Systematic review

DOI: 10.1111/j.1471-0528.2009.02427.x
www.bjog.org

Maternal and perinatal outcome in women with

threatened miscarriage in the first trimester:
a systematic review
L Saraswat,a S Bhattacharya,b A Maheshwari,c S Bhattacharyad
a
Department of Obstetrics and Gynaecology b Dugald Baird Centre for Research on Womens Health c University of Aberdeen d School of
Medicine and Dentistry, University of Aberdeen, Aberdeen Maternity Hospital, Aberdeen, UK
Correspondence: Dr L Saraswat, Department of Obstetrics and Gynaecology, Aberdeen Maternity Hospital, Aberdeen AB25 2ZL, UK. Email
luckysaraswat@doctors.org.uk

Accepted 24 September 2009. Published Online 26 November 2009.

Background Threatened miscarriage is a common complication in

the first trimester of pregnancy and is often associated with

anxiety regarding pregnancy outcome.
Objective We undertook a systematic review to explore the effects

of threatened miscarriage in the first trimester on maternal and

perinatal outcomes.
Search strategy An electronic literature search using MEDLINE

and EMBASE, and bibliographies of retrieved primary articles. No

language restrictions were applied.
Selection criteria All studies analysing outcomes of first-trimester

bleeding where viability was confirmed on ultrasound or the

pregnancy continued beyond viability.
Data collection and analysis Two review authors independently

selected studies and extracted data on study characteristics, quality

and accuracy. Meta-analysis was performed using Review
Manager software
Main outcome measures The outcome was broadly categorised

into maternal and perinatal outcomes. The chief maternal

outcomes included pre-eclampsia/eclampsia or pregnancy-induced
hypertension, antepartum haemorrhage, preterm prelabour
rupture of membranes (PPROM) and mode of delivery. The

perinatal outcomes evaluated were preterm delivery, low

birthweight, intrauterine growth restriction, perinatal mortality,
indicators of perinatal morbidity (Apgar scores and neonatal unit
admission) and presence of congenital anomalies.
Main results Fourteen studies met the inclusion criteria. Women

with threatened miscarriage had a significantly higher incidence of

antepartum haemorrhage due to placenta praevia [odds ratio
(OR) 1.62, 95% CI 1.19, 2.22] or antepartum haemorrhage of
unknown origin (OR 2.47, 95% CI 1.52, 4.02) when compared
with those without first-trimester bleeding. They were more likely
to experience PPROM (OR 1.78, 95% CI 1.28, 2.48), preterm
delivery (OR 2.05, 95% CI 1.76, 2.4) and to have babies with
intrauterine growth restriction (OR 1.54, 95% CI 1.18, 2.00).
First-trimester bleeding was associated with significantly higher
rates of perinatal mortality (OR 2.15, 95% CI 1.41, 3.27) and
low-birthweight babies (OR 1.83, 95% CI 1.48, 2.28).
Authors conclusions Threatened miscarriage in the first trimester
is associated with increased incidence of adverse maternal and
perinatal outcome.
Keywords First-trimester bleeding, maternal outcome, perinatal

outcome.

Please cite this paper as: Saraswat L, Bhattacharya S, Maheshwari A, Bhattacharya S. Maternal and perinatal outcome in women with threatened miscarriage
in the first trimester: a systematic review. BJOG 2010;117:245257.

Introduction
First-trimester bleeding is a common complication which
affects 1625% of all pregnancies.1 Threatened miscarriage
is diagnosed on the basis of documented fetal cardiac activity on ultrasound with a history of vaginal bleeding in the
presence of a closed cervix. Bleeding during pregnancy
can cause maternal anxiety and emerging evidence suggests

that it may be associated with poor fetal and maternal

outcomes.29
It is hypothesised that first-trimester bleeding may indicate an underlying placental dysfunction, which may manifest later in pregnancy causing adverse outcomes such as
increased risk of pre-eclampsia, preterm delivery, preterm
prelabour rupture of membranes (PPROM), placental
abruption and intrauterine growth restriction (IUGR).8

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Saraswat et al.

