Recurrent pregnancy loss

Kamel Mohamed IbrahimM.B.B.CH – MSC ain shams University maternity

hospitalSpecialist in fetomaternal medicine Member of Egyptian fertility societyMember of Egyptian association of

Gynelaparoscopists

INTRODUCTION

• The loss of pregnancy at any stage can be a devastating experience and particular sensitivity is required in assessing and counseling couples with recurrent miscarriage

• A woman who has suffered a single sporadic miscarriage has an 80% chance and a woman with three consecutive miscarriages a 40-60% chance of her next pregnancy being successful

This is our hope.

Our Learning Objectives

• Identify possible causes of early pregnancy loss.

• Outline basic evaluation for recurrent pregnancy loss (RPL).

• Review current treatment approaches for these patients.

Definition• Miscarriage is defined as the spontaneous loss of

pregnancy before the fetus reaches viability.

• A recurrent miscarriage ₌ recurrent pregnancy loss (RPL) is 3 or more consecutive, spontaneous pregnancy losses (clinically recognized pregnancies) , under 20 week .

Am J Obstet Gynecol 2005;192:240–6

SUB TYPES :

All pregnancy losses, no viable pregnancy

Viable pregnancy followed by pregnancy losses

Pregnancy losses interspersed with viable

pregnanciesRPL-TYPES :• Primary recurrent pregnancy loss" refers to couples that have never had a live birth, • “Secondary RPL" refers to those who have had repetitive losses following a successful pregnancy

Easier to divide into 1st or 2nd trimester losses

• 1st trimester losses :– PCOS (Polycystic ovary syndrome)– APS (Antiphospholipid syndrome)– Chromosomal abnormalities– Endocrine disorders (untreated DM, thyroid disease)– Uterine abnormalities

• Submucous fibroid• Subseptate uterus

• 2nd trimester losses :– Cervical incompetence– Asherman syndrome (intrauterine synechiae)– Bacterial vaginosis– Uterine abnormalities

• Congenital – bicornuate, septate, subseptate, hypoplasia• Myomas

– Thrombophilias

Epidemiology

• 50% of all conceptions fail (most unrecognized)

• 13-15% of recognized pregnancies are lost, 90 % of these before 12-14 weeks

• 10-20% of pregnant women have 1sporadic spontaneous abortion

• 2% have 2 consecutive Spontaneous Abortion.

• 0.4-1% have 3 consecutive Spontaneous Abortion.

• Spontaneous successful pregnancy after 2miscarriage is 80%

Lee Semin Reprod Med 2000;18(4):433-40

Risk factors Advanced maternal age :

12-19 year:13%20 -24 year: 11%Risk factors 25-30 year: 12%31-35 year: 15%36-40 year: 25%>40 year: 50%

BMJ 2000;320:1708–12.

Previous miscarriage :

↑ up to 40% after 3 consecutive pregnancy losses & prognosis worsens ѐ↑maternal age. Recurrent Pregnancy Loss 2007

Environmental Risk Factors:The evidence on the effect of environmental risk factors

is based mainly on data studying women with sporadic rather than recurrent miscarriage.

Confirmed associationIonizing irradiationOrganic solventsAlcoholMercuryLead (Gardella & Hill Semin Reprod Med 2000;18(4):407-424)

Suspected association Caffeine (> 300 mg/day) Cigarette smoking

(However, current evidence is insufficient to confirm this association)

Acta Obstet Gynecol Scand 2003;82:182–8.

Working with or using video display terminals does not increase the risk of miscarriage. (J Am Med Womens Assoc 2000;55:84–8, 105.)

The evidence on the effect of anaesthetic gases for theatre workers is conflicting. (Mayo Clin Proc 2000;75:273–7).

obesity increases the risk of both sporadic and recurrent miscarriage. (Fertil Steril 2010;94:290–5).

AETIOLOGY

1. Genetic (embryonic and parental )

2. Immunologic (autoimmune/alloimmune )

3. Anatomical Factors (Uterine )

4. Infectious causes .

5. Environmental

6. Endocrine

7. Hematologic disorders

Only in 50 %, the cause can be determined (Explained ) Lee Semin Reprod Med 2000;18(4):433-40

Genetic

• Advanced Maternal age α errors in meiosis .• Oocytes ovulated earlier in life less prone to non

dysjunction• Repetitive first trimester losses• Anembryonic pregnancies• History of malformations or mental retardation.

