RCOG GUIDELINES ON

RECURRENT LOSS OF
PREGNANCIES
 Definition
 Miscarriage is defined as the spontaneous loss of pregnancy before the
fetus reaches the viability.
 The term therefore includes all pregnancy losses from the time of
conception until 24 weeks of gestation

 It should be noted that advances in neonatal care have resulted in a

small number of babies surviving birth before 24 weeks of gestation.

 RECURRENT MISCARRIAGE, defined as the loss of three or more

pregnancies, affects 1% of couples trying to conceive.

 It has been estimated that 1-2% of second trimester pregnancies

miscarry before 24 weeks of gestation.

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Risk factors for recurrent miscarriage
Epidemiological factors

 Maternal age and number of previous miscarriages are two independent

risk factors for a further miscarriage

 Advancing maternal age is associated with a decline in both the

number and quality of the remaining oocytes.

 The age related risk of miscarriage in recognized pregnancies to be

12-19years- 13%

20- 24years-11%
 25-29 years- 12%

 30-34years- 15%

 35-39years- 25%

 40-44 years –51%

 > 45years – 93%

 Advanced paternal age has also been identified as a risk factor

for miscarriage

 The risk of miscarriage is highest among couples where the

woman is >35 years of age and the man >40 years of age
 Previous reproductive history is an independent predictor of future
pregnancy outcome.

 The risk of a further miscarriage increases after each successive

pregnancy loss, reaching approximately 40% after three consecutive
pregnancy losses, and the prognosis worsens with increasing maternal
age.

 A previous live birth does not preclude a woman developing recurrent

miscarriage
 Maternal cigarette smoking and caffeine consumption have been associated with an
increased risk of spontaneous miscarriage.

 However , current situation is insufficient to confirm this association

 Maternal cigarette smoking and caffeine consumption and the fetus.

 Even moderate consumption of five or more units per week may increase the risk of
sporadic miscarriage.

 Working with or using video display tutorials does not increase the risk of
miscarriage

 The evidence on the effect of anaesthetic gases for theater workers is conflicting

 Recent retrospective studies have reported that obesity increases the risk of both
sporadic and recurrent miscarriage.

 See the next slide to modify your content

Risk factors for recurrent miscarriage

 Maternal age and number of  APLA

previous miscarriages  Parental chromosomal
 Advancing maternal age rearrangements
 Advanced paternal age  Congenital uterine malformations
 Maternal cigarette smoking  Cervical weakness
 caffeine consumption  Endocrine factors
 Maternal cigarette smoking and  Infective agents
caffeine consumption  Inherited thrombophilic defects
 successive pregnancy loss  Unexplained recurrent
 First list out causes and then miscarriage
explain one by one cause
 ANTIPHOSPHOLIPID SYNDROME
 APLAS is the most important treatable cause of recurrent miscarriage.

 It refers to the association between antiphospholipid antibodies- lupus

anticoagulant ,anticardiolipin antibodies and anti beta 2 glycoprotein1
antibodies and adverse outcome or vascular thrombosis.

Adverse pregnancy outcomes include:

 3 or more consecutive miscarriages before 10 weeks of gestation

 3 or more morphologically normal fetus losses after the 10th week of

gestation

 1 or more preterm births before the 34th week of gestation owing to

placental disease organise content
 The mechanism by which antiphospholipid antibodies cause pregnancy
morbidity include inhibition of trophoblastic function and
differentiation

 Activation of complement pathways at the maternal- fetal interface

resulting in a local inflammatory response

 In the later pregnancy, thrombosis of the uteroplacental vasculature

 In vitro studies have shown that the effect of antiphospholipid

antibodies on trophoblast function and complement activation is
reversed by HEPARIN
 Antiphospholipid antibodies are present in 15% of women with
recurrent miscarriage.

 By comparison , the prevalence of antiphospholipid antibodies in

women with a low risk obstetric history is less than 2%.