Knowledge about the outcome of ongoing pregnancies

following first-trimester bleeding is relevant to both women
and their obstetricians in order to plan antenatal care and
consider clinical interventions in pregnancy. Several primary studies have sought to identify adverse fetal outcomes, but very few have commented on maternal
complications. A previous meta-analysis summarised the
evidence on adverse perinatal outcome following vaginal
bleeding in the first and second trimesters of pregnancy,10
but language restrictions in its search strategy and the lack
of quality assessment of the studies included potentially
limit the strength of its inferences. Moreover, several new
primary studies have been published since that warrant
inclusion in an updated systematic review. To date, we
know of no systematic review that has looked into both
maternal and perinatal outcomes following first-trimester
bleeding. We therefore undertook a comprehensive systematic review on maternal and perinatal outcomes following
first-trimester bleeding.

Methods
A study protocol stating the research question to be
addressed, the population and conditions of interest, the
exposure and outcomes considered, the criteria used for
identifying and selecting or excluding studies, and the
methods used for extracting and analysing data preceded
this systematic review. We followed the guidelines of the
Meta-analysis of Observational Studies in Epidemiology
(MOOSE) group.11

Literature search
Prospective and retrospective observational studies evaluating the association between threatened miscarriage and
maternal and perinatal outcomes were identified using the
computerised databases MEDLINE (US National Library of
Medicine, Bethesda, MD, USA) and EMBASE (Elsevier,
Amsterdam, the Netherlands). The searches were conducted
for published literature from January 1976 to April 2009,
without language restrictions. The search strategy was written in Ovid, then modified and run in each database. Adjacency operators and truncation were used. Our search term
combination for electronic databases was MeSH headings
(Medical Subject Headings, US National Library of Medicine), text words, and word variants for threatened miscarriage and for maternal and perinatal outcomes.
The citation lists were independently reviewed by two
authors (LS and SB). Titles and abstracts were screened and
articles were retrieved if they passed the relevance filter or if
there was uncertainty as to whether or not they were relevant. References from identified studies were also screened
for relevant citations. Retrieved articles were then reviewed

246

for inclusion/exclusion criteria. Those articles that met the

criteria were then kept for critical appraisal and data collection using a standard data-capture form. A review of literature suggested that the use of ultrasound scan in early
pregnancy diagnosis only became popular in the late 1970s
and early 1980s. Therefore, following a general consensus
among the authors, we decided to include only the published literature from 1976 to April 2009. As more than one
database was searched, there was some degree of duplication
in the citations identified. Therefore references were managed using RefWorks software (RefWorks-COS, Proquest,
Ann Arbor, MI, USA) and duplicates were removed.

Study selection
Inclusion and exclusion criteria
There were variations in the definitions of threatened miscarriage and first trimester among published studies. We
therefore adopted an inclusive approach and selected all
studies that took into account pregnant women with firsttrimester bleeding where viability was confirmed on ultrasound or the pregnancy continued beyond viability. Only
casecontrol or cohort studies were included in the review.
Case series and studies without controls were excluded.

Outcome measures
We categorised outcomes broadly into maternal and perinatal outcomes. The maternal outcomes included, preeclampsia/eclampsia or pregnancy-induced hypertension
(PIH), antepartum haemorrhage (APH; placenta praevia,
abruption, other APH), PPROM, mode of delivery (instrumental and caesarean deliveries), postpartum haemorrhage
(PPH) and retained placenta. The perinatal outcomes evaluated were preterm delivery (delivery before 37 completed
weeks), low birthweight (birthweight 2500 g), IUGR, perinatal mortality, indicators of perinatal morbidity (Apgar
scores and neonatal unit admission) and presence of congenital malformations.