Genetic • Embryonic chromosomal abnormalities : account for 30–57% of further miscarriages. (Hum Reprod 2002;17:446–51)

– gametogenic error (^ with maternal age) .– Recurrent aneuploidy– Euploid abortion

• Parental chromosomal abnormality 3-5% :The risk of miscarriage is influenced by the size and the genetic content of the rearranged chromosomal segments.– most commonly a balanced reciprocal or Robertsonian

translocation. (BMJ 2006; 332:1012.)

– Inversion– X chromosome mosaicsm

Autoimmune : (directed to self)

Systemic Lupus Erythmatosus Antiphospholipid Syndrome

Alloimmune :(directed to foreign tissues/cells)

An abnormal maternal immune response to fetal or placental antigen.

Immune factors

Systemic Lupus Erythmatosus (SLE) : -Risk for loss is 20%,mostly in 2nd and 3rd trimester of pregnancy and associated with antiphospholipid antibodies.

Antiphospholipid syndrome (APA) :5 - 15 % of women with RPL may have APA .inhibition of trophoblastic function and differentiation.

Am J Obstet Gynecol 2005;192:23–30.

activation of complement pathways at the maternal-fetal interface resulting in a local inflammatory response .( Lupus 2003;12:535–8.)

in later pregnancy, thrombosis of the uteroplacental vasculature . (Am J Obstet Gynecol 1993;169:1403–6)

Antiphospholipid syndrome An Autoimmune disorder having specific clinical & lab criteria:

Clinical 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

Laboratory features :• Anti-cardiolipin (aCL) antibodies: IgG or IgM at moderate or

high levels on 2 or more occasions at least 12 weeks apart• Lupus anticoagulant (LA) antibodies: detected on 2 or more

occasions at least 12 weeks apart

Diagnosed by Revised Sapporo classification (2006):At least one clinical criteria and one laboratory criteria

Clinical Laboratory

Thrombosis ≥1 documented episodes of: Arterial Venous and/or Small vessel thrombosis

ACA ACA of IgG and/or IgM isotype in medium/high titre (> 40 IU) or >99th percentile

Pregnancy morbidity

≥1 unexplained fetal deaths of ≥ 10 weeks POA(morphologically normal fetus)

LA Detected

≥1 premature births of ≤ 34th week POA d/t:

Severe PE or Placental insufficiency (IUGR)

(morphologically normal neonate)

Anti-beta2-glycoprotein

>99th percentile

≥3 unexplained consecutive spontaneous abortions < 10 week POA

* On 2 or more occasionsAt least 12 weeks apart

Alloimmune :

Immune response to non-self components of pregnancy• Cytotoxic antibodies• Absence of maternal blocking antibodies• Inappropriate sharing of HLA• Disturbances in natural killer cell function and distribution.

Porter Semin Reprod Med 2000;18(4):393-400

Natural killer cells:There is no clear evidence that altered peripheral blood

NK cells are related to recurrent miscarriage.Hum Reprod 2005;20:1123–6.

T helper (Th1) immunodystrophismA meta-analysis concluded that the available data are not consistent with associations between

cytokine polymorphisms and recurrent miscarriage. (Evidence level 2++)

Uterine anomalies : prevalence of uterine anomalies in recurrent miscarriage populations ranges between 1.8% and 37.6%

• Uterine septum (the anomaly most commonly associated with pregnancy loss)• Hemiuterus (unicornuate uterus)• Bicornuate uterus• Didelphic uteri

Diethylstilbestrol-linked conditionAcquired defects (eg, Asherman syndrome)Incompetent cervixLeiomyomasUterine polypsDefective endometrial receptivity

Anatomical Factors (Uterine )

Hum Reprod 2003;18:162–6.

the role of uterine anomalies in recurrent miscarriage will remain debatable.untreated uterine anomalies let women experience high rates of miscarriage and preterm delivery, with a term delivery rate of only 50%.

Hum Reprod Update 2001;7:161–74.

Fertil Steril 1988; 49:944.

• a septate uterus Where as a partial septum increases the risk to 60%-75%; a total septum carries a risk for loss of up to 90%.

