Maternal and perinatal outcome in women with … Threatened miscarriage is a common complication in the ﬁrst trimester of pregnancy and is often associated with anxiety regarding

Maternal and perinatal outcome in women withthreatened miscarriage in the first trimester:a systematic reviewL Saraswat,a S Bhattacharya,b A Maheshwari,c S Bhattacharyad

a Department of Obstetrics and Gynaecology b Dugald Baird Centre for Research on Women’s 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

[email protected]

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;117:245–257.

Introduction

First-trimester bleeding is a common complication which

affects 16–25% of all pregnancies.1 Threatened miscarriage

is diagnosed on the basis of documented fetal cardiac activ-

ity 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.2–9

It is hypothesised that first-trimester bleeding may indi-

cate an underlying placental dysfunction, which may mani-

fest 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

ª 2009 The Authors Journal compilation ª RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology 245

DOI: 10.1111/j.1471-0528.2009.02427.x

www.bjog.orgSystematic review

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 pri-

mary studies have sought to identify adverse fetal out-

comes, 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 system-

atic 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 evaluat-

ing 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 writ-

ten in Ovid, then modified and run in each database. Adja-

cency operators and truncation were used. Our search term

combination for electronic databases was MeSH headings

(Medical Subject Headings, US National Library of Medi-

cine), text words, and word variants for threatened miscar-

riage 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 rele-

vant. References from identified studies were also screened

for relevant citations. Retrieved articles were then reviewed

for inclusion/exclusion criteria. Those articles that met the

criteria were then kept for critical appraisal and data collec-

tion using a standard data-capture form. A review of litera-

ture 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 pub-

lished 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 man-

aged using ‘RefWorks’ software (RefWorks-COS, Proquest,

Ann Arbor, MI, USA) and duplicates were removed.

Study selection

Inclusion and exclusion criteriaThere were variations in the definitions of ‘threatened mis-

carriage’ and ‘first trimester’ among published studies. We

therefore adopted an inclusive approach and selected all

studies that took into account pregnant women with first-

trimester bleeding where viability was confirmed on ultra-

sound or the pregnancy continued beyond viability. Only

case–control or cohort studies were included in the review.

Case series and studies without controls were excluded.

Outcome measuresWe categorised outcomes broadly into maternal and peri-

natal outcomes. The maternal outcomes included, pre-

eclampsia/eclampsia or pregnancy-induced hypertension

(PIH), antepartum haemorrhage (APH; placenta praevia,

abruption, other APH), PPROM, mode of delivery (instru-

mental and caesarean deliveries), postpartum haemorrhage

(PPH) and retained placenta. The perinatal outcomes eval-

uated were preterm delivery (delivery before 37 completed

weeks), low birthweight (birthweight £2500 g), IUGR, peri-

natal mortality, indicators of perinatal morbidity (Apgar

scores and neonatal unit admission) and presence of con-

genital malformations.

Data synthesis and statistical analysisWe assessed the methodological quality of each study using

the Newcastle–Ottawa scale.12 All studies that met our inclu-

sion 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 mea-

sure. As adjustments for confounding variables varied

Saraswat et al.

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

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.

Results

Thirty-one publications evaluating the effect of threatened

miscarriage on maternal or perinatal outcome were identi-

fied. A hand search of references of the above papers iden-

tified another seven potentially useful references.

These 38 references were reviewed for inclusion and

exclusion criteria. Figure 1 summarises the process of liter-

ature 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 145–9,15–23 stud-

ies 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 case–control

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

Pregnancy-induced hypertension, pre-eclampsiaand eclampsiaSix of the 14 studies reported on PIH, pre-eclampsia and

eclampsia. The incidence of PIH, pre-eclampsia or eclamp-

sia was not significantly altered by bleeding in first tri-

mester; 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 sig-

nificant heterogeneity (P = 0.19) in results across the dif-

ferent studies (Figure 2A).

Antepartum haemorrhageWomen with first-trimester bleeding were prone to subse-

quent APH in pregnancy. The meta-analysis included all

those studies that analysed outcomes following first-trimes-

ter 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 sig-

nificant 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 membranesThe 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 hetero-

geneity for PPROM was significant (P = 0.01) (Figure 2C).

Mode of deliveryFirst-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 outcomesThe only study in the meta-analysis that evaluated PPH

and retained placenta as an outcome is by Wijesiriwardana

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)

Studies included in the review (n = 14)

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

Figure 1. Study selection process.

Threatened miscarriage and pregnancy outcome


Tab

le1.

