Recurrent miscarriage

Dr. Kang Marcus

O&G Consultant

Hospital Sibu

Recurrent miscarriage @ Habitual abortion @ Recurrent pregnancy loss

Definition : 3 or more consecutive miscarriage

Epidemiology 1% of all women

Spontaneous abortion: 10-15% of all clinically recognised pregnancies

2 consecutive miscarriage : 2%

Theoretical risk of 3 consecutive miscarriage: 0.15 x 0.15 x 0.15 = 0.3% Probable underlying problem leading to recurrent

miscarriage The reason why need to investigate further if

recurrent miscarriage

Recurrent miscarriage What about 2 consecutive miscarriage?

American Society of reproductive medicine (ASRM 2008) Define as 2 consecutive miscarriage

Royal college of O&G, UK (RCOG 2011) Define as 3 consecutive miscarriage

Different practices between O&G specialist Local practice – usually take 3 consecutive miscarriage Earlier investigation/referral should be considered for

special cases: Advanced maternal age (? How old) Bad obstetric history (e.g. ectopic, IUD) History of infertility Patient request due to social reasons

Causes Idiopathic in 40-50% of cases

Easier to divide into 1st or 2nd trimester losses 1st trimester losses (PACE U)

PCOS (Polycystic ovary syndrome) APS (Antiphospholipid syndrome) Chromosomal abnormalities Endocrine disorders (untreated DM, thyroid

disease) Uterine abnormalities

Submucous fibroid Subseptate uterus

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

Congenital – bicornuate, septate, subseptate, hypoplasia

Myomas Thrombophilias

Others – SLE, hyperprolactinaemia

Polycystic ovary syndrome (PCOS) Criteria for diagnosis (Revised 2003

international consensus) 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

Antiphospholipid syndrome (APS) Most important treatable cause of recurrent

miscarriage Diagnosed by Revised Sapporo classification

(2006): At least one clinical criteria and one laboratory

criteria

Clinical LaboratoryThrombosis ≥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

Chromosomal abnormalities - Karyotyping

Chromosomal abnormalities Balanced translocation

Reciprocal or Robertsonian

Chromosomal abnormalities

Endocrine factors Usually DM or thyroid disease

Well-controlled DM and treated thyroid dysfunction are not risk factors for recurrent miscarriage

Uterine abnormalities

Uterine abnormalities

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) No satisfactory objective test

Asherman syndrome

Normal uterus

• Usually caused by pregnancy-related D&C

Intrauterine synechiae

Bacterial vaginosis Presence of BV in the first trimester

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

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.

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

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

Management Should refer to hospital with specialist for

further management. Preliminary management that can be done in

district hospital/clinics: History Examination

History Full history including: Complete obstetric history

Year of miscarriage Gestation How was the pregnancy confirmed?

UPT? Ultrasound? Assumed pregnant as missed menses?

Spontaneous, D&C or termination? Life embryo at miscarriage? Any complications

If 2nd timester loss, ask for features of cervical incompetence

History Any surgical history esp uterine

instrumentation, cervical surgery Any medical illnesses Consanguinity?

Examination Features of PCOS Features of SLE Speculum

Any features of genital tract infection

Investigations PCOS screen

Se testosterone SHBG

Antiphospholipid antibodies Anticardiolipin antibodies (ACA) & Lupus anticoagulant Anti-beta2 glycoprotein – if available

Karyotyping (both couples) To detect chromosomal abnormalities i.e. balanced

translocations Should be performed on 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.

If karyotype of the miscarried pregnancy is abnormal, there is a better prognosis for the next pregnancy Risk of miscarriage as a result of fetal aneuploidy

decreases with an increasing number of pregnancy loss

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

Thrombophilia screen – for 2nd trimester miscarriage

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

risk of miscarriage, some authors recommend doing TFT

TORCHES – Not useful

Investigations Routine cervical cultures for Chlamydia sp. Or

mycoplasma sp. and vaginal evaluation for bacterial vaginosis are not useful among healthy women.

Management – Unexplained RM Good prognosis for future pregnancy outcome

75% chance of a eventual live birth in subsequent pregnancy

However, prognosis worsens with: Increasing maternal age Number of previous miscarriages

Maternal age and number of previous miscarriage are two independent risk factors for a further miscarriage. Advancing maternal age is associated with a

decline in the number and quality of the remaining oocytes.

Management – Unexplained RM Unexplained recurrent miscarriage (idiopathic)

Role of progesterone Role of aspirin

Efficacy of progestogens in recurrent miscarriage

33Haas & Ramsey 2008; Swyer & Daley 1953; Goldzieher 1964; LeVine 1964; El-Zibdeh 2005

Study or Progestogen Placebo Peto Odds Ratio Weight Peto Odds Ratio

subgroup n/N n/N Peto Fixed 95% CI Peto Fixed 95% CI

El-Zibdeh 2005 11/82 14/48 46.9% 0.37 [0.15, 0.90]

Goldzieher 1964 1/6 4/10 8.5% 0.36 [0.04, 2.99]

Le Vine 1964 4/15 8/15 18.4% 0.34 [0.08, 1.44]

Swyer 1953 7/27 9/20 26.1% 0.44 [0.13, 1.46]

Total (95% CI) 130 93 100.0% 0.38 [0.20, 0.70]Total events 23 (Progestogen), 35 (Placebo)

Heterogenety: Chi2 = 0.08, df = 3 (P = 0.99) i2 = 0.0%

Test for overall effect: Z = 3.10 (P = 0.0020)

0.1 10

Favours progestogen Favours placebo

Management – Unexplained RM Role of aspirin

Usually prescribed for women with unexplained recurrent miscarriage

Alone or in combination with heparin 2 recent RCTs – neither treatment improves

live birth rate among these women. Use of this empirical treatment is unnecessary and

should be resisted (RCOG, UK April 2011)

Management Idiopathic or not investigated

Start when pregnancy confirmed: T. Duphaston 10mg od/bd till 20/52 POA

Insufficient evidence to evaluate the effect of progesterone supplementation in pregnancy (RCOG, UK April 2011)

Lifestyle modification – can increase fertility potential Stop smoking Reduce alcohol intake Reduce BMI (for obese women)

Cervical incompetence 2 options in the next pregnancy

Cervical surveillance Start at 14-16 weeks Every 2 weeks as long as cervical length >30mm Increase frequency to weekly if 25-29mm If <25mm before 24 weeks, consider cerclage

Cervical cerclage at 12-14 weeks POA

Management - APS Low-dose aspirin and heparin until 36 weeks

of pregnancy

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

Endocrine Optimize disease

Should be stable for around 6 months Refer Prepregnancy Clinic when plan to

embark on pregnancy Counselling Drug adjustment – minimize, safe