pregnancysubsequent pregnancy
Lee Semin Reprod Med 2000;18(4):433-40
EvaluationEvaluation HistoryHistory
Pattern and trimester of pregnancy Pattern and trimester of pregnancy losses and whether a live embryo or losses and whether a live embryo or fetus was presentfetus was present
Exposure to environmental,toxins or Exposure to environmental,toxins or drugsdrugs
Known gynecological or obstetrical Known gynecological or obstetrical infectionsinfections
Features associated with APSFeatures associated with APS
EvaluationEvaluation HistoryHistory
Family history of RPL or syndrome Family history of RPL or syndrome associated with embryonic or fetal associated with embryonic or fetal lossloss
Previous diagnostic tests and Previous diagnostic tests and treatmentstreatments
EvaluationEvaluation PhysicalPhysical
General physical examGeneral physical exam Pelvic examPelvic exam
EvaluationEvaluation
TestsTests Saline Sonogram or hysteroscopySaline Sonogram or hysteroscopy Hysterosalpingogram Hysterosalpingogram ?? Luteal phase endometrial biopsy; ?? Luteal phase endometrial biopsy;
repeat in next cycle if abnormalrepeat in next cycle if abnormal Placental FISH analysisPlacental FISH analysis Parental karyotypesParental karyotypes Lupus anticoagulantLupus anticoagulant Anticardiolipin antibodies IgG and IgMAnticardiolipin antibodies IgG and IgM
EvaluationEvaluation TestsTests
Antiphosphatidylserine antibody Antiphosphatidylserine antibody IgG and IgMIgG and IgM
Platelet countPlatelet count Thrombophilia mutations and Thrombophilia mutations and
functional assaysfunctional assays Thyroid stimulating hormoneThyroid stimulating hormone
EvaluationEvaluation
Tests NOT usefulTests NOT useful Other anti-phospholipid antibodiesOther anti-phospholipid antibodies ANAANA Maternal anti-paternal leukocyte antibodiesMaternal anti-paternal leukocyte antibodies Mixed lymphocyte maternal-paternal cell Mixed lymphocyte maternal-paternal cell
culturescultures HLA genotypingHLA genotyping Mouse embryotoxicity assaysMouse embryotoxicity assays Immunophenotype panels (CD56, CD16)Immunophenotype panels (CD56, CD16)
Hill ASRM 2002 Course 6 p.58-59
Treatment - Treatment - ThrombophiliaThrombophilia
For heritable or acquired For heritable or acquired thrombophilia: heparin thrombophilia: heparin anticoagulationanticoagulation
For bonafide APS, multiple For bonafide APS, multiple studies support use of heparin studies support use of heparin and aspirinand aspirin
Treatment - APSTreatment - APS Aspirin 81 mg po/dayAspirin 81 mg po/day Subcutaneous heparin 10K-Subcutaneous heparin 10K-
20K units/day divided doses20K units/day divided doses Alternative: low-molecular-Alternative: low-molecular-
weight heparin 2500-5000 weight heparin 2500-5000 units/day single doseunits/day single dose
Calcium supplementationCalcium supplementation
Treatment - Treatment - ThrombophiliaThrombophilia
For elevated homocysteinemia For elevated homocysteinemia without thrombosis historywithout thrombosis history Supplementation with Vitamin B6, Supplementation with Vitamin B6,
B12 and folic acidB12 and folic acid Heparin anticoagulation for Heparin anticoagulation for
history of thrombosis or history of thrombosis or homozygous MTHFR mutation homozygous MTHFR mutation or pregnancy outcomes or pregnancy outcomes unresponsive to vitamin unresponsive to vitamin supplementationsupplementation
Empiric Treatment Empiric Treatment Use of aspirin alone Use of aspirin alone
attractive because of ease of attractive because of ease of use and relative safety use and relative safety profile, barring profile, barring contraindication to low-dose contraindication to low-dose aspirin useaspirin use
Supporting data lackingSupporting data lacking
Treatment - Treatment - ImmunotherapyImmunotherapy ““Blocking antibody” Blocking antibody”
hypothesishypothesis Paternal leukocyte immunization Paternal leukocyte immunization
or desensitizationor desensitization Efficacy disproven May increase risk of loss Potential adverse effects:
transfusion reaction, immunization, infection, IUGR, GVH, thrombocytopenia
Treatment - Treatment - ImmunotherapyImmunotherapy ““Blocking antibody” hypothesisBlocking antibody” hypothesis
Intravenous immunoglobulinIntravenous immunoglobulin Studies and meta-analyses show