Char

acte

rist

ics

of

the

studie

sin

cluded

Stu

dy

Stu

dy

desi

gn

Part

icip

an

tsD

efi

nit

ion

of

thre

ate

ned

mis

carr

iag

e

Excl

usi

on

crit

eri

aO

utc

om

e

evalu

ate

d

1A

rafa

etal

.15

Ret

rosp

ective

cohort

study

Cas

es:

wom

enw

ith

firs

t-an

d

seco

nd-t

rim

este

rble

edin

g

Contr

ols

:w

om

enw

ithout

ble

edin

g

Wom

enw

ith

firs

t-an

d

seco

nd-t

rim

este

rble

edin

g,

incl

uded

both

light

and

hea

vy

ble

edin

g

Outc

om

eas

sess

edse

par

atel

yfo

r

firs

t-an

dse

cond-t

rim

este

r

ble

edin

g

Excl

uded

multip

lebirth

s,

ble

edin

gin

third

trim

este

ronly

,

wher

eth

ere

was

confu

sion

regar

din

gsp

ott

ing

and

mis

sed

abort

ion

1.

Low

birth

wei

ght

2.

Prem

aturity

3.G

row

thre

strict

ion

4.

Congen

ital

anom

aly

5.

Perinat

aldea

th

2D

avar

i-Ta

nha

etal

.16

Prosp

ective

cohort

study

Cas

es:

wom

enw

ith

firs

t-tr

imes

ter

ble

edin

g

Contr

ols

:w

om

enw

ithout

ble

edin

g

Wom

enw

ith

ble

edin

gin

firs

t

trim

este

r

Not

defi

ned

1.

Pre-

ecla

mpsi

a

2.

Plac

enta

pra

evia

3.

Plac

enta

lab

ruption

4.

PPRO

M

5.

Cae

sare

andel

iver

y

6.

Pret

erm

del

iver

y

7.

IUG

R

8.

Low

birth

wei

ght

9.

Intr

aute

rine

dea

th

3H

oss

ain

etal

.17

Cas

e–co

ntr

ol

Cas

es:

wom

enw

ith

pre

term

del

iver

y

Contr

ols

:w

om

enw

ithout

pre

term

del

iver

y

Wom

enw

ith

ble

edin

gin

firs

tor

seco

nd

trim

este

r.O

utc

om

e

asse

ssed

separ

atel

yfo

rfirs

t-

and

seco

nd-t

rim

este

rble

edin

g

Multip

lepre

gnan

cies

,fe

tal

dem

ise

prior

to28

wee

ks,

wom

enlo

stto

follo

w-u

p

1.

Pret

erm

del

iver

y

2.

PPRO

M

4Jo

hns

etal

.18

Ret

rosp

ective

cohort

Cas

es:

pre

gnan

tw

om

enw

ith

ble

edin

gor

abdom

inal

pai

nat

<12

wee

ks

Contr

ols

:as

ympto

mat

icw

om

en

atte

ndin

gdat

ing

scan

at

11–1

4w

eeks

mat

ched

for

age

and

par

ity

Vag

inal

ble

edin

gor

abdom

inal

pai

nat

<12

com

ple

ted

wee

ks

Multip

lepre

gnan

cies

Wom

enw

ho

opte

dfo

r

term

inat

ion

1.

PIH

2.

Feta

lgro

wth

rest

rict

ion

3.

Plac

enta

lab

ruption

(and

intr

aute

rine

dea

th)

4.

PPRO

M

5.

Pret

erm

labour

5Jo

hns

and

Jaunia

ux1

9

Prosp

ective

cohort

Cas

es:

wom

enw

ith

vagin

alble

edin

g

at<

14

com

ple

ted

wee

ks

Contr

ols

:ag

e-m

atch

edw

om

enw

ho

booke

dfo

ran

tenat

alca

rein

the

hosp

ital

during

the

sam

etim

e

per

iod

Vag

inal

ble

edin

gin

anongoin

g

pre

gnan

cyof

<14

wee

ks,

only

wom

enw

ith

fres

hre

dble

edin

g

wer

eel

igib

le

Excl

uded

wom

enw

ith

‘spott

ing’

only

.

Twin

s,co

ngen

ital

ute

rine

anom

aly,

larg

ele

iom

yom

ata

dis

tort

ing

the

ute

rine

cavi

ty,

know

nth

rom

bophili

a

1.

Pret

erm

labour

2.

Late

mis

carr

iage

(14

to

22

+6

wee

ks)

3.

PPRO

M

4.

Pre-

ecla

mpsi

a

5.

Abru

ption

6.

Plac

enta

pra

evia

7.

Congen

ital

anom

alie

s

Saraswat et al.


Tab

le1.