Data synthesis and statistical analysis

We assessed the methodological quality of each study using
the NewcastleOttawa scale.12 All studies that met our inclusion criteria were independently evaluated by two reviewers
(LS and SB). We designed a data abstraction form, and the
two reviewers abstracted the data separately. Discrepancies
regarding the inclusion of studies or abstracted data were
resolved by discussion. Where necessary, we contacted
researchers to obtain additional information about study
methods or outcome measures. We entered and analysed the
data using RevMan 4.2 (Cochrane Collaboration, Oxford,
UK). For each outcome, data were only pooled if there were
at least two studies available for a particular outcome measure. As adjustments for confounding variables varied

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Threatened miscarriage and pregnancy outcome

among different studies, we used the raw numbers from each

study to calculate the crude odds ratios (OR) and 95% CI
for each outcome before pooling the data. A random effect
model was used (because of statistical heterogeneity in the
outcome data) to calculate combined OR, 95% CI. Tests of
heterogeneity were performed before pooling the data.

study. Of the cohort studies, six had a retrospective design

and the other seven used prospective cohorts. The study
characteristics are described in Table 1.
Women with first-trimester bleeding had an elevated risk
of adverse maternal and perinatal outcome.

Maternal outcomes
Results
Thirty-one publications evaluating the effect of threatened
miscarriage on maternal or perinatal outcome were identified. A hand search of references of the above papers identified another seven potentially useful references.
These 38 references were reviewed for inclusion and
exclusion criteria. Figure 1 summarises the process of literature identification and selection.
Of these references, 16 met the inclusion criteria,
although there was variation in the definition of threatened
miscarriage in terms of gestational age. However, two of
these articles were excluded because of insufficient data.13,14
In both cases, the authors were contacted but no response
was obtained. As a consequence, a total of 1459,1523 studies were included in the meta-analysis. Thirteen of the 14
studies included in the meta-analysis employed a cohort
design. The report by Hossain et al.17 was a casecontrol
Total citations identified from initial search
(n = 6043)

Citations excluded after removing

duplicates and screening titles
and/or abstracts
(n = 6012)

Potential references reviewed for detailed evaluation (n = 38)

From electronic search (n = 31)
From reference list (n = 7)

Pregnancy-induced hypertension, pre-eclampsia

and eclampsia
Six of the 14 studies reported on PIH, pre-eclampsia and
eclampsia. The incidence of PIH, pre-eclampsia or eclampsia was not significantly altered by bleeding in first trimester; OR (95% CI) of 0.99 (0.84, 1.17). These results
could be attributed to the influence of two large studies by
Weiss et al.8 and Wijesiriwardana et al.9 There was no significant heterogeneity (P = 0.19) in results across the different studies (Figure 2A).

Antepartum haemorrhage
Women with first-trimester bleeding were prone to subsequent APH in pregnancy. The meta-analysis included all
those studies that analysed outcomes following first-trimester bleeding where the pregnancy continued beyond
viability. In this context we have defined APH as bleeding
beyond viability (24 weeks). These women were more
likely to have placenta praevia (OR 1.62, 95% CI 1.19, 2.22)
as well as placental abruption (OR 1.46, 95% CI 1.00, 2.14).
Antepartum haemorrhage of unknown origin was twice as
likely in those with threatened miscarriage (OR 2.47, 95%
CI 1.52, 4.02) as in women without first-trimester bleeding.
Except for placental abruption (P = 0.03) there was no significant statistical heterogeneity (placenta praevia P = 0.46,
APH of unknown origin P = 0.07) when results were
pooled across the different studies (Figure 2B).

Preterm prelabour rupture of membranes

The incidence of PPROM was significantly higher in
women whose pregnancy was complicated by first-trimester
bleeding (OR 1.78, 95% CI 1.28, 2.48). The test of heterogeneity for PPROM was significant (P = 0.01) (Figure 2C).

Excluded studies (n = 24)

Reason for exclusion
Review =1
No control group = 3
Bleeding in assisted reproductive technique pregnancies = 2
Bleeding beyond first trimester = 14
Threatened miscarriage with intrauterine haematoma = 2
Insufficient data =2

Studies included in the review

(n = 14)

Figure 1. Study selection process.

