What are the causes of recurrent first trimester miscarriage and second trimester miscarriage?
1)- Epidemiological factors
Maternal age and number of previous miscarriages are two independent risk factors for a further miscarriage.
Previous reproductive history is an independent predictor of future pregnancy outcome.
A previous live birth does not preclude a woman developing recurrent miscarriage.
The evidence on the effect of environmental risk factors is based mainly on data studying women with sporadic rather than recurrent miscarriage. The results are conflicting and biased by difficulties in controlling for confounding factors and the inaccuracy of data on exposure and the measurement of toxin dose.
Working with or using video display terminals does not increase the risk of miscarriage.The evidence on the effect of
anaesthetic gases for theatre workers is conflicting.
2. Antiphospholipid syndrome
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
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 if peripheral blood karyotyping is performed .
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.40,41
4.4 Anatomical factors
4.4.1 Congenital uterine malformations
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 firsttrimester
miscarriages,but this may be related to the cervical weakness that is frequently associated with
uterine malformation.44 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.45
A retrospective review of reproductive performance in women with untreated uterine anomalies has
suggested that these women experience high rates of miscarriage and preterm delivery, with a term
delivery rate of only 50%.42 However, retrospective studies are biased by patient selection and, until well
controlled prospective data become available, the role of uterine anomalies in recurrent miscarriage will
remain debatable.
4.4.2 Cervical weakness
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
The prevalence of diabetes mellitus
and thyroid dysfunction in women who suffer recurrent miscarriage is similar to that reported in the
general population.49,50
Anti-thyroid antibodies have been linked to recurrent miscarriage. However, one case–control
study51 from 1998 has reported that women with recurrent miscarriages are no more likely
than women without recurrent miscarriage to have circulating thyroid antibodies. A single
prospective study52 has shown that the presence of thyroid antibodies in euthyroid women
with a history of recurrent miscarriage does not affect future pregnancy outcome.
Polycystic ovary syndrome (PCOS) has been linked to an increased risk of miscarriage but the exact
mechanism remains unclear. Polycystic ovarian morphology, elevated serum luteinising hormone levels or
elevated serum testosterone levels, although markers of PCOS, do not predict an increased risk of future
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pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously.
53 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.54 An elevated free androgen
index appears to be a prognostic factor for a subsequent miscarriage in women with recurrent miscarriage.55
Immune factors
There is no clear evidence that
altered peripheral blood NK cells are related to recurrent miscarriage.57,58Therefore, testing for peripheral
blood NK cells as a surrogate marker of the events at the maternal–fetal interface is inappropriate and
should not be offered routinely in the investigation of couples with recurrent miscarriage.
It has been suggested that uNK cells may play a role in trophoblastic invasion and angiogenesis in addition
to being an important component of the local maternal immune response to pathogens.59 It should be
noted that the largest study60 examining the relationship between uNK cell numbers and future pregnancy
outcome reported that raised uNK cell numbers in women with recurrent miscarriage was not associated
with an increased risk of miscarriage. This remains a research field and testing for uNK cells should not be
offered routinely in the investigation of recurrent miscarriage.
Cytokines are immune molecules that control both immune and other cells. Cytokine responses are
generally characterised either as T-helper-1 (Th-1) type,with production of the pro-inflammatory cytokines
interleukin 2, interferon and tumour necrosis factor (TNFô€€€) alpha, or as T-helper-2 (Th-2) type, with
production of the anti-inflammatory cytokines interleukins 4, 6 and 10. It has been suggested that normal
pregnancy might be the result of a predominantly Th-2 cytokine response, whereas women with recurrent
miscarriage have a bias towards mounting a Th-1 cytokine response.
A meta-analysis61 concluded that the available data are not consistent with more than modest
associations between cytokine polymorphisms and recurrent miscarriage. Further research is
required to assess the contribution that disordered cytokines make to recurrent miscarriage
before routine cytokine tests can be introduced to clinical practice.
Infective agents
The role of infection in recurrent miscarriage is unclear. For an infective agent to be implicated in
the aetiology of repeated pregnancy loss, it must be capable of persisting in the genital tract and
avoiding detection,or must cause insufficient symptoms to disturb the woman.