• Most common.• poorest reproductive outcome.• Fetal survival with untreated cases 6

to 28 %• The mechanism–Not clearly understood– Poor blood supply »»» poor

implantation

SEPTATE UTERUS

• 10% of anomalies• Incomplete fusion of Uterine horns at level of

fundus• Two separate but communicating endometrial

cavities• Abortion rate 30%• Preterm labour 20%• Metroplasty .

Bicornuate Uterus

• 20% of anomalies• Agenesis or hypoplasia of one Mullerian duct• May be alone or accompanied by Rudimentary horn With presence / absence of cavity Communicating /

Non communicating• Associated Renal anomalies occur in 40% patients Ipsilateral to hypoplastic horn

Unicornuate Uterus

• Least common anomaly -5-7%• associated with a miscarriage rate of 20.9% and a

preterm delivery rate of 24.4%

Uterus Didelphys

Hum Reprod 2003; 18:162–6.

Cervical incompetence

• Diagnosis is clinical, usually based on history– Miscarriage• 2nd-trimester miscarriage• Subsequent miscarriages are usually earlier• Preceded by spontaneous rupture of membranes• Bulging membranes through the cervix prior to onset of

labour• Painless and progressive cervical dilatation• Fetus alive during miscarriage

– History of cervical surgery (cone biopsy, LLETZ)

Unclear relationship between uterine leiomyomata and RPL

• Submucous• The mechanism -–Their position–Poor endometrial receptivity–Degeneration with increasing cytokine production

LEIOMYOMA

OTHER UTERINE CAUSES

• Endometrial polyps• Intrauterine adhesions–Curettage for pregnancy complications .– Traumatize basalis layer granulation

tissue– Insufficient endometrium to support

fetoplacental growth –Menstrual irregularities (hypomenorrhea,

amenorrhea), cyclic pelvic pain, infertility.

• Poorly controlled diabetes :– (↑Blood glucose & HbA1c levels in 1st trimester)

↑ risk for loss.– Miscarriage risk rises with the level of HbA1c– Well-controlled No ↑ risk

• thyroid disease .• Anti-thyroid antibodies have been linked to recurrent miscarriage.• Hyperprolactinemia• Polycystic ovary syndrome (PCOS)

Presence of at least 2 of the following 3 criteria:– Polycystic ovaries

• ≥ 12 follicles in each ovary (<10 mm (2-9 mm in diameter)) and/or• Ovarian volume > 10 cm3

– Oligomenorrhea and/or anovulation– Clinical and/or biochemical hyperandrogenism

Endocrine factors

• The increased risk of miscarriage in women with PCOS has been recently attributed to insulin resistance,hyperinsulinaemia and hyperandrogenaemia. (Hum Reprod 2000;15:612–5.)

• An elevated free androgen index appears to be a prognostic factor for a subsequent miscarriage in women with recurrent miscarriage. (Hum Reprod 2008;23:797–802).

• No infectious agent has been proven to cause recurrent pregnancy loss

• Certain infections have been associated with spontaneous loss– Toxoplasma Gondi, rubella, HSV, CMV, measles, coxsackie

Lee Semin Reprod Med 2000;18(4):433-40

• Routine TORCH screening should be abandoned.RCOG, 2011.

Infective agents

Bacterial vaginosis• Presence of BV in the first trimester

– Reported as a risk factor for 2nd-trimester miscarriage or preterm delivery.

Best Pract Res Clin Obstet Gynaecol 2007;21:375–90.

• A RCT reported that treatment of BV early in the 2nd-trimester with oral clindamycin significantly reduces the incidence of second-trimester miscarriage and preterm birth in the general population.

Lancet 2003;361:983–8.

• No data to assess the role of antibiotic therapy in women with a previous second-trimester miscarriage.

Inherited thrombophilic defects : • Activated protein C resistance (most commonly due to factor V

Leiden gene mutation).• deficiencies of protein C/S and antithrombin III• hyperhomocysteinaemia • prothrombin gene mutation

Hematologic disorders

are established causes of systemic thrombosis

Women with heritable or acquired thrombophilic disorders have significantly increased risks of pregnancy loss . Kutteh Semin Reprod Med 2006;24(1):54-65

Arch Intern Med 2004;164:558–63.