Mode of delivery
First-trimester bleeding did not appear to influence the mode
of delivery. The risk of instrumental delivery (OR 1.01, 95%
CI 0.96, 1.07) or caesarean section (OR 0.92, 95% CI 0.73,
1.16) was not significantly altered. There was evidence of
significant statistical heterogeneity (P = 0.00001) in results
relating to the risk of caesarean section (Figure 2D).

Other maternal outcomes

The only study in the meta-analysis that evaluated PPH
and retained placenta as an outcome is by Wijesiriwardana

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248

Retrospective
cohort

Hossain
et al.17

Johns et al.18

Johns and
Jauniaux19

Prospective
cohort

Casecontrol

Davari-Tanha
et al.16

Prospective
cohort study

Retrospective
cohort study

Arafa et al.15

Study
design

Study

Participants

Cases: pregnant women with

bleeding or abdominal pain at
<12 weeks
Controls: asymptomatic women
attending dating scan at
1114 weeks matched for age
and parity
Cases: women with vaginal bleeding
at <14 completed weeks
Controls: age-matched women who
booked for antenatal care in the
hospital during the same time
period

Cases: women with preterm delivery

Controls: women without preterm
delivery

Cases: women with first-trimester

bleeding
Controls: women without bleeding

Cases: women with first- and

second-trimester bleeding
Controls: women without bleeding

Table 1. Characteristics of the studies included

Vaginal bleeding in an ongoing

pregnancy of <14 weeks, only
women with fresh red bleeding
were eligible

Women with bleeding in first or

second trimester. Outcome
assessed separately for firstand second-trimester bleeding
Vaginal bleeding or abdominal
pain at <12 completed weeks

Women with first- and

second-trimester bleeding,
included both light and heavy
bleeding
Outcome assessed separately for
first- and second-trimester
bleeding
Women with bleeding in first
trimester

Definition of threatened
miscarriage

Excluded women with spotting

only.
Twins, congenital uterine
anomaly, large leiomyomata
distorting the uterine cavity,
known thrombophilia

Multiple pregnancies
Women who opted for
termination

Multiple pregnancies, fetal

demise prior to 28 weeks,
women lost to follow-up

Not defined

Excluded multiple births,

bleeding in third trimester only,
where there was confusion
regarding spotting and missed
abortion

Exclusion criteria

Pre-eclampsia
Placenta praevia
Placental abruption
PPROM
Caesarean delivery
Preterm delivery
IUGR
Low birthweight
Intrauterine death
Preterm delivery
PPROM

1. Preterm labour
2. Late miscarriage (14 to
22 + 6 weeks)
3. PPROM
4. Pre-eclampsia
5. Abruption
6. Placenta praevia
7. Congenital anomalies

1. PIH
2. Fetal growth restriction
3. Placental abruption (and
intrauterine death)
4. PPROM
5. Preterm labour

1.
2.
3.
4.
5.
6.
7.
8.
9.
1.
2.

1. Low birthweight
2. Prematurity
3.Growth restriction
4. Congenital anomaly
5. Perinatal death

Outcome
evaluated

Saraswat et al.

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Study
design
Prospective
cohort

Retrospective
cohort

Retrospective
cohort

Prospective
cohort

Study

Konje et al.20

Mulik et al.5

Obed and Adewole21

Sipila et al.6

Table 1. (Continued)

Cases: women with

first-trimester uterine bleeding,
included only singleton
pregnancies that carried beyond
28 weeks
Controls: women without threa
tened abortion matched for age
and parity
Cases: Pregnancies complicated
by bleeding during first and
second trimester
Controls: women without
bleeding

Cases: women with threatened

miscarriage
Controls: women without early
pregnancy bleeding

Cases: Bleeding before 28 weeks

Controls: booked women
without threatened abortion

Participants

2009 The Authors Journal compilation RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology

Bleeding up to 24 weeks
Cases split according to
first- and second-trimester
bleeding and light or heavy
bleeding

First-trimester uterine bleeding,

gestational age not specified.

