Human Reproduction, Vol.25, No.1 pp.

265274, 2010
Advanced Access publication on November 7, 2009 doi:10.1093/humrep/dep376

ORIGINAL ARTICLE Reproductive epidemiology

Prevalence and risk factors for

obstetric haemorrhage in 6730
singleton births after assisted
reproductive technology in
Victoria Australia
1
Department of Obstetrics and Gynaecology, Monash University, Level 5, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168
Australia 2Monash IVF, Richmond, Australia 3Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia
4
Melbourne IVF Reproductive Services, The Royal Womens Hospital, Parkville, Australia 5Melbourne Assisted Conception Centre,
Heidelberg, Australia 6Murdoch Childrens Research Institute, Melbourne, Australia 7Department of Paediatrics, University of Melbourne,
Melbourne, Australia
8

Correspondence address. Tel: 61-03-9594-5374; Fax: 61-03-9594-6389; E-mail: david.healy@med.monash.edu.au

background: Obstetric haemorrhages have been reported to be increased after assisted reproduction technologies (ART) but the
mechanisms involved are unclear.
methods: This retrospective cohort study compared the prevalence of antepartum haemorrhage (APH), placenta praevia (PP), placental
abruption (PA) and primary post-partum haemorrhage (PPH) in women with singleton births between 1991 and 2004 in Victoria Australia:
6730 after IVF/ICSI, 24 619 from the general population, 779 after gamete intrafallopian transfer (GIFT) and 2167 non-ART conceptions in
infertile patients. Risk factors for haemorrhages in the IVF/ICSI group were examined by logistic regression.
results: The IVF/ICSI group had more APH: 6.7 versus 3.6% (adjusted OR 2.0; 95% CI 1.8 2.3), PP: 2.6 versus 1.1% (2.3; 1.9 2.9),
PA: 0.9 versus 0.4% (2.1; 1.4 3.0) and PPH: 11.1 versus 7.9% (1.3; 1.2 1.4) than the general population. APH, PP and PA were as frequent
in the GIFT group as in the IVF/ICSI group, but were less frequent in the non-ART group. Within the IVF/ICSI group, fresh compared with
frozen thawed embryo transfers (FET) was associated with more frequent APH (1.5; 1.21.8) and PA (2.1; 1.23.7) and the odds
ratio increased with number of oocytes collected (1.02; 1.00 1.04). Endometriosis patients had more PP (1.7; 1.2 2.4) and PPH (1.3;
1.1 1.6) than those without endometriosis. FET in articial cycles was associated with increased PPH (1.8; 1.3 2.6) compared with FET
in natural cycles.

conclusions: Obstetric haemorrhages are more frequent with singleton births after IVF, ICSI and GIFT. The exploratory analysis of
factors in the IVF/ICSI group, showing associations with fresh embryo transfers in stimulated cycles, endometriosis and hormone treatments,
suggests that events around the time of implantation may be responsible and that suboptimal endometrial function is the critical mechanism.
Key words: IVF / obstetrics / antepartum haemorrhage / post-partum haemorrhage / assisted reproductive technology

Introduction
Obstetric haemorrhage and primary post-partum haemorrhage (PPH)
are important causes of maternal mortality worldwide (World Health
Organisation, 2007). Antepartum haemorrhage (APH), placenta
praevia (PP) and placental abruption (PA) are major obstetric complications in all countries. Increased frequencies of these complications

with births after assisted reproduction technology (ART) have been

reported by several groups (Daniel et al., 2000; Perri et al., 2001;
Smithers et al., 2003; Jackson et al., 2004; Kallen et al., 2005b;
Shevell et al., 2005; Romundstad et al., 2006; Schieve et al., 2007).
Although increased multiple births after ART were an important
factor increasing obstetric haemorrhages, PP and PA are also known
to be more frequent with singleton deliveries after ART than after

& The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
For Permissions, please email: journals.permissions@oxfordjournals.org

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 24, 2014

D.L. Healy 1,2,8, S. Breheny 2, J. Halliday6,7, A. Jaques 6, D. Rushford 3,

C. Garrett 3, J.M. Talbot 5, and H.W.G. Baker3,4

266

Materials and Methods

The project was approved by each Human Research and Ethics committee
of the hospitals involved and the Victorian Department of Human Services.