A randomised placebo-controlled trial67 reported that treatment of bacterial vaginosis early in the second trimester with oral clindamycin significantly reduces the
incidence of second-trimester miscarriage and preterm birth in the general population. There are no
published data to assess the role of antibiotic therapy in women with a previous second-trimester
miscarriage.
Inherited thrombophilic defects
A meta-analysis68 of pooled data from 31 retrospective studies suggested that the magnitude of
the association between inherited thrombophilias and fetal loss varies according to type of fetal
loss and type of thrombophilia. The association between thrombophilia and late pregnancy loss
has been consistently stronger than for early pregnancy loss. Methylenetetrahydrofolate
mutation and protein C and antithrombin deficiencies were not associated with fetal
loss. However, since protein C and antithrombin III deficiencies are rare, the number of women
included in the study was too small to show any difference in pregnancy outcome.
Similarly, another meta-analysis69 of 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.
Prospective data on the outcome of untreated pregnancies in women with hereditary
thrombophilias are scarce. One small study70 of six hereditary thrombophilias reported no
adverse effects on the live birth rate of women with recurrent miscarriage. By contrast, two
small prospective studies71,72 reported an increased risk of miscarriage in untreated pregnancies
for women with recurrent miscarriage who carry the factor V Leiden mutation compared with
those with a normal factor V genotype.
5. What are the recommended investigations of couples with recurrent first-trimester
miscarriage and second-trimester 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.
The loss of pregnancy at any stage can be a devastating experience and particular sensitivity is required
in assessing and counselling couples with recurrent miscarriage. Ideally, the couple should be seen together
at a dedicated recurrent miscarriage clinic and given accurate information to facilitate decision making
about future pregnancies. Clearly written patient leaflets are recommended to provide written information
that the couple can take home.
5.1 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.
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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.31Anticardiolipin antibodies are detected using a standardised enzymelinked
immunosorbent assay.
The detection of antiphospholipid antibodies is subject to considerable inter-laboratory variation.73 This
is a result of temporal fluctuation of antiphospholipid antibody titres in individual women, transient
positivity secondary to infections, suboptimal sample collection and preparation and lack of standardisation
of laboratory tests for their detection.
5.2 Karyotyping
Cytogenetic analysis should be performed on products of conception of the third and
subsequent consecutive miscarriage(s).
Parental peripheral blood karyotyping of both partners should be performed in
couples with recurrent miscarriage where testing of products of conception reports
an unbalanced structural chromosomal abnormality.
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.41 If the karyotype of the
miscarried pregnancy is abnormal, there is a better prognosis for the next pregnancy.39
A Dutch study38 reported that couples with balanced translocations have a low risk (0.8%) of
pregnancies with an unbalanced karyotype surviving into the second trimester and that their
chance of having a healthy child is 83%. A recent retrospective UK audit74 of four UK centres
over periods of 5–30 years reported that balanced translocations were found in 1.9% (406 of 20
432) 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. At an estimated cost of £3–4 million (the total cost of karyotyping 20
432 individuals calculated at £160–200 per karyotype), the data suggest that routine karyotyping
of couples with recurrent miscarriage cannot be justified. Selective parental karyotyping may
be more appropriate when an unbalanced chromosome abnormality is identified in the
products of conception.
5.3 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.
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A review75 of studies comparing the diagnostic accuracy of various imaging modalities has
reported that two-dimensional ultrasound scanning and/or hysterosalpingography can be used
as an initial screening test. Combined hysteroscopy and laparoscopy and possibly threedimensional
ultrasound scanning should be used for definitive diagnosis. The value of magnetic
resonance imaging scanning remains undetermined.
5.4 Thrombophilias
Women with second-trimester miscarriage should be screened for inherited
thrombophilias including factor V Leiden, factor II (prothrombin) gene mutation and
protein S.
A meta-analysis68 of retrospective studies has reported a strong association between secondtrimester
miscarriage and inherited thrombophilias: factor V Leiden, factor II (prothrombin)
gene mutation and protein S deficiency.
6. Treatment options for recurrent miscarriage
6.1 What are the treatment options for recurrent first trimester and second trimester miscarriage?
Women with recurrent miscarriage should be offered referral to a specialist clinic.
6.2 Antiphospholipid syndrome
Pregnant women with antiphospholipid syndrome should be considered for
treatment with low-dose aspirin plus heparin to prevent further miscarriage.