Vaginal bleeding with fetal heart

activity on ultrasound.
Amount of vaginal bleeding and
gestational age not specified

Bleeding before 28 weeks

Cases split into first- and
second-trimester bleeding and
compared with controls

Definition of threatened
miscarriage

Miscarriage before 24 weeks

Cases with inadequate data
on bleeding
Multiple pregnancies

History of previous caesarean

section, Patients with
factors associated with APH
other than placenta praevia,
and placental abruption

Multiple pregnancy, fetal

congenital anomalies, past
or present medical history,
surgical disorders, PIH and
pre-eclampsia

Excluded if women failed to

attend follow-up clinics,
delivered at home or were
lost to follow-up

Exclusion criteria

1. Low birthweight
2. Preterm delivery
3. Small for dates
4. Neonatal admission
5. Congenital malformations
6. Stillbirth
7. Perinatal mortality <7
days including stillbirth

1.Preterm labour
2. PPROM
3. APH
4. PIH
5. Intrauterine death
6. Gestational age at delivery
7. Asphyxia neonatorum
8. Birthweight
9. Stillbirth
10. Neonatal death
11. Congenital anomaly
1. Preterm delivery
2. Placenta praevia
3. Abruption
4. Unexplained APH
5. Low birthweight
6. Stillbirth
7. Early neonatal death
8. Late neonatal death
1.Placenta praevia
2. Placental abruption

Outcome
evaluated

Threatened miscarriage and pregnancy outcome

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12

11

10

Prospective
cohort

Prospective
cohort

Tongsong et al.22

Prospective
cohort

Strobino and Pantel7

Weiss et al.

Study
design

Study

Table 1. (Continued)

Cases: women with bleeding

up to 14 weeks
Controls: Women without
first-trimester bleeding

Cases: women with

first-trimester bleeding
Controls: women without
first-trimester bleeding

Cases: women with vaginal

bleeding in pregnancy
Controls: Prenatal women
registered before 22 weeks

Participants

Vaginal bleeding in first

trimester. Cases split
according to light and
heavy bleeding

First-trimester bleeding
with single viable
intrauterine pregnancy
on ultrasound

First-trimester bleeding.
Bleeding split into light
and heavy bleeding

Definition of threatened
miscarriage

Not defined.
Adjustments made in
statistical model for
potential confounding
factors

Multiple births, Lost to

follow-up

Multiple births, lost to

follow-up, unknown
bleeding histories

Exclusion criteria

1. Low birthweight
2. Preterm delivery
3. Small for gestational age
4. Placebtal abruption and
placenta praevia
5. Chromosomal anomaly
6. Malformation
1. Spontaneous abortion
(before 20 completed weeks)
2. Preterm delivery
3. Premature rupture of
membranes
4. APH
5. PIH
6.Chorioamnionitis
7. Congenital anomalies
8. Fetal growth restriction
9. Stillbirth
10. Low birthweight
11. Caesarean section
12. Apgar score at 5 min <7
13. Mean birthweight
1. IUGR
2. Gestational hypertension
3. Pre-eclampsia
4. Preterm delivery
5. PPROM
6. Placental abruption
7. Placenta praevia
8. Caesarean delivery

Outcome
evaluated

Saraswat et al.

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Retrospective
cohort

Williams et al.23

14
Cases: women with firsttrimester bleeding who
delivered after 20 weeks
Controls: women with no
vaginal bleeding

Cases: women with

vaginal bleeding before
12 weeks where
pregnancy continued to
a minimum of 24 weeks
Controls: Women
delivering after
24 weeks within the
same time period, but
without first-trimester
bleeding

Participants

Vaginal bleeding or
spotting limited to first
trimester

Women with vaginal

bleeding before
12 weeks where
pregnancy continued to
a minimum of 24 weeks

Definition of threatened
miscarriage

Pregnancies complicated
with diabetes, placenta
praevia, placental
abruption, or idiopathic
bleeding beginning in
trimesters other than
the first

Women with complete,

incomplete, or missed
miscarriage.
Women opting for
termination
Multiple pregnancies
Pregnancies with fetal
malformation
Hydatidiform moles
Second-trimester
miscarriages