Carriers of factor V Leiden or prothrombin gene mutation have double the risk of experiencing recurrent miscarriage compared with women without these thrombophilic mutations.

MISCELLANEOUS • Environmental chemicals

– Anesthetic gases

• Sporadic spontaneous loss

• No evidence of associations with RPL

• Personal habits – Obesity »» ↑ Risk of Sporadic spontaneous loss and

RPL

– Smoking associated with ↑ Risk of spontaneous loss

– Alcohol »» ↑ Risk of Sporadic spontaneous loss.

– Caffeine associated with ↑ Risk of spontaneous loss

• Exercise– does not ↑ sporadic or RPL

Male factor :

• Advanced paternal age may be a risk factor for miscarriage (at more advanced age than females) • Paternal HLA sharing not risk factor for RPL.• Aside from cytogenetic abnormalities, male factor contribution to RPL unknown

Hill ASRM 2002 Course 6 p.56

• More than 50% of couples with RPL have no explanation despite extensive evaluation(s)

• Informative and sympathetic counseling appears to play an important role

Idiopathic (Unexplained)

Lee Semin Reprod Med 2000;18(4):433-40

How to approach RPL?

Detailed history :

personal history : Age-<16y, >35 MH:oligomenorrhoea, PCOPresent history: Pattern of losses and if a live embryo or fetus was present

Exposure to environmental,toxins or drugsKnown gynecological or obstetrical infectionsFeatures associated with APS

OBH : GA<^6 w, 6-8w, FHR+/-Past Surgical & Medical history: renal, look for autoimmune disease (SLE) , D&C , Previous diagnostic tests and treatments Family history : thrombophilia, birth defects, Consanguinity,RPL

Examination :

– General physical examWt, HT,BMIFeatures of PCOSFeatures of SLEFeatures of thyroid diseases

– Pelvic examSpeculum–Any features of genital tract infection,

anomalies, fibroids

How and when to investigate?

Ideally after 3 losses but American Society of reproductive medicine (ASRM 2008) Define as 2 consecutive miscarriageEarlier investigation/referral should be considered for special cases:

Advanced maternal age (? How old)Bad obstetric history (e.g. ectopic, IUD) Medical disordersHistory of infertility, known family history. Patient request due to social reasons

How to Investigate ?Investigate commoner and treatable causes firstDo not order a blind screen

• Antiphospholipid antibodies : ( Grade D)– Anticardiolipin antibodies (ACA) & Lupus anticoagulant2 +ve tests (12 weeks apart )

• Karyotyping : (Grade D )– Should be performed on products of conception (POC)of the

3rd and subsequent consecutive miscarriages– Parenteral karyotyping of both partners should be performed

when testing of POC reports an unbalanced structural chormosomal abnormality.

• Pelvic ultrasound – assess uterine anatomy : (√ )– HSG can also be used as an initial screening test– Suspected uterine anomalies may require further

investigations to confirm diagnosis:• Hysteroscopy• Laparoscopy• 3D ultrasound

• 2D ultrasound scanning and/or HSG can be used as an initial screening test. Combined hysteroscopy and laparoscopy and possibly 3D ultrasound scanning should be used for definitive diagnosis. (3)

Hum Reprod Update 2008;14:415–29.

Thrombophilias :Women with second-trimester miscarriage should be

screened for inherited thrombophilias including factor V Leiden, factor II (prothrombin) genemutation and protein S.

Lancet 2003;361:901–8.( 2++)

away from the acute eventwhen anticoagulation is discontinuedwhen the woman is not pregnant or on the combined contraceptive pill.

• PCOS screen– Serum testosterone– SHBG

• Screening for diabetes, thyroid disorders is only indicated if there is clinical suspicion. Not recommended as a routine test.

Infective agents

• TORCHES»»

Endocrine factors

Not useful

Recurrent Pregnancy Loss Causes, Controversies and Treatment 2007

How to manage ?