(Continued

)

Stu

dy

Stu

dy

desi

gn

Part

icip

an

tsD

efi

nit

ion

of

thre

ate

ned

mis

carr

iag

e

Excl

usi

on

crit

eri

aO

utc

om

e

evalu

ate

d

6K

onje

etal

.20

Prosp

ective

cohort

Cas

es:

Ble

edin

gbef

ore

28

wee

ks

Contr

ols

:booke

dw

om

en

without

thre

aten

edab

ort

ion

Ble

edin

gbef

ore

28

wee

ks

Cas

essp

litin

tofirs

t-an

d

seco

nd-t

rim

este

rble

edin

gan

d

com

par

edw

ith

contr

ols

Excl

uded

ifw

om

enfa

iled

to

atte

nd

follo

w-u

pcl

inic

s,

del

iver

edat

hom

eor

wer

e

lost

tofo

llow

-up

1.P

rete

rmla

bour

2.

PPRO

M

3.

APH

4.

PIH

5.

Intr

aute

rine

dea

th

6.

Ges

tational

age

atdel

iver

y

7.

Asp

hyx

ianeo

nat

oru

m

8.

Birth

wei

ght

9.

Still

birth

10.

Neo

nat

aldea

th

11.

Congen

ital

anom

aly

7M

ulik

etal

.5Ret

rosp

ective

cohort

Cas

es:

wom

enw

ith

thre

aten

ed

mis

carr

iage

Contr

ols

:w

om

enw

ithout

early

pre

gnan

cyble

edin

g

Vag

inal

ble

edin

gw

ith

feta

lhea

rt

activi

tyon

ultra

sound.

Am

ount

of

vagin

alble

edin

gan

d

ges

tational

age

not

spec

ified

Multip

lepre

gnan

cy,

feta

l

congen

ital

anom

alie

s,pas

t

or

pre

sent

med

ical

his

tory

,

surg

ical

dis

ord

ers,

PIH

and

pre

-ecl

ampsi

a

1.

Pret

erm

del

iver

y

2.

Plac

enta

pra

evia

3.

Abru

ption

4.

Unex

pla

ined

APH

5.

Low

birth

wei

ght

6.

Still

birth

7.

Early

neo

nat

aldea

th

8.

Late

neo

nat

aldea

th

8O

bed

and

Adew

ole

21

Ret

rosp

ective

cohort

Cas

es:

wom

enw

ith

firs

t-tr

imes

ter

ute

rine

ble

edin

g,

incl

uded

only

single

ton

pre

gnan

cies

that

carr

ied

bey

ond

28

wee

ks

Contr

ols

:w

om

enw

ithout

thre

a

tened

abort

ion

mat

ched

for

age

and

par

ity

Firs

t-tr

imes

ter

ute

rine

ble

edin

g,

ges

tational

age

not

spec

ified

.

His

tory

of

pre

vious

caes

area

n

sect

ion,

Patien

tsw

ith

fact

ors

asso

ciat

edw

ith

APH

oth

erth

anpla

centa

pra

evia

,

and

pla

centa

lab

ruption

1.P

lace

nta

pra

evia

2.

Plac

enta

lab

ruption

9Si

pila

etal

.6Pr

osp

ective

cohort

Cas

es:

Preg

nan

cies

com

plic

ated

by

ble

edin

gduring

firs

tan

d

seco

nd

trim

este

r

Contr

ols

:w

om

enw

ithout

ble

edin

g

Ble

edin

gup

to24

wee

ks

Cas

essp

litac

cord

ing

to

firs

t-an

dse

cond-t

rim

este

r

ble

edin

gan

dlig

ht

or

hea

vy

ble

edin

g

Mis

carr

iage

bef

ore

24

wee

ks

Cas

esw

ith

inad

equat

edat

a

on

ble

edin

g

Multip

lepre

gnan

cies

1.

Low

birth

wei

ght

2.

Pret

erm

del

iver

y

3.

Smal

lfo

rdat

es

4.

Neo

nat

alad

mis

sion

5.

Congen

ital

mal

form

atio

ns

6.

Still

birth

7.

Perinat

alm

ort

ality

<7

day

sin

cludin

gst

illbirth



Tab

le1.

(Continued

)

Stu

dy

Stu

dy

desi

gn

Part

icip

an

tsD

efi

nit

ion

of

thre

ate

ned

mis

carr

iag

e

Excl

usi

on

crit

eri

aO

utc

om

e

evalu

ate

d

10

Stro

bin

oan

dPa

nte

l7Pr

osp

ective

cohort

Cas

es:

wom

enw

ith

vagin

al

ble

edin

gin

pre

gnan

cy

Contr

ols

:Pr

enat

alw

om

en

regis

tere

dbef

ore

22

wee

ks

Firs

t-tr

imes

ter

ble

edin

g.

Ble

edin

gsp

litin

tolig

ht

and

hea

vyble

edin

g

Multip

lebirth

s,lo

stto

follo

w-u

p,

unkn

ow

n

ble

edin

ghis

tories

1.

Low

birth

wei

ght

2.

Pret

erm

del

iver

y

3.

Smal

lfo

rges

tational

age

4.

Plac

ebta

lab

ruption

and

pla

centa

pra

evia

5.

Chro

moso

mal

anom

aly

6.

Mal

form

atio

n

11

Tongso

ng

etal

.22

Prosp

ective

cohort

Cas

es:

wom

enw

ith

firs

t-tr

imes

ter

ble

edin

g

Contr

ols

:w

om

enw

ithout

firs

t-tr

imes

ter

ble

edin

g

Firs

t-tr

imes

ter

ble

edin

g

with

single

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Saraswat et al.


Tab

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(Continued

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.



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

95% CI 1.04, 1.23) and manual removal of retained pla-

centa (OR 1.45, 95% CI 1.26, 1.68). However, in the origi-

nal study, after adjusting for potential confounders the

increase in PPH was no longer significant.

Perinatal outcome

First-trimester bleeding was a predictor of poor perinatal

outcome.

Preterm deliveryThe reported risk of preterm delivery in women with threa-

tened miscarriage varied between 1.5 and 4.5 across the dif-

ferent 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 restrictionA 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-tri-

mester threatened miscarriage. Once again there was evi-

dence of significant statistical heterogeneity (P = 0.0002) in

the reported results (Figure 3B).

Low birthweightThe 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) (Fig-

ure 3C).

Perinatal mortalityPerinatal deaths were observed to be nearly twice as fre-

quent 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 sta-

tistical heterogeneity (P = 0.001) (Figure 3D).

Perinatal morbidityThe women with history of early pregnancy bleeding were

more likely to deliver babies with Apgar score <7 at 5 min-

utes 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).

Congenital malformationsFour 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).

Discussion

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 out-

comes associated with first-trimester bleeding. It was rigor-

ously 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 col-

lected information important for evaluation of the validity

of the observed associations, potential for bias, and causal-

ity.

Our literature search identified one previous meta-analy-

sis 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 birth-

weight, preterm birth, stillbirth, perinatal death and con-

genital 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 cur-

rent 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 evalu-

ated outcome following first-trimester and second-trimester

bleeding and performed separate analysis for each trimes-

ter. 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 preg-

nancy outcomes for women who had threatened miscar-

riage in the first trimester.

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.

Saraswat et al.


A

B

C

D



A

B

C

D

E

F

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.

Saraswat et al.


Women with threatened miscarriage have a higher likeli-

hood of miscarrying. Some of the studies included in the

review reported miscarriage rates whereas others only

included women where pregnancy continued beyond viabil-

ity. 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 miscar-

riage 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 tri-

mester 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 experi-

ence ‘light’ versus ‘heavy’ bleeding. While some studies

have attempted to distinguish between light and heavy

bleeding,6–8 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 sys-

tematic review and quantitative summary. Although we rig-

orously 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 experi-

mental 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 defini-

tions with questionable validity or reliability to discrimi-

nate 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 con-

strained 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 out-

come such as maternal age, social class, ethnicity and previ-

ous 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 assump-

tion 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 distin-

guish 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 thin-

ner and fragmented trophoblast shell and reduced cyto-

trophoblast 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 develop-

ment may therefore explain why women with threatened

miscarriage are more likely to have placenta praevia, pla-

cental 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 prematu-

rity can be linked to maternal complications such as APH,



growth restriction suggests a degree of placental compro-

mise.

Overall, our results suggest that pregnancies with first-

trimester bleeding are at a higher risk for poor fetal and

maternal outcome compared with women without bleed-

ing. 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 case–control 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 gesta-

tion, 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 indi-

vidual 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 compli-

cations.

Disclosure of interestsNone of the authors report any conflict of interest or

financial interest.

Contribution to authorshipL.S. prepared the protocol, collected data, assessed eligibil-

ity 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 statisti-

cal analysis and S.B. conceived the idea, provided com-

ments on the manuscript and supervised the review.

Details of ethics approvalApproval was not required.

FundingNot required. j

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Documents

Maternal and perinatal outcome in women with … Threatened miscarriage is a common complication in the ﬁrst trimester of pregnancy and is often associated with anxiety regarding