Data sources
Art clinic databases
The infertility clinics are required to keep comprehensive records of all
procedures that result in birth by Victorian State regulations and for
reporting to the Fertility Society of Australias Reproductive Technology
Accreditation Committee and all patients sign consent forms acknowledging this. The databases include information on clinical features, diagnosis,
treatments and the embryos. Additional information about investigations
and lifestyle factors was added from the patients records.

Victorian birth data

In the Victorian Department of Human Services, the Perinatal Data Collection Unit (PDCU) oversees mandatory registration of all births of 20
weeks gestation and over. There were approximately 862 000 singleton
births in the study period (1991 2004). Miscarriages and terminations
of pregnancy at ,20 weeks gestation are not registered as births in Victoria unless a birth defect is recorded. Data on the existing maternal
medical conditions, previous pregnancies, gestation at birth, maternal
complications of pregnancy and mode of delivery are provided on forms
by midwives involved with the births and entered on computer centrally.
Over 99.6% of all births in Victoria were reported to the PDCU in 1996
(Riley and Grifn, 1997).

Subjects
The ART data relate to women treated in the state of Victoria by any of
three infertility services: Melbourne IVF, Monash IVF and the Melbourne
Assisted Conception Centre (MACC) between January 1991 and
December 2004. Only the subjects rst singleton birth during the study
period were included. This is a retrospective cohort study using record
linkage to obtain the information on obstetric haemorrhages in infertile
women conceiving after IVF or ICSI and three comparison groups:
women conceiving in the general community and infertile women
conceiving by GIFT or without ART.

In vitro fertilization/intracytoplasmic sperm injection

For this group, oocytes were collected by transvaginal ultrasound guided
oocyte collections under neurolept or general anaesthesia. ICSI was introduced in 1993. Treatment of male infertility was attempted with standard
IVF before the introduction of ICSI. Stimulation regimens involved clomiphene, human menopausal gonadotrophin and human chorionic gonadotrophin up to 1993. The oral contraceptive pill was used increasingly
after 1995 to regulate the starting time of gonadotrophin treatment.
Long down-regulation with gonadotrophin releasing hormone agonists
was used after 2001. Recombinant FSH was used after 1994. Gonadotrophin releasing hormone antagonists were used in increasing numbers
of patients after 2000.
Culture media changed from human tubal uid to multi-stage media in
2000. The protein supplement was human serum albumin until 2000 and
highly puried albumin thereafter. Embryo cryopreservation involved propanediol with embryo freezing on day 2, 3 or 5. Cryopreserved embryos
were thawed and transferred on the same day as their age after ovulation
in natural or articial cycles until 1996. After September 1997, all cryopreserved embryos were thawed the day before transfer and cultured overnight so they would be on average 18 h more advanced than embryos
transferred fresh. Frozen-thawed ET (FET) was usually performed in
natural menstrual cycles but women with oligomenorrhoea or amenorrhoea had articial cycles induced with cyclical estradiol and progesterone
treatment. Some other patients had luteal phase support with hCG or
progesterone. During the time of the study relatively low numbers of
embryos were transferred and the multiple pregnancy rate was ,20%.
Embryo cryopreservation was common and approximately one third of
the singleton births were from FET.
National health funding of ART covered about half of the patients costs.
Patients without private health insurance or their own specialist gynaecologist were classied as semiprivate and this is an indicator of socioeconomic status.

General population
For each IVF/ICSI subject, three records of singleton births were randomly
selected from the PDCU data matching on year of maternal age and year
of birth of the baby to balance the exposed and unexposed groups on