Management Emotional aspect

Lost of pregnancy – can be a devastating traumatic experience

Can lead to anxiety, stress & depression Instead of getting sympathy and support,

often made to feel that it is somehow her fault

Under intense pressure to provide a child for the family

May even lead to family problem @ divorce Sensitivity is required in assessing and

counselling couples Approach with sympathy and understanding DO NOT blame, scold or make her feel at

fault

• Pregnant women with APS should be treated with low-dose aspirin plus heparin to prevent further miscarriage. (B) (RCOG 2011)

• Aspirin 81 mg po/day .• Subcutaneous unfractionated heparin 5000 - 10000

units/12 hours .• Alternative: LMWH(e.g., enoxaparin 1mg/kg/day)

every 12 hourspotential advantages: less heparin-induced thrombocytopenia .administered once daily .lower risk of heparin-induced osteoporosis. (RCOG 2011)

Treatment - APS

Neither corticosteroids nor intravenous immunoglobulin therapy improve the live birth rate of women with recurrent miscarriage associated with APS. (A) (RCOG 2011)

Management: Genetic LossesAbnormal parental karyotype should be referred to a geneticist. (D)

Genetic counselling »» Reproductive options »»» a further natural pregnancy with or without a prenatal diagnosis test, gamete donation and adoption.

Preimplantation Genetic Diagnosis (PGD) : proposed as a treatment option for translocation carriers

Hum Fertil (Camb) 2001;4:168–71.

Uterine Abnormalities Treatment

Uterine septum: Hysteroscopy septal resection and temporary intrauterine device.Intrauterine adhesions : hysteroscopic division and temporary intrauterine device: postoperative course of cyclic estrogen and progesterone therapy.Fibroids: myomectomy

In women with a singleton pregnancy and a history of one second-trimester miscarriage attributable to cervical factors, an ultrasound-indicated cerclage should be offered if a cervical length of 25mm or less is detected by transvaginal scan before 24 weeks . (B) RCOG 2011

Management : Endocrine factors

There is insufficient evidence to evaluate the effect of progesterone supplementation in pregnancy to prevent a miscarriage (RCOG 2011)

However newer evidences is coming up as large multicentre study PROMISE is currently on the way.

(PROMISE,http://www.medscinet.net/promise)

There is insufficient evidence to evaluate the effect of human chorionic gonadotrophin supplementation in pregnancy to prevent a miscarriage in women with recurrent miscarriage. (B)

Suppression of high luteinising hormone levels among ovulatory women with recurrent miscarriage and polycystic ovaries does not improve the live birth rate. (A)

(RCOG 2011)

PCOS

• Role of Metformin– Previously prescribed to reduce risk of recurrent

miscarriage– Insufficient evidence to evaluate the effect of

metformin supplementation– Recent meta-analysis of 17 RCTs - metformin has

no effect on sporadic miscarriage risk– Uncontrolled small studies (no RCTs) – associated

with reduction in miscarriage rate in women with recurrent miscarriage

Immunotherapy Paternal cell immunisation third-party donor leucocytes trophoblast membranes and intravenous immunoglobulin (IVIG)»»»»previous unexplained recurrent miscarriage does not improve the live birth rate . (A)

Treatment Inherited thrombophilias

For heritable or acquired thrombophilia: heparin anticoagulation

For elevated homocysteinemia without thrombosis history (Supplementation with Vitamin B6, B12 and folic acid)(Heparin anticoagulation for history of thrombosis)

Heparin therapy during pregnancy may improve the live birth rate of women with second-trimester miscarriage associated with inherited thrombophilias. (A)

Management – Unexplained RM• Women with unexplained recurrent miscarriage have an

excellent prognosis for future pregnancy outcome without pharmacological intervention if offered supportive care alone in the setting of a dedicated early pregnancy assessment unit. (B)

• 75% chance of a eventual live birth in subsequent pregnancy However, prognosis worsens with:

• Increasing maternal age• Number of previous miscarriages

the use of empirical treatment in unexplained recurrent miscarriage is unnecessary and should be resisted

RCOG 2011

Unexplained recurrent miscarriage

Preimplantation genetic screening with in vitro fertilisation treatment in women with unexplained recurrent miscarriage does not improve live birth rates. (C)

Two recent randomised controlled trials reported that neither of (Aspirin alone or in combination with heparin)improves the live birth rate among women with unexplained recurrent miscarriage. (N Engl J Med 2010;362:1586–96.) (Blood 2010;115:4162–7.)

immunological

• Paternal cell immunisation, third-party donor leucocytes, trophoblast membranes

• and intravenous immunoglobulin in women with previous unexplained recurrent

• miscarriage does not improve the live birth rate

Thank You