no benefit Extremely expensive $7-14,000 Side effects: headache,
hypotension, nausea Potential anaphylaxis in IgA
deficient patients Potential for prion disease
transmission due to large pool of donors
Treatment - Treatment - ImmunotherapyImmunotherapy Progesterone called Progesterone called
“nature’s “nature’s immunosuppressant” due to immunosuppressant” due to inhibition of immune cells at inhibition of immune cells at maternal-fetal interfacematernal-fetal interface
No verification yet through No verification yet through RCTRCT
Safe and inexpensiveSafe and inexpensive Dose: 100 mg BID vaginal Dose: 100 mg BID vaginal
suppositories, beginning 3 suppositories, beginning 3 days after ovulationdays after ovulation
Supportive TreatmentSupportive Treatment
60-90% chance of pregnancy 60-90% chance of pregnancy success with supportive care success with supportive care and ...and ... Timed intercourse for genetic Timed intercourse for genetic
and idiopathic RPLand idiopathic RPL Surgery for selected anatomic Surgery for selected anatomic
factorsfactors PP44 and/or ovulation induction for and/or ovulation induction for
LPDLPD
Supportive TreatmentSupportive Treatment
60-90% chance of pregnancy 60-90% chance of pregnancy success with supportive care success with supportive care and ...and ... Immunosuppresive PImmunosuppresive P44 for for
presumed alloimmune factorspresumed alloimmune factors Thyroid replacement for Thyroid replacement for
hypothyroidismhypothyroidism Appropriate anticoagulation for Appropriate anticoagulation for
APS/thrombophiliasAPS/thrombophilias
Management: Genetic Management: Genetic LossesLosses
Consider Preimplantation Consider Preimplantation Genetic Diagnosis (PGD)Genetic Diagnosis (PGD) IVFIVF Day 3 blastomere biopsy (single Day 3 blastomere biopsy (single
cell)cell) FISH for most common FISH for most common
aneuploidies or single gene aneuploidies or single gene defect (if probe available)defect (if probe available)
Blastocyst biopsy on day 5 allows Blastocyst biopsy on day 5 allows detection of entire genomedetection of entire genome
Van Voorhis B. N Engl J Med 2007;356:379-386
The Process of IVF
Rebar, R. W. et al. N Engl J Med 2004;350:1603-1604
Embryos and Blastocysts during Assisted Reproduction (x20)
Van Voorhis B. N Engl J Med 2007;356:379-386
Biopsy and Preimplantation Genetic Diagnosis of a 3-Day-Old (Eight-Cell) Embryo
Embryo Evaluation Embryo Evaluation “omics”“omics” GENomicsGENomics
FISH – day 3FISH – day 3 Array CGH – day 5Array CGH – day 5 SNPsSNPs
TRANSCIPTTRANSCIPTomicsomics Gene transcriptionGene transcription
PROTEomicsPROTEomics ProteinsProteins SecretomicsSecretomics
METABOLomicsMETABOLomics MetabolitesMetabolites Amino AcidsAmino Acids
Braude P. N Engl J Med 2006;355:541-543
In Vitro Fertilization and Preimplantation Genetic Haplotyping
Elias S. N Engl J Med 2001;345:1569-1571
Analysis by Comparative Genomic Hybridization of a Blastomere Obtained by Biopsy of a Six-to-Eight-Cell Embryo
Management: Genetic Management: Genetic LossesLosses
DrawbacksDrawbacks ExpenseExpense Possibility of no transferPossibility of no transfer 10-25% mosaicism and potential 10-25% mosaicism and potential
for misidentificationfor misidentification No large scale studies supporting No large scale studies supporting
benefitbenefit
Norwitz, E. R. et al. N Engl J Med 2001;345:1400-1408
Blastocyst Apposition and Adhesion
Norwitz, E. R. et al. N Engl J Med 2001;345:1400-1408
Blastocyst Implantation
Norwitz, E. R. et al. N Engl J Med 2001;345:1400-1408
Maintenance of Early Pregnancy
SummarySummary
Early pregnancy loss is a frustrating Early pregnancy loss is a frustrating entity for both patients and entity for both patients and providersproviders
Possibility of successful pregnancy Possibility of successful pregnancy outcome high, depending on outcome high, depending on maternal age and number of prior maternal age and number of prior losseslosses
Understanding the potential Understanding the potential underlying mechanisms of loss along underlying mechanisms of loss along with empathetic supportive care with empathetic supportive care decreases emotional stress and decreases emotional stress and facilitates cost-effective evaluation facilitates cost-effective evaluation and therapyand therapy
Thank you all .Thank you all .