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 24, 2014

natural conceptions in matched controls but the mechanisms involved

are not clear and deserve further study (Schieve et al., 2007).
We have previously reported a high frequency of APH and PP in IVF
twin pregnancies (Smithers et al., 2003). We speculated this was a
consequence of embryo transfer through the vagina and cervix, compared with in-vivo conception and implantation via the uterine tube.
More recently, Romundstad et al. (2006) conrmed an increased
risk of PP [adjusted OR 5.6, 95% condence interval (CI) 4.4 7.0]
in 5581 singleton ART births. They also compared results of two
births in the same woman who had both an ART and a natural conception and found that the risk of PP was also higher (OR 2.9) in
the ART pregnancy. These authors suggested the higher risk of PP
was largely attributed to factors related to the ART and that APH
and PP may occur as a consequence of embryo transfer through the
vagina and cervix.
Studying factors affecting obstetric haemorrhage after ART is
important because ART accounts for 35% of all births in developed
countries and is increasing in use. Understanding the mechanisms
might lead to prevention not only of these haemorrhages in ART pregnancies but also those in the general community. PPH has not previously been reported in detail in ART patients (Kallen et al.,
2005b), yet PPH is a leading cause of maternal death. Studying singleton births is appropriate with the general move to elective single
embryo transfer to minimize the multiple pregnancy rate with ART.
Here we report a multi-centre study of obstetric haemorrhage and
PPH in singleton births of patients who conceived with IVF or ICSI and
comparison groups from the general community, women who conceived with gamete intrafallopian transfer (GIFT), and infertile
women who became pregnant without ART. Our strategy was as
follows: rstly, to replicate the ndings that the risks of these haemorrhages are greater after IVF/ICSI than in the general population after
adjusting for confounding factors; secondly, to compare the frequencies of the haemorrhages after IVF/ICSI and GIFT to assess the
effect of manipulation and culture of the embryos in the embryology
laboratory as this does not occur with GIFT; thirdly, to compare the
frequencies of the haemorrhages after IVF/ICSI and non-ART conception in infertile women to examine the effect of infertility; and
fourthly, to examine factors within the IVF/ICSI group that might be
related to haemorrhages.

Healy et al.

267

Increased obstetric haemorrhage after ART

maternal age and possible temporal changes in ascertainment of the obstetric haemorrhages.

Record linkage

The results of singleton births from GIFT were analysed to determine if the
in-vitro fertilization and embryology laboratory procedures contributed to
the outcome, as these do not occur with GIFT. GIFT was performed
under general anaesthesia and involved laparoscopic placement of the
oocytes and spermatozoa into the ampulla of a uterine tube via the mbrial end of the tube. Most of the GIFT was performed between 1990
and 1998. Except at one centre (MACC), extra oocytes not transferred
were inseminated and embryos resulting were cryopreserved.

With the aid of a computer programme, LinkageWiz, probabilistic record

linkage was used to match the ART data to the PDCU common identifying
variables: name, date of birth and postcode (Tayor, 1998). Once record
linkage was complete, IVF clinical data were used to ensure matches to singleton births were correct. Cross-checking between the Victorian ART
clinics was done to ensure the birth was not the result of ART at
another clinic. Data were extracted for rst singleton births within the
study period of greater than 19 weeks gestation for the groups: IVF/
ICSI (6730), population control (24 619), GIFT (779) and non-ART
(2167). Stillbirths, late terminations and neonatal deaths (within 28 days
of birth) were included.

Non-ART

Data analysis

Gamete intrafallopian transfer

Exclusions
Donor oocyte and embryo recipients (n 339) were excluded. By
chance, some women in the IVF/ICSI, GIFT and non-ART groups who
also had naturally conceived children were matched with other IVF/ICSI
group subjects. Similarly some women with more than one birth were
in the general population group. All these second and subsequent pregnancies in the study groups were excluded so that each woman was
only analysed once thus avoiding correlations between outcomes that
might otherwise occur.

Primary outcome: haemorrhages

The obstetric haemorrhages were dened using the Victorian PDCU electronic user manual. APH was coded when bleeding of 15 ml or more
occurred from the birth canal after 20 weeks gestation and before the
birth of the baby. This overarching category includes PP, PA and APH
for other reasons. PP was coded where the placenta was located over
or very close to the cervical os as veried by independent ultrasound
examination and conrmed at birth. APH may or may not have occurred.
The standardized form sent to the PDCU does not differentiate between
marginal PP (grade I) from more major PP (grade II III) to grade IV PP
which cover the internal cervical os. PA was coded where there was premature separation of the placenta. There was evidence of retroplacental
bleeding and the amount of blood lost was always moderate or severe
whether out of the vagina or internally. PPH was coded when there was
blood loss greater than 500 ml within 24 h of vaginal delivery or childbirth
or greater than 750 ml after Caesarean section. The PDCU denitions are
consistent with the International Classication of Diseases (ICD10) coding
system. In this study, six women had both PP and PA. Also 70 women with
PP had no bleeding and were not classied as having APH.