 In women with recurrent miscarriage associated with antiphospholipid

antibodies, the live birth rate in pregnancies with no pharmacological
intervention has been reported to be as low as 10%.
 Genetic factors

Parental chromosomal rearrangements

 > In approximately 2–5% of couples with recurrent miscarriage, one of

the partners carries a balanced structural chromosomal anomaly:most
commonly a balanced reciprocal or Robertsonian translocation

 Although carriers of a balanced translocation are usually phenotypically

normal, their pregnancies are at increased risk of miscarriage and may
result in a live birth with multiple congenital malformation and/or
mental disability secondary to an unbalanced chromosomal
arrangement.

 The risk of miscarriage is influenced by the size and the genetic content
of the rearranged chromosomal segments.
Embryonic chromosomal abnormalities

 In couples with recurrent miscarriage, chromosomal abnormalities of the

embryo account for 30–57% of further miscarriages

 The risk of miscarriage resulting from chromosomal abnormalities of the

embryo increases with advancing maternal age.

 However, it is important to note that as the number of miscarriages

increases, the risk of euploid pregnancy loss increases
 Anatomical factors
Congenital uterine malformations
 The reported prevalence of uterine anomalies in recurrent miscarriage populations
ranges between 1.8% and 37.6%

 This variability reflects the differences in the criteria and techniques used for
diagnosis and the fact that available studies have included women with two, three or
more miscarriages in both the first and second trimester of pregnancy.

 The prevalence of uterine malformations appears to be higher in women with

second-trimester miscarriages compared with women who suffer first trimester
miscarriages, but this may be related to the cervical weakness that is frequently
associated with uterine malformation.

 It has been reported that women with arcuate uteri tend to miscarry more in the
second trimester while women with septate uteri are more likely to miscarry in the
first trimester
Cervical weakness

 Cervical weakness is a recognized cause of second-trimester

miscarriage, but the true incidence is unknown, since the diagnosis is
essentially a clinical one. There is currently no satisfactory objective
test that can identify women with cervical weakness in the non-
pregnant state. The diagnosis is usually based on a history of second-
trimester miscarriage preceded by spontaneous rupture of membranes
or painless cervical dilatation.
 Endocrine factors

 Systemic maternal endocrine disorders such as diabetes mellitus and

thyroid disease have been associated with miscarriage.

 Women with diabetes who have high haemoglobin A1c levels in the
first trimester are at risk of miscarriage and fetal malformation

 However, well-controlled diabetes mellitus is not a risk factor for

recurrent miscarriage, nor is treated thyroid dysfunction

 Anti-thyroid antibodies have been linked to recurrent miscarriage.

However, one case–control study from 1998 has reported that women
with recurrent miscarriages are no more likely than women without
recurrent miscarriage to have circulating thyroid antibodies
 Polycystic ovary syndrome (PCOS) has been linked to an increased risk of
miscarriage but the exact mechanism remains unclear

 The increased risk of miscarriage in women with PCOS has been recently
attributed to insulin resistance, hyperinsulinaemia and hyperandrogenaemia

 The prevalence of insulin resistance is increased in women with recurrent

miscarriage compared with matched fertile controls

 An elevated free androgen index appears to be a prognostic factor for a

subsequent miscarriage in women with recurrent miscarriage
 Infective agents

 Any severe infection that leads to bacteraemia or viraemia can cause

sporadic miscarriage.

 The presence of bacterial vaginosis in the first trimester of pregnancy

has been reported as a risk factor for second-trimester miscarriage
and preterm delivery
 Inherited thrombophilic defects
 Both inherited and acquired thrombophilias, including activated protein C
resistance (most commonly due to factor V Leiden mutation), deficiencies of
protein C/S and antithrombin III, hyperhomocysteinaemia and prothrombin
gene mutation, are established causes of systemic thrombosis

 In addition, inherited thrombophilias have been implicated as a possible

cause in recurrent miscarriage and late pregnancy complications with the
presumed mechanism being thrombosis of the uteroplacental circulation.

 meta-analysis 16 case–control studies reported that carriers of factor V Leiden

or prothrombin gene mutation have double the risk of experiencing recurrent
miscarriage compared with women without these thrombophilic mutations.
 Recommended investigations of couples with
recurrent miscarriage

 Women with recurrent first-trimester and second-trimester

miscarriage should be looked after by a health professional with the
necessary skills and expertise.