Exclusion criteria

Outcome
evaluated
1. Pre-eclampsia
2. Eclampsia
3. Placental abruption
4. Placenta praevia
5.Other APH
6. PPROM
7. Induced labour
8. Instrumental delivery
9. Elective caesarean
10. Emergency caesarean
11. Postpartum haemorrhage
12. Manual removal of placenta
13. Preterm delivery
14. Malpresentation
15. Stillbirth
16. Neonatal death
17. Birthweight <2500 g
18. Apgar at 5 min <7
19. Admission to neonatal unit
1. Low birthweight
2. Preterm birth
3. Term low birthweight
4. Stillbirth
5. Neonatal death

APH, antepartum haemorrhage; IUGR, intrauterine growth restriction; PIH, pregnancy-induced hypertension; PPROM, preterm prelabour rupture of membranes.

Retrospective
cohort

Wijesiriwardana
et al.9

Study
design

13

Study

Table 1. (Continued)

Threatened miscarriage and pregnancy outcome

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Saraswat et al.

et al.9 They reported increased incidence of PPH (OR 1.13,

95% CI 1.04, 1.23) and manual removal of retained placenta (OR 1.45, 95% CI 1.26, 1.68). However, in the original study, after adjusting for potential confounders the
increase in PPH was no longer significant.

Congenital malformations

Perinatal outcome

Discussion

First-trimester bleeding was a predictor of poor perinatal

outcome.

In this comprehensive review we evaluated 12 different

maternal and perinatal outcomes and found a consistent
association between first-trimester bleeding and adverse
fetal and maternal outcomes.
To our knowledge this is the first report to systematically
review and pool data on both maternal and perinatal outcomes associated with first-trimester bleeding. It was rigorously carried out without language restrictions and met the
criteria laid down in the MOOSE statement.11 We paid
careful attention to quality assessment of studies and collected information important for evaluation of the validity
of the observed associations, potential for bias, and causality.
Our literature search identified one previous meta-analysis by Ananth and Savitz,10 which evaluated the effect of
vaginal bleeding up to 28 weeks and focused on perinatal
outcomes only. This systematic review included 28 studies
published between 1950 and 1992 and found that vaginal
bleeding was associated with increased risk of low birthweight, preterm birth, stillbirth, perinatal death and congenital malformations in infants. However, with changes in
practice and advances in medical technology, the limit of
viability is now 20 weeks (World Health Organization) or
24 weeks (UK) and therefore the 28-week cutoff used by
Ananth and Savitz10 is no longer compatible with the current practice as there would be overlap between exposure
and outcome with this approach. Moreover, the objective
of our meta-analysis was to evaluate the association of
bleeding primarily in the first trimester with both maternal
as well as perinatal outcome. Only those studies that have
used first-trimester bleeding as inclusion criteria for the
women or have performed an independent analysis for
first-trimester or any subsequent bleeding were included in
the review. Among the included studies, five studies evaluated outcome following first-trimester and second-trimester
bleeding and performed separate analysis for each trimester. For the purpose of the review, we have only used data
relating to first-trimester bleeding. As a consequence, this
meta-analysis aims to provide information regarding pregnancy outcomes for women who had threatened miscarriage in the first trimester.

Preterm delivery
The reported risk of preterm delivery in women with threatened miscarriage varied between 1.5 and 4.5 across the different studies. The overall adjusted risk of preterm delivery
was 2.05 (95% CI 1.76, 2.4) in women who experienced
first-trimester bleeding. There was evidence of significant
statistical heterogeneity in reported results (P < 0.0001)
(Figure 3A).

Intrauterine growth restriction

A significant association existed between first-trimester
bleeding and IUGR. The risk of having a baby with IUGR
was 1.54 (95% CI 1.18, 2.0) times in women with first-trimester threatened miscarriage. Once again there was evidence of significant statistical heterogeneity (P = 0.0002) in
the reported results (Figure 3B).