The background characteristics of the births in each of the four comparison groups were described using means and ranges for quantitative variables and percentages for categorical variables. The proportions of
APH, PP, PA and PPH in each group were compared between the IVF/
ICSI group and each of the general population, GIFT and non-ART
groups using the x2 test. Logistic regression was performed using
GenStat 11th Edition (McCullagh and Nelder, 1989) to compare the
odds of each complication between the IVF/ICSI and general population
groups in unadjusted analyses and analyses adjusted for potential confounders: age, year of birth of baby, marital status, parity, previous miscarriage
or termination of pregnancy, country of birth and vertex presentation
(Model 1). Also giving birth in tertiary, private or other maternity hospitals
was also included with the other factors in model (Model 2). For PPH, the
effect of adjusting for other complications of pregnancy: pre-eclampsia,
APH, PP, PA, premature rupture of membranes and induced labour,
were added to Models 1 and 2. Also, because of the different denitions
of post-partum haemorrhage for vaginal and Caesarean section deliveries,
these were examined separately.
To determine which factors within the IVF/ICSI group were independently related to obstetric haemorrhages, causes of infertility, ovarian
stimulation, fertilization procedure (IVF or ICSI), transfer of fresh or
frozen embryos, number of embryos transferred, average embryo
quality, average cell number, luteal phase support and number of fetal
hearts were examined by logistic regression to adjust for the potential confounders listed above. Graphs were plotted to check the linearity and
nature of the relationships between the data and the t of the models.
Additional analyses were performed omitting factors which might be an
effect of the obstetric complication being studied, such as birth in a tertiary
maternity hospital, to determine if these affected the relationship between
the ART or infertility factor and the end-point. To study the possible
effects of ovarian stimulation, oocyte numbers, fertilization rate and
embryo numbers, and births resulting from fresh embryo transfer were
analysed separately. Similarly, FET was analysed separately to examine
factors specic to this group such as the effects of natural and articial
cycles and overnight culture of embryos after thawing.

Results
IVF/ICSI group compared with the control
groups
The main differences in characteristics in the subjects in the groups are
summarized in Table I. Compared with the IVF/ICSI group, the
general population group were more likely to be born in Asia or the
Middle East and migrated to Australia, to have previous pregnancies
and to have a vertex presentation, and less likely to be married,

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 24, 2014

Infertile women who conceived without ART (non-ART group) were analysed to determine the contribution of infertility itself to the outcomes.
The women were classied as infertile because they were seen in the
Melbourne or Monash clinics between 1991 and 2000 but were known
not to have given birth after IVF, ICSI, GIFT or donor insemination at
the three Melbourne clinics. They were found in the Victorian PDCU
birth data to have given birth to a singleton baby within 5 years of registration at the clinics. They may or may not have had ART treatment but
any ART treatments did not result in a birth after 20 or more weeks gestation. Some patients may have been treated by ovulation induction or
articial insemination but most would have naturally conceived. The possibility that they had conceived by ART at other clinics interstate or overseas
was checked by inspection of the patient records. The three Melbourne
clinics performed most of the ART procedures in the State during the
time of the study (.98% of clinical pregnancies, www.ita.org.au) and
reproductive tourism was infrequent.

268

Healy et al.

vaginal deliveries and Caesarean section births separately produced

similar results. Thus there is some evidence for an additional effect
of IVF/ICSI on post-partum haemorrhage independent of the
increases in other maternal complications of pregnancy. The difference
in the frequencies of the haemorrhages in Primiparous women in the
IVF/ICSI group and in the general population group, by age, is shown
in Fig. 1.

Factors within the IVF/ICSI group affecting

the risk of the haemorrhagic complications
Fresh versus frozen-thawed embryo transfers
APH was more frequent with fresh embryo transfer than with FET
(Tables IV and V). Adjusting for other covariates made little difference
to the OR for fresh embryo transfer versus FET. The weak evidence
(P 0.1 0.01) for effects of female infertility, tubal disease, three
or more embryos transferred and luteal phase support with hCG
was lost when fresh embryo transfer versus FET was included in the
regression models. The data for PA were sparse (not shown) but
there was moderately strong evidence (P 0.01) that PA was more
frequent with fresh embryo transfer (49/422, 1.2%) than with FET

Table I Characteristics of the subjects

Characteristic

IVF/ICSI

General population

GIFT

Non-ART

.............................................................................................................................................................................................
Number
Age
COB Asia or ME*
Married
Gravidity
Parity 2 3
.3

6730
34 (20 45)
641 (9.5)
6326 (94.0)
0.8 (0 16)
1345 (20.0)

24 619
34 (2050)
3100 (12.6)
20 345 (82.6)
1.8 (0 22)
13 880 (56.4)

779
33 (23 46)