 Where available, this might be within a recurrent miscarriage clinic.

 Ideally, the couple should be seen together at a dedicated recurrent

miscarriage clinic and given accurate information to facilitate decision
making about future pregnancies.
 Antiphospholipid antibodies
 All women with recurrent first-trimester miscarriage and all women with one
or more second-trimester miscarriage should be screened before pregnancy
for antiphospholipid antibodies.

 To diagnose antiphospholipid syndrome it is mandatory that the woman has

two positive tests at least 12 weeks apart for either lupus anticoagulant or
anticardiolipin antibodies of immunoglobulin G and/or immunoglobulin M class
present in a medium or high titre over 40 g/l or ml/l, or above the 99th
percentile).
 In the detection of lupus anticoagulant, the dilute Russell’s viper venom
time test together with a platelet neutralisation procedure is more
sensitive and specific than either the activated partial thromboplastin time
test or the kaolin clotting time test

Karyotyping

 Cytogenetic analysis should be performed on products of conception of the

third and subsequent consecutive miscarriage(s).

 While a sporadic fetal chromosome abnormality is the most common cause

of any single miscarriage, the risk of miscarriage as a result of fetal
aneuploidy decreases with an increasing number of pregnancy losses
 Knowledge of the karyotype of the products of conception allows an informed
prognosis for a future pregnancy outcome to be given.

 While a sporadic fetal chromosome abnormality is the most common cause of any
single miscarriage, the risk of miscarriage as a result of fetal aneuploidy decreases
with an increasing number of pregnancy losses.

 If the karyotype of the miscarried pregnancy is abnormal, there is a better

prognosis for the next pregnancy.

 A recent retrospective UK audit74 of four UK centres over periods of 5–30 years

reported that balanced translocations were found in 1.9% of parents with recurrent
miscarriage

 but only four unbalanced translocations were found after referral for prenatal
diagnosis because of balanced parental translocation ascertained for recurrent
miscarriage.
 Anatomical factors

 All women with recurrent first-trimester miscarriage and all women

with one or more second-trimester miscarriages should have a pelvic
ultrasound to assess uterine anatomy

 Suspected uterine anomalies may require further investigations to

confirm the diagnosis, using hysteroscopy, laparoscopy or three-
dimensional pelvic ultrasound

Thrombophilias
 Women with second-trimester miscarriage should be screened for
inherited thrombophilias including factor V Leiden, factor II
(prothrombin) gene mutation and protein S
TREATMENT OPTIONS FOR RECURRING MISCARRIAGE
Antiphospholipid syndrome

 Pregnant women with antiphospholipid syndrome should be

considered for treatment with low-dose aspirin plus heparin to
prevent further miscarriage.

 This treatment combination significantly reduces the miscarriage rate

by 54% (aspirin plus unfractionated heparin compared with aspirin
alone: RR 0.46, 95% CI 0.29–0.71).

 There are no adverse fetal outcomes reported in the meta-analysis of

randomised controlled trials of low-dose aspirin for the prevention of
pre-eclampsia in pregnancy
 Heparin does not cross the placenta and hence there is no potential to
cause fetal haemorrhage or teratogenicity.

 Heparin can, however, be associated with maternal complications

including bleeding, hypersensitivity reactions, heparin-induced
thrombocytopenia and, when used long term, osteopenia and vertebral
fractures

 studies have shown that the loss of bone mineral density at the lumbar
spine associated with low-dose long-term heparin therapy is similar to
that which occurs physiologically during normal pregnancy

 Low-molecular-weight heparin is as safe as unfractionated heparin and

has potential advantages during pregnancy, since it causes less heparin-
induced thrombocytopenia, can be administered once daily and is
associated with a lower risk of heparin-induced osteoporosis.
 Pregnancies associated with antiphospholipid antibodies treated with
aspirin and heparin remain at high risk of complications during all
three trimesters