A meta-analysis76 of randomised controlled trials examined the outcomes of various treatments –
including aspirin, steroids, intravenous globulin and heparin – given to improve pregnancy
outcome of women with recurrent miscarriage associated with antiphospholipid antibodies.
This meta-analysis reported that the only treatment or treatment combination that leads to a
significant increase in the live birth rate among women with antiphospholipid syndrome is
aspirin plus unfractionated heparin. 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).
Two small prospective studies77,78 reported no difference in efficacy and safety between unfra -
ctionated heparin and low-molecular-weight heparin when combined with aspirin in the
treatment of women with recurrent miscarriage associated with antiphospholipid antibodies.
The value of heparin has been questioned in two studies.79,80 However, there were methodological
weaknesses in both demographic and laboratory entry criteria and time of randomisation.
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.81 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. Two prospective studies82,83 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.
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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.84
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.
What is the role of Corticosteroids or IV Immunoglobulin in improving Birth rate ?
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-analysis76 of randomised controlled trials 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.
Steroid therapy is associated
with significant maternal and fetal morbidity.
A randomised controlled trial87 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 (RR 2.28, 95%
CI 0.81–6.4). Similarly, another randomised controlled trial88 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
(OR 1.80, 95% CI 1.14–2.84).
6.3 Genetic factors
The finding of an abnormal parental karyotype should prompt referral to a clinical
geneticist.
Genetic counselling offers the couple a prognosis for the risk of future pregnancies with an unbalanced
chromosome complement and the opportunity for familial chromosome studies.
Reproductive options in couples with chromosomal rearrangements include proceeding to a further
natural pregnancy with or without a prenatal diagnosis test, gamete donation and adoption.
Preimplantation genetic diagnosis has been proposed as a treatment option for translocation
carriers.89,90 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. Furthermore, they should be informed that they have
a higher (50–70%) chance of a healthy live birth in future untreated pregnancies following
natural conception37,38,91 than is currently achieved after preimplantation genetic diagnosis/in
vitro fertilisation (approximately 30%).92
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Preimplantation genetic screening with in vitro fertilisation treatment in women with
unexplained recurrent miscarriage does not improve live birth rates.
Preimplantation genetic screening in conjunction with in vitro fertilisation has been advocated
as a treatment option for women with recurrent miscarriage, the rationale being that the identification
and transfer of what are thought to be genetically normal embryos will lead to a live
birth. 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%).92–95
6.4 Anatomical factors
6.4.1 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.
There are no published randomised trials assessing the benefits of surgical correction of uterine
abnormalities on pregnancy outcome. Open uterine surgery has never been assessed in prospective trials
but is associated with postoperative infertility and carries a significant risk of uterine scar rupture during
pregnancy.96 These complications are less likely to occur after transcervical hysteroscopic resection of
uterine septae; experience from case series appears promising.97 However, before a clear judgement can
be made, this procedure must be evaluated in a prospective controlled trial.
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.
The role of cervical cerclage in the prevention of preterm birth has been examined in a recently published
RCOG Green-top Guideline.98 A Cochrane review99 of four randomised controlled trials found no
conclusive evidence that prophylactic cerclage reduces the risk of pregnancy loss and preterm delivery
in women at risk of preterm birth or mid-trimester loss owing to cervical factors. Furthermore, the
procedure was associated with a high risk of minor morbidity but no serious morbidity. A small reduction
in deliveries before 33 weeks of gestation was noted in the largest trial.100 The benefit was most marked
in women with three or more second-trimester miscarriages or preterm births. However, there was no
significant improvement in perinatal survival.
A short cervical length on transvaginal ultrasound during pregnancy may be useful in predicting
preterm birth in some cases of suspected cervical weakness. A meta-analysis101 of individual
patient-level data from four randomised controlled trials reported that in a subgroup analysis of
women with singleton pregnancies, a short cervix (less than 25 mm) and previous secondtrimester
miscarriage, cerclage may reduce the incidence of preterm birth before 35 weeks of
gestation (RR 0.57, 95% CI 0.33–99).