2167
33 (1947)

54 (6.9)

273 (12.6)

766 (98.3)

2048 (94.5)

0.7 (06)

1.1 (0 13)

174 (22.3)

530 (24.4)

122 (1.8)

3204 (13.0)

8 (1.0)

39 (1.8)

Any abortions**

2013 (29.9)

8790 (35.7)

197 (25.3)

898 (41.4)

Tertiary hospital

1566 (23.3)

5381 (21.8)

207 (26.6)

488 (22.5)

Private hospital

3941 (58.6)

8528 (34.6)

437 (56.1)

1184 (54.6)

Year of birth

1999 (1991 2004)

Vertex presentation

6143 (91.3)

1999 (1991 2004)

23 126 (93.9)

1995 (19912004)
703 (90.2)

1997 (1991 2004)

1995 (92.1)

Induced labour

2138 (31.8)

6383 (25.9)

214 (27.5)

644 (29.7)

Caesarean section

2681 (39.8)

6689 (27.2)

236 (30.3)

763 (35.2)

The number and (%) or mean and (range) is shown.

*COB: country of birth; ME: middle East **Abortions include miscarriages and terminations of pregnancy before 20 weeks gestation.

Table II Obstetric haemorrhages: APH, PP, PA and PPH in IVF/ICSI and general population, GIFT and Non-ART groups
Complication

IVF/ICSI (6730)

General Population (24 619)

GIFT (779)

Non-ART (2167)

.............................................................................................................................................................................................
APH

454 (6.7)

881 (3.6), P , 0.001

78 (10.0), P 0.001

98 (4.5), P , 0.001

PP

174 (2.6)

273 (1.1), P , 0.001

21 (2.7), P 0.85

26 (1.2), P , 0.001

PA

63 (0.9)

107 (0.4), P , 0.001

11 (1.4), P 0.20

13 (0.6), P 0.14

PPH

746 (11.1)

1954 (7.9), P , 0.001

54 (6.9), P , 0.001

192 (8.9), P 0.003

APH, antepartum haemorrhage; PA, placental abruption; PP, placenta praevia; PPH, primary post-partum haemorrhage; GIFT, gamete intro-fallopian transfer.
The number and (%) in each group is shown with the P-value for the comparison with the IVF/ICSI group.

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 24, 2014

give birth in a private hospital, have an induced labour or have an Caesarean section. Compared with the IVF/ICSI group, the GIFT patients
were slightly younger, more often married, treated earlier in the study
period and less likely to have Caesarean sections. The non-ART group
were younger, more often born in Asia or the Middle East, more likely
to have previous pregnancies, miscarriages and termination of pregnancy, and less likely to use a private hospital and have a Caesarean
section than the IVF/ICSI group. The IVF/ICSI group had higher
rates of all the haemorrhagic complications than the general population (Table II). For GIFT, APH was more frequent than in the IVF/
ICSI group, whereas frequencies of PP and PA were similar and postpartum haemorrhage was less frequent than in the IVF/ICSI group.
The non-ART group had frequencies of these complications intermediate between those in the general population and the IVF/ICSI
group (Table II).
The IVF/ICSI group had more of the obstetric haemorrhage complications than the general population group. The ORs changed little
for APH, PP, PA and other APHs after the adjustments for confounders were made (Table III). For post-partum haemorrhage, adjusting
for covariates reduced the OR. The factors producing the greatest
change in the OR were parity and Caesarean section. Analysing

269

Increased obstetric haemorrhage after ART

Table III Odds ratios of obstetric haemorrhages: APH, PP, PA and PPH in the IVF/ICSI group compared with the general
population group unadjusted and adjusted for possible confounding
OR (95% CI), P-value

Model 1 Ad OR (95% CI), P-value

Model 2 Ad OR (95% CI), P-value

.............................................................................................................................................................................................
APH