Low birthweight
The overall risk of having a low-birthweight baby was
higher in women who bled in the first trimester (OR 1.83,
95% CI 1.48, 2.28) than in women who did not. The risk
varied from 1.1 to 3.7 across the different studies. The test
for heterogeneity was highly significant (P < 0.0001) (Figure 3C).

Perinatal mortality
Perinatal deaths were observed to be nearly twice as frequent in women who experienced threatened miscarriage
when pooled across different studies (OR 2.15, 95% CI
1.41, 3.27). The results displayed evidence of significant statistical heterogeneity (P = 0.001) (Figure 3D).

Perinatal morbidity
The women with history of early pregnancy bleeding were
more likely to deliver babies with Apgar score <7 at 5 minutes after birth (OR 1.2, 95% CI 1.03, 1.4) and babies that
were admitted to the neonatal unit (OR1.13, 95% CI 1.03,
1.23) (Figure 3E).

Four studies reported the incidence of congenital anomalies

in babies born to mothers with early pregnancy bleeding.
The odds of having a baby with a congenital anomaly was
1.26 (95% CI 0.89, 1.79) (Figure 3F).

Figure 2. Maternal outcome: (A) pregnancy-induced hypertension, pre-eclampsia, eclampsia; (B) antepartum haemorrhage placental praevia,
placental abruption and antepartum haemorrhage of unknown origin; (C) preterm prelabour rupture of membranes; (D) mode of delivery
instrumental delivery and caesarean section.

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Saraswat et al.

Figure 3. Perinatal outcome: (A) preterm delivery; (B) intrauterine growth restriction; (C) low birthweight; (D) perinatal mortality; (E) perinatal
morbidity Apgar score and neonatal unit admission; (F) congenital anomalies.

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Threatened miscarriage and pregnancy outcome

Women with threatened miscarriage have a higher likelihood of miscarrying. Some of the studies included in the
review reported miscarriage rates whereas others only
included women where pregnancy continued beyond viability. Five out of the 14 studies reported miscarriage rates.
Davari-Tanha et al.16 quoted a figure as high as 42.7%
spontaneous pregnancy loss in first trimester whereas other
studies reported miscarriage incidence of 7.8% by
14 weeks,18 9.3% in first trimester,19 5.5% by 20 weeks22
and Weiss et al.8 reported a rate of 1% for light bleeding
and 2% for heavy bleeding by 24 weeks. However, none of
these studies excluded these women from the denominator
when reporting results.
One of the challenges of performing this systematic
review was the fact that the definition of threatened miscarriage is rarely stated in explicit terms. Some studies have
defined first trimester up to 12 weeks,5,9 some up to
14 weeks8,19 whereas others have just mentioned first trimester without defining gestational age in terms of
weeks.6,16,22,23 Moreover, it is possible that the risk of
adverse outcome may be different in women who experience light versus heavy bleeding. While some studies
have attempted to distinguish between light and heavy
bleeding,68 others have failed to do so. However, in this
context it is important to realise that subjective assessment
of blood loss is often erroneous in such situations and
objective assessment is often impractical.

Limitations and potential bias

Meta-analyses are limited by biases introduced through
individual studies as well as through the processes of systematic review and quantitative summary. Although we rigorously carried out an extensive literature search, we were
unable to search the grey literature and unpublished data.
Hence publication bias may have an impact on our results.
Moreover, in meta-analyses of observational data secondary
researchers are unable to adjust for potential confounders;
however, the present topic does not lend itself to experimental studies including randomised trials. Despite this,
the consistent associations seen in large primary studies
included in our review would suggest that the direction of
association would remain even if we had missed smaller
studies with equivocal or negative associations.
Other concerns relate to the use of non-standard definitions with questionable validity or reliability to discriminate between the exposure and the outcome. Often studies
were lacking in one or another quality feature. For these
reasons, associations that are not strong and consistent
should be viewed as no more than hypothesis generating.
Also, confidence in some of the findings may be constrained as certain outcomes have been evaluated only by
one or two studies. The study by Wijesiriwardana et al.9

was the only one that looked at outcomes like PPH, and
retained placenta.
Diverse factors are associated with poor pregnancy outcome such as maternal age, social class, ethnicity and previous obstetric history so it is difficult to compare directly
the results of individual outcomes across all studies because
of varying degrees of control for potential confounders.
For certain outcomes like placental abruption, PPROM,
preterm delivery, IUGR and low birthweight the assumption of homogeneity was violated when the overall risks
were adjusted for different studies and designs. The way
around this would be to perform a meta-regression, but
the number of studies looking at each individual outcome
was too small.