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Transabdominal cerclage has been advocated as a treatment for second-trimester miscarriage and the
prevention of early preterm labour in selected women with a previous failed transvaginal cerclage and/or
a very short and scarred cervix.102–104 In the absence of any control groups, the reported improvement in
pregnancy outcome is difficult to assess. A systematic review105 compared abdominal with vaginal cerclage
in women with failed vaginal cerclage in a previous pregnancy. This review concluded that abdominal
cerclage may be associated with a lower risk of perinatal death or delivery before 24 weeks of gestation
and a higher risk of serious operative complications. Whether to perform transabdominal cerclage before
pregnancy or during pregnancy remains uncertain.106
6.5 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
anti-inflammatory Th-2 cytokine response.107 A meta-analysis108 to assess progesterone support
for pregnancy showed that it did not reduce the sporadic miscarriage rate. However, in a
subgroup analysis of trials involving women with recurrent miscarriage, progesterone treatment
offered a statistically significant decrease in miscarriage rate compared with placebo or no
treatment (OR 0.38, 95% CI 0.2–0.7). However, this meta-analysis was based on three small
controlled studies, none of which detected a significant improvement in pregnancy outcome.
A large multicentre study (PROMISE, http://www.medscinet.net/promise) is currently under
way to assess the benefit of progesterone supplementation in women with unexplained
recurrent miscarriage.
There is insufficient evidence to evaluate the effect of human chorionic gonado -
trophin supplementation in pregnancy to prevent a miscarriage in women with
recurrent miscarriage.
A multicentre placebo-controlled study of human chorionic gonadotrophin supplementation in
early pregnancy failed to show any benefit in pregnancy outcome.109 However, another small
placebo-controlled study stated that the benefit of human chorionic gonadotrophin is confined
to a small subgroup (n = 23) of women with recurrent miscarriage and oligomenorrhoea.110
Human chorionic gonadotrophin supplementation in early pregnancy should be used only in
the context of randomised controlled trials.
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. A randomised controlled trial111 has shown that prepregnancy
pituitary suppression of luteinising hormone among ovulatory women with recurrent
miscarriage and polycystic ovaries who hypersecrete luteinising hormone does not improve
the live birth rate. Furthermore, the outcome of pregnancy without pituitary suppression is
similar to that of women without raised luteinising hormone.
There is insufficient evidence to evaluate the effect of metformin supplementation in
pregnancy to prevent a miscarriage in women with recurrent miscarriage.
The increased risk of miscarriage in women with PCOS has been attributed to insulin resistance
and hyperinsulinaemia. However, a meta-analysis112 of 17 randomised controlled trials of
metformin, an insulin-sensitising agent, in women with PCOS and infertility showed that
metformin has no effect on the sporadic miscarriage risk when administered prepregnancy.
Uncontrolled small studies113 have shown that use of metformin during pregnancy is associated with a
reduction in the miscarriage rate in women with recurrent miscarriage and PCOS. However, there are no
randomised controlled trials to assess the role of metformin in women with recurrent miscarriage.
6.6 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.
A Cochrane systematic review114 has shown that the use of various forms of immunotherapy,
including paternal cell immunisation, third-party donor leucocytes, trophoblast membranes and
intravenous immunoglobulin, in women with unexplained recurrent miscarriage provides no
significant beneficial effect over placebo in preventing further miscarriage. A 2010 metaanalysis115
confirmed this conclusion with respect to intravenous immunoglobulin. Moreover,
immunotherapy is expensive and has potentially serious adverse effects including transfusion
reaction, anaphylactic shock and hepatitis. The use of immunotherapy should no longer be
offered to women with unexplained recurrent miscarriage.
There are no published data on the use of anti-TNF agents to improve pregnancy outcome in women with
recurrent miscarriage. Furthermore, anti-TNF agents could potentially cause serious morbidity including
lymphoma, granulomatous disease such as tuberculosis, demyelinating disease, congestive heart failure
and syndromes similar to systemic lupus erythematosus.
Immune treatments should not be offered routinely to women with recurrent miscarriage outside formal
research studies.
6.7 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.
Women with known heritable thrombophilia are at an increased risk of venous thromboembolism. See
RCOG Green-top Guideline No. 37a: Reducing the risk of thrombosis and embolism during pregnancy
and the puerperium.116
The efficacy of thromboprophylaxis during pregnancy in women with recurrent first-trimester
miscarriage who have inherited thrombophilias, but who are otherwise asymptomatic, has not
been assessed in prospective randomised controlled trials. Cohort studies117–119 have suggested
that heparin therapy may improve the live birth rate for these women.
One prospective randomised trial120 demonstrated the efficacy of the low-molecular-weight
heparin enoxaparin for the treatment of women with a history of a single late miscarriage after
10 weeks of gestation who carry the factor V Leiden or prothrombin gene mutation or have
protein S deficiency. The live birth rate of women treated with enoxaparin was 86% compared
with 29% in women taking low-dose aspirin alone (OR 15.5, 95% CI 7–34).
6.8 Unexplained recurrent miscarriage
Women with unexplained recurrent miscarriage have an excellent prognosis for
future pregnancy outcome without pharmacological intervention if offered support -
ive care alone in the setting of a dedicated early pregnancy assessment unit.
A significant proportion of cases of recurrent miscarriage remain unexplained despite detailed
investigation. These women can be reassured that the prognosis for a successful future
pregnancy with supportive care alone is in the region of 75%.6,121 However, the prognosis
worsens with increasing maternal age and the number of previous miscarriages. The value of
psychological support in improving pregnancy outcome has not been tested in the form of a
randomised controlled trial. However, data from several non-randomised studies6,121,122 have
suggested that attendance at a dedicated early pregnancy clinic has a beneficial effect, although
the mechanism is unclear.
Aspirin alone or in combination with heparin is being prescribed for women with unexplained
recurrent miscarriage, with the aim of improving pregnancy outcome. Two recent randomised
controlled trials reported that neither of these interventions improves the live birth rate among
women with unexplained recurrent miscarriage.123,124 However, it should be noted that both
studies included a significant number of women with only two previous miscarriages (40% and
57% of the study population, respectively).
These data suggest that the use of empirical treatment in women with unexplained recurrent miscarriage
is unnecessary and should be resisted. Furthermore, clinical evaluation of future treatments for recurrent
miscarriage should be performed only in the context of randomised trials of sufficient power to determine
efficacy.
Management of miscarriage
Threatened miscarriage
Advise
a woman with a confirmed intrauterine pregnancy with a fetal heartbeat who
presents with vaginal bleeding, but has no history of previous miscarriage,
that:-
If her bleeding gets worse, or
persists beyond 14 days, she should return for further assessment.
If the bleeding stops, she should
start or continue routine antenatal care. [2012, amended 2021]
Offer
vaginal micronised progesterone 400 mg twice daily to women with an
intrauterine pregnancy confirmed by a scan, if they have vaginal bleeding and
have previously had a miscarriage. [2021]
If
a fetal heartbeat is confirmed, continue progesterone until 16 completed
weeks of pregnancy. [2021]
Expectant management
Use
expectant management for 7 to 14 days as the first-line management
strategy for women with a confirmed diagnosis of miscarriage. Explore
management options other than expectant management if:
·
the woman is at increased risk of
haemorrhage (for example, she is in the late first trimester) or
·
she has previous adverse and/or
traumatic experience associated with pregnancy (for example, stillbirth,
miscarriage or antepartum haemorrhage) or
·
she is at increased risk from the
effects of haemorrhage (for example, if she has coagulopathies or is unable to
have a blood transfusion) or
·
there is evidence of infection. [2012]
1.5.5Offer
medical management to women with a confirmed diagnosis of miscarriage if
expectant management is not acceptable to the woman. [2012]
1.5.6Explain
what expectant management involves and that most women will need no further
treatment. Also provide women with oral and written information about further
treatment options. [2012]
1.5.7Give
all women undergoing expectant management of miscarriage oral and written
information about what to expect throughout the process, advice on pain relief
and where and when to get help in an emergency. See also for details
of further information that should be provided. [2012]
1.5.8If
the resolution of bleeding and pain indicate that the miscarriage has completed
during 7 to 14 days of expectant management, advise the woman to take
a urine pregnancy test after 3 weeks, and to return for individualised
care if it is positive. [2012]
1.5.9Offer
a repeat scan if after the period of expectant management, the bleeding and
pain:
·
have not started (suggesting that
the process of miscarriage has not begun) or
·
are persisting and/or increasing
(suggesting incomplete miscarriage).
Discuss all treatment options (continued expectant management, medical
management and surgical management) with the woman to allow her to make an
informed choice. [2012]
1.5.10Review
the condition of a woman who opts for continued expectant management of
miscarriage at a minimum of 14 days after the first follow‑up
appointment. [2012]
Medical management
1.5.11Do
not offer mifepristone as a treatment for missed or incomplete
miscarriage. [2012]
1.5.12Offer
vaginal misoprostol for the medical treatment of missed or incomplete
miscarriage. Oral administration is an acceptable alternative if this is the
woman's preference. [2012]
1.5.13For
women with a missed miscarriage, use a single dose of 800 micrograms of
misoprostol. [2012]
1.5.14Advise
the woman that if bleeding has not started 24 hours after treatment, she
should contact her healthcare professional to determine ongoing individualised
care. [2012]
1.5.15For
women with an incomplete miscarriage, use a single dose of 600 micrograms
of misoprostol. (800 micrograms can be used as an alternative to allow
alignment of treatment protocols for both missed and incomplete miscarriage.) [2012]
1.5.16Offer
all women receiving medical management of miscarriage pain relief and
anti-emetics as needed. [2012]
1.5.17Inform
women undergoing medical management of miscarriage about what to expect
throughout the process, including the length and extent of bleeding and the
potential side effects of treatment including pain, diarrhoea and
vomiting. [2012]
1.5.18Provide
women with a urine pregnancy test to carry out at home 3 weeks after
medical management of miscarriage unless they experience worsening symptoms, in
which case advise them to return to the healthcare professional responsible for
providing their medical management. [2012, amended 2021]
1.5.19Advise
women with a positive urine pregnancy test after 3 weeks to return for a
review by a healthcare professional to ensure that there is no molar or ectopic
pregnancy. [2012]
Surgical management
1.5.20Where
clinically appropriate, offer women undergoing a miscarriage a choice of:
·
manual vacuum aspiration under
local anaesthetic in an outpatient or clinic setting or
·
surgical management in a theatre
under general anaesthetic. [2012]
1.5.21Provide
oral and written information to all women undergoing surgical management of
miscarriage about the treatment options available and what to expect during and
after the procedure.
1.6 Management of tubal ectopic pregnancy
1.6.1Give
all women with an ectopic pregnancy oral and written information about:
·
the treatment options and what to
expect during and after treatment
·
how they can contact a healthcare
professional for advice after treatment if needed, and who this will be
·
where and when to get help in an
emergency.
1.6.2Inform
women who have had an ectopic pregnancy that they can self-refer to an early
pregnancy assessment service in future pregnancies if they have any early
concerns. [2012]
Expectant management
1.6.3Offer
expectant management as an option to women who:
·
are clinically stable and pain
free and
·
have a tubal ectopic pregnancy
measuring less than 35 mm with no visible heartbeat on transvaginal
ultrasound scan and
·
have serum hCG levels of
1,000 IU/L or less and
·
are able to return for
follow-up. [2019]
1.6.4Consider
expectant management as an option for women who:
·
are clinically stable and pain
free and
·
have a tubal ectopic pregnancy
measuring less than 35 mm with no visible heartbeat on transvaginal
ultrasound scan and
·
have serum hCG levels above
1,000 IU/L and below 1,500 IU/L and
·
are able to return for follow-up. [2019]
1.6.5For
women with a tubal ectopic pregnancy being managed expectantly, repeat hCG
levels on days 2, 4 and 7 after the original test and:
·
if hCG levels drop by 15% or more
from the previous value on days 2, 4 and 7, then repeat weekly
until a negative result (less than 20 IU/L) is obtained or
·
if hCG levels do not fall by 15%,
stay the same or rise from the previous value, review the woman's clinical
condition and seek senior advice to help decide further management. [2019]
1.6.6Advise
women that, based on limited evidence, there seems to be no difference
following expectant or medical management in:
·
the rate of ectopic pregnancies
ending naturally
·
the risk of tubal rupture
·
the need for additional treatment,
but that they might need to be admitted urgently if their condition
deteriorates
·
health status, depression or
anxiety scores. [2019]
1.6.7Advise
women that the time taken for ectopic pregnancies to resolve and future
fertility outcomes are likely to be the same with either expectant or medical
management. [2019]
Medical and surgical management
Offer
systemic methotrexate to women who:
·
have no significant pain and
·
have an unruptured tubal ectopic
pregnancy with an adnexal mass smaller than 35 mm with no visible
heartbeat and
·
have a serum hCG level less than
1,500 IU/litre and
·
do not have an intrauterine
pregnancy (as confirmed on an ultrasound scan) and
·
are able to return for follow-up.
Methotrexate should only be offered on a first visit when there is a definitive
diagnosis of an ectopic pregnancy, and a viable intrauterine pregnancy has been
excluded. Offer surgery where treatment with methotrexate is not acceptable to
the woman. [2012, amended 2019]
1.6.9Offer
surgery as a first-line treatment to women who are unable to return for
follow-up after methotrexate treatment or who have any of the following:
·
an ectopic pregnancy and
significant pain
·
an ectopic pregnancy with an
adnexal mass of 35 mm or larger
·
an ectopic pregnancy with a fetal
heartbeat visible on an ultrasound scan
·
an ectopic pregnancy and a serum
hCG level of 5,000 IU/litre or more. [2012]
1.6.10Offer
the choice of either methotrexate or surgical management to women with an
ectopic pregnancy who have a serum hCG level of at least 1,500 IU/litre
and less than 5,000 IU/litre, who are able to return for follow‑up and who
meet all of the following criteria:
·
no significant pain
·
an unruptured ectopic pregnancy
with an adnexal mass smaller than 35 mm with no visible heartbeat
·
no intrauterine pregnancy (as
confirmed on an ultrasound scan).
Advise women who choose methotrexate that their chance of needing further
intervention is increased and they may need to be urgently admitted if their
condition deteriorates. [2012]
1.6.11For
women with ectopic pregnancy who have had methotrexate, take 2 serum hCG
measurements in the first week (days 4 and 7) after treatment
and then 1 serum hCG measurement per week until a negative result is
obtained. If hCG levels plateau or rise, reassess the woman's condition for
further treatment. [2012]
Performing laparoscopy
1.6.12When
surgical treatment is indicated for women with an ectopic pregnancy, it should
be performed laparoscopically whenever possible, taking into account the
condition of the woman and the complexity of the surgical procedure. [2012]
1.6.13Surgeons
providing care to women with ectopic pregnancy should be competent to perform
laparoscopic surgery. [2012]
1.6.14Commissioners
and managers should ensure that equipment for laparoscopic surgery is
available. [2012]
Salpingectomy and salpingotomy
1.6.15Offer
a salpingectomy to women undergoing surgery for an ectopic pregnancy unless
they have other risk factors for infertility. [2012]
1.6.16Consider
salpingotomy as an alternative to salpingectomy for women with risk factors for
infertility such as contralateral tube damage. [2012]
1.6.17Inform
women having a salpingotomy that up to 1 in 5 women may need
further treatment. This treatment may include methotrexate and/or a
salpingectomy. [2012]
1.6.18For
women who have had a salpingotomy, take 1 serum hCG measurement at
7 days after surgery, then 1 serum hCG measurement per week until a
negative result is obtained. [2012]
1.6.19Advise
women who have had a salpingectomy that they should take a urine pregnancy test
after 3 weeks. Advise women to return for further assessment if the test
is positive. [2012]
1.7 Anti-D rhesus prophylaxis
1.7.1Offer
anti-D rhesus prophylaxis at a dose of 250 IU (50 micrograms) to all
rhesus-negative women who have a surgical procedure to manage an ectopic
pregnancy or a miscarriage. [2012]
1.7.2Do
not offer anti‑D rhesus prophylaxis to women who:
·
receive solely medical management
for an ectopic pregnancy or miscarriage or
·
have a threatened miscarriage or
·
have a complete miscarriage or
·
have a pregnancy of unknown
location. [2012]
1.7.3Do
not use a Kleihauer test for quantifying feto-maternal haemorrhage. [2012]
Terms used in this guideline
Early pregnancy
Pregnancy
in the first trimester (that is, up to 13 completed weeks of pregnancy).
Expectant management
A
management approach, also called 'wait and watch', when no medical or surgical
treatment is given. The aim is to see if the condition will resolve naturally.
Pregnancy of unknown location
When
a woman has a positive pregnancy test, but no intrauterine or extrauterine
pregnancy can be seen with a transvaginal ultrasound scan.
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