1.95 (1.73 2.19), ,0.001

1.98 (1.73 2.26)*, ,0.001

2.04 (1.78 2.33)*, ,0.001

PP

2.37 (1.95 2.87), ,0.001

2.27 (1.82 2.83)*, ,0.001

2.34 (1.87 2.92)*, ,0.001

PA

2.16 (1.58 2.96), ,0.001

2.02 (1.41 2.88)*, ,0.001

2.07 (1.44 2.98)*, ,0.001

Other APH

1.59 (1.36 1.85), ,0.001

1.67 (1.40 1.99)*, ,0.001

1.74 (1.46 2.07)*, ,0.001

PPH

1.45 (1.32 1.58), ,0.001

1.19 (1.07 1.32)$, ,0.001

1.28 (1.16 1.42)$, ,0.001

Vaginal PPH

1.46 (1.29 1.65), ,0.001

1.18 (1.03 1.35)#, 0.02

1.24 (1.08 1.42)#, 0.002

Caesarean PPH

1.23 (1.07 1.40), 0.002

1.18 (1.01 1.38) , 0.03

1.31 (1.12 1.54)#, ,0.001

Figure 1 The effect of maternal age on the frequency of obstetric haemorrhage: APH, PP, PA and PPH in Primiparous women in the IVF/ICSI and
general population groups (error bars indicate the 95% CI). APH, antepartum haemorrhage; PA, placental abruption; PP, placenta praevia; PPH,
primary post-partum haemorrhage.

(14/2503, 0.6%), OR 2.1 (1.2 3.7), Model 2 adjusted OR 2.1 (1.2

3.9). There was also some evidence that fresh transfers were associated with increased PP, but with less post-partum haemorrhage, indicating increased rates of post-partum haemorrhage with FET
(Table IV).
The results for fresh embryo transfer in FSH stimulated cycles (fresh
transfers in natural cycles excluded) and for FET in natural cycles (articial cycles excluded) are compared in Table V. There were more

APH and PA after fresh embryo transfer. There was also a trend to
higher PP with the fresh transfers but no evidence of a difference in
the frequency of post-partum haemorrhage with fresh embryo transfer
or FET.

Number of oocytes collected before fresh embryo transfers

Analysing the results of fresh embryo transfer alone produced moderate evidence for an increase in frequency of APH with the number of

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 24, 2014

APH, antepartum haemorrhage; PA, placental abruption; PP, placenta praevia; PPH, primary post-partum haemorrhage.
*Model 1 adjusted for age, year of birth, marital status, parity, any miscarriages or terminations of pregnancy and vertex presentation. Model 2 adjusted in addition for tertiary and private
hospital status.
$
Model 1 adjusted for age, year of birth, marital status, parity, any miscarriages or terminations of pregnancy, vertex presentation, pre-eclampsia, APH, PP, PA, premature rupture of
membranes, induced labour, Caesarean section. Model 2 adjusted in addition for tertiary and private hospital status.
#
Model 1 adjusted for age, year of birth, marital status, parity, any miscarriages or terminations of pregnancy, vertex presentation, pre-eclampsia, APH, PP, PA, premature rupture of
membranes, induced labour. Model 2 adjusted in addition for tertiary and private hospital status.

270

Table IV Factors in IVF/ICSI group related to APH, PP and PPH

Factors

Total

APH

.................................................................
n (%)

OR (95% CI)

Ad OR (95% CI)*

PP

................................................................

n (%)

OR (95% CI)

Ad OR (95% CI)*

PPH

.................................................................

n (%)

OR (95% CI)

Ad OR (95% CI)$

..........................................................................................................................................................................................................................................................
Not female infertility

3274

195 (6.0)

332 (10.1)

Female infertility

3456

259 (7.5)

1.28 (1.06 1.55)

1.27 (1.051.55)

107 (3.1)

1.53 (1.12 2.08)

1.55 (1.13 2.12)

414 (12.0)

1.21 (1.04 1.40)

1.14 (0.97 1.33)

Not endometriosis

5465

356 (6.5)

126 (2.3)

581 (10.6)

Endometriosis

1265

98 (7.7)

Not ovulatory

5742

380 (7.7)

Ovulatory disorder
Not tubal

988

74 (6.5)

5076

320 (6.3)

1.20 (0.95 1.52)

1.21 (0.951.53)

1.14 (0.88 1.48)

1.14 (0.871.48)

67 (2.0)

48 (3.8)
145 (2.5)
29 (2.9)
122 (2.4)

1.67 (1.19 2.34)

1.65 (1.18 2.32)

165 (13.0)

1.26 (1.05 1.52)

1.28 (1.06 1.56)

610 (10.6)

1.17 (0.78 1.75)

1.14 (0.75 1.74)

136 (13.8)

1.34 (1.10 1.64)

1.27 (1.031.57)

564 (11.1)

Tubal disease

1654

134 (8.1)

1.31 (1.0621.62)

1.34 (1.0821.67)

52 (3.1)