 Although aspirin plus heparin treatment substantially improves the live

birth rate of women with recurrent miscarriage associated with
antiphospholipid antibodies, these pregnancies remain at high risk of
complications during all three trimesters, including repeated
miscarriage, pre-eclampsia, fetal growth restriction and preterm
birth;85,86 this necessitates careful antenatal surveillance
 Neither corticosteroids nor intravenous immunoglobulin therapy improve the
live birth rate of women with recurrent miscarriage associated with
antiphospholipid antibodies compared with other treatment modalities; their
use may provoke significant maternal and fetal morbidity

 A meta-analysis of RCT reported that treating women who suffer recurrent

miscarriage associated with antiphospholipid antibodies with corticosteroids
during pregnancy does not improve the live birth rate compared with aspirin
or aspirin plus heparin
 A randomised controlled trial reported that women with recurrent
miscarriage associated with antiphospholipid antibodies treated with
low-molecular-weight heparin plus aspirin had a higher rate of live
births than those treated with intravenous immunoglobulin

 Another RCT reported that low-molecular-weight heparin plus aspirin

resulted in a higher live birth rate than intravenous immunoglobulin in
the treatment of women with recurrent miscarriage associated with
antiphospholipid antibodies
 Genetic factors

 The finding of an abnormal parental karyotype should prompt referral to a

clinical geneticist

 Preimplantation genetic diagnosis has been proposed as a treatment option for

translocation carriers.

 Since preimplantation genetic diagnosis necessitates that the couple undergo

in vitro fertilisation to produce embryos, couples with proven fertility need to
be aware of the financial cost as well as implantation and live birth rates per
cycle following in vitro fertilisation/preimplantation genetic diagnosis.
 Preimplantation genetic screening with in vitro fertilisation
treatment in women with unexplained recurrent miscarriage does
not improve live birth rates.

 The live birth rate of women with unexplained recurrent miscarriage

who conceive naturally is significantly higher than currently achieved
after preimplantation genetic screening/in vitro fertilisation (20–30%)
 Anatomical factors
Congenital uterine malformations

 There is insufficient evidence to assess the effect of uterine septum

resection in women with recurrent miscarriage and uterine septum to
prevent further miscarriage

Cervical weakness and cervical cerclage

 Cervical cerclage is associated with potential hazards related to the surgery

and the risk of stimulating uterine contractions and hence should be
considered only in women who are likely to benefit

 Women with a history of second-trimester miscarriage and suspected

cervical weakness who have not undergone a history-indicated cerclage may
be offered serial cervical sonographic surveillance.
 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 25 mm or
less is detected by transvaginal scan before 24 weeks of gestation

 A short cervical length on transvaginal ultrasound during pregnancy

may be useful in predicting preterm birth in some cases of suspected
cervical weakness.
 Endocrine factors

 There is insufficient evidence to evaluate the effect of progesterone

supplementation in pregnancy to prevent a miscarriage in women with
recurrent miscarriage

 Progesterone is necessary for successful implantation and the

maintenance of pregnancy. This benefit of progesterone could be
explained by its immmunomodulatory actions in inducing a pregnancy-
protective shift from pro-inflammatory Th-1 cytokine responses to a
more favourable ant i-inflammatory Th-2 cytokine response

 There is insufficient evidence to evaluate the effect of human chorionic

gonadotrophin supplementation in pregnancy to prevent a miscarriage in
women with recurrent miscarriage.
 Suppression of high luteinising hormone levels among ovulatory women with

recurrent miscarriage and polycystic ovaries does not improve the live birth

rate.

 Luteinising hormone hypersecretion, a frequent feature of PCOS, has been

reported as a risk factor for early pregnancy loss

 There is insufficient evidence to evaluate the effect of metformin

supplementation in pregnancy to prevent a miscarriage in women with

recurrent miscarriage.
 Immunotherapy

 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.

Inherited thrombophilias

 There is insufficient evidence to evaluate the effect of heparin in pregnancy to

prevent a miscarriage in women with recurrent first-trimester miscarriage
associated with inherited thrombophilia.

 Heparin therapy during pregnancy may improve the live birth rate of women
with second-trimester miscarriage associated with inherited thrombophilias
 Unexplained recurrent miscarriage

 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.

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