Inter-related risk factors

It is important to disentangle the relative importance of
key outcomes that may be inter-related. For instance,
women with PPROM are more likely to have preterm
babies who may in turn be of low birthweight. We could
not perform multivariate analysis in our meta-analyses to
explore such interactions between factors. Pooling of raw
data from relevant studies in meta-analysis from individual
women might help to clarify the causality of some observed
associations. Moreover, for certain outcomes like preterm
labour/delivery, most studies have given the overall risk of
preterm labour/delivery and not made an attempt to distinguish between spontaneous labour or iatrogenic preterm
delivery and therefore the association should be interpreted
with caution.

Meaning of findings
Reasons for the association between first-trimester bleeding
and adverse pregnancy outcomes are poorly understood.
Bleeding in the first trimester may be associated with a
chronic inflammatory reaction in the decidua. It is known
that in about two-thirds of early pregnancy failures, there
is evidence of defective placentation, characterised by thinner and fragmented trophoblast shell and reduced cytotrophoblast invasion of the spiral arterioles. Later
pregnancy complications such as pre-eclampsia, preterm
labour and PPROM have been shown to be associated with
impaired placentation and failure of physiological invasion
of the spiral arterioles. Problems with placental development may therefore explain why women with threatened
miscarriage are more likely to have placenta praevia, placental abruption and APH of unknown origin.
Our data highlight the fact that first-trimester bleeding
increases the risk of prematurity, growth restriction and
perinatal deaths. While some of the incidences of prematurity can be linked to maternal complications such as APH,

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Saraswat et al.

growth restriction suggests a degree of placental compromise.

Overall, our results suggest that pregnancies with firsttrimester bleeding are at a higher risk for poor fetal and
maternal outcome compared with women without bleeding. However owing to the risk of adverse outcomes being
relatively modest (OR 2) and the lack of availability of
any specific interventions to prevent these adverse events, it
would be premature to suggest a policy of increased fetal
and maternal surveillance.

Further research
Our review consists of six retrospective cohort studies and
seven studies with a prospective cohort design as well as
one casecontrol study. Prospective cohort studies are a
more reliable way of establishing a causal association
because retrospective designs are subject to recall bias.
However, bearing in mind the significant cost (both
financial and manpower) implications of implementing a
programme of increased surveillance and the limitations
of the studies included in the meta-analysis, perhaps what
is needed are more prospective studies on women with
and without vaginal bleeding in early pregnancy that are
large enough to allow subgroup analyses based on gestation, severity and duration of bleeding to be performed
with a degree of confidence. Another possibility is to
aggregate raw data from existing studies to perform individual women data meta-analysis, which will permit
adjustment for confounders and meaningful subgroup
analyses.
In conclusion, the current meta-analysis reports that
women with first-trimester threatened miscarriage are at
increased risk of adverse maternal and perinatal outcome,
although in the majority of women the risks are low
(OR 2). As a consequence, in the interim, it would be
rational to use the findings of our review to reassure
women with first-trimester bleeding and at the same
time alert clinicians for the signs of the possible complications.

Disclosure of interests
None of the authors report any conflict of interest or
financial interest.

Contribution to authorship
L.S. prepared the protocol, collected data, assessed eligibility and methodological quality of studies and wrote the
review. S.B. conceived the idea, conducted searches,
assessed eligibility and quality of studies, and provided
comments on the manuscript. A.M. performed the statistical analysis and S.B. conceived the idea, provided comments on the manuscript and supervised the review.

256

Details of ethics approval

Approval was not required.

Funding
Not required. j

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