1.32 (0.95 1.83)

1.41 (1.00 1.98)

182 (11.0)

0.99 (0.83 1.18)

0.94 (0.78 1.13)

IVF

3340

232 (6.9)

95 (2.8)

376 (11.3)

ICSI

3390

222 (6.5)

0.94 (0.78 1.14)

0.89 (0.721.09)

79 (2.3)

0.82 (0.60 1.10)

0.72 (0.52 1.00)

370 (10.9)

0.96 (0.83 1.12)

0.94 (0.80 1.12)

Fresh transfer

4227

321 (7.6)

1.46 (1.1921.80)

1.46 (1.181.80)

123 (2.9)

1.44 (1.04 2.00)

1.40(1.001.95)

432 (10.2)

0.79 (0.68 0.92)

0.81(0.69 0.95)

FET

2503

133 (5.3)

51 (2.0)

314 (12.5)

Number transferred 1

1024

73 (7.1)

1.11 (0.86 1.45)

1.06 (0.811.38)

29 (2.8)

1.16 (0.77 1.75)

1.08 (0.71 1.65)

118 (11.5)

1.02 (0.83 1.27)

1.00 (0.80 1.25)

Number transferred 2

4807

310 (6.4)

542 (11.3)

899

71 (7.9)

1.24 (0.95 1.63)

1.37 (1.031.80)

1.23 (0.80 1.88)

1.42 (0.91 2.22)

0.83 (0.66 1.06)

0.88 (0.69 1.14)

Number transferred .2
Average cell number ,4

118 (2.4)
27 (3.0)

887

66 (7.4)

Average cell number 4

2804

188 (6.7)

Average cell number .4

2050

139 (6.8)

1.01 (0.81 1.27)

1.04 (0.821.30)

61 (3.0)

1.25 (0.88 1.78)

1.26 (0.88 1.79)

232 (11.3)

1.02(0.85 1.22)

1.07(0.89 1.29)

989

61 (6.2)

0.91 (0.68 1.23)

1.01 (0.711.43)

20 (2.0)

0.84 (0.51 1.39)

1.02 (0.57 1.82)

108 (10.9)

0.98(0.78 1.23)

1.01(0.76 1.34)

Luteal phase hCG

1345

104 (7.7)

1.28 (1.01 1.62)

1.31 (1.031.67)

41 (3.0)

1.20 (0.83 1.72)

1.26 (0.87 1.82)

115 (8.6)

0.70 (0.57 0.86)

0.72 (0.58 0.90)

Progesterone

1200

93 (7.8)

1.28 (1.00 1.64)

1.26 (0.981.61)

26 (2.2)

0.84 (0.55 1.30)

0.82 (0.53 1.27)

138 (11.5)

None

4185

257 (6.1)

107 (2.6)

493 (11.8)

0.97(0.80 1.19)

0.93(0.76 1.15)

Fetal heart 1

6456

439 (6.8)

169 (2.6)

719 (11.1)

274

15 (5.5)

0.79 (0.47 1.35)

0.79 (0.461.34)

0.69 (0.28 1.68)

0.69 (0.28 1.70)

0.87 (0.58 1.31)

0.86 (0.57 1.30)

Unknown

Fetal heart .1

1.12 (0.84 1.50)

1.16 (0.861.56)

26 (2.9)

1.23 (0.78 1.95)

1.30 (0.82 2.08)

67 (2.4)

86 (9.6)

5 (1.8)

94 (10.6)
312 (11.1)

27 (9.8)

0.95 (0.74 1.21)

0.94 (0.73 1.21)

APH, antepartum haemorrhage; PA, placental abruption; PP, placenta praevia.

*Adjusted for age, year of birth, country of birth Asia and Middle East, marital status, parity, any miscarriages or terminations of pregnancy, vertex presentation, tertiary and private hospital status (Model 2).
$
Adjusted for age, year of birth, country of birth Asia and Middle East, marital status, parity, any miscarriages or terminations of pregnancy, vertex presentation, tertiary and private hospital status, pre-eclampsia, APH, PP, PA, premature rupture of
membranes, induced labour, Caesarean section (Model 2).

Healy et al.

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 24, 2014

271

Increased obstetric haemorrhage after ART

Table V Obstetric complications in IVF/ICSI patients with fresh embryo transfer (embryo transfer) in a stimulated cycle
or FET in a natural cycle [number (%), unadjusted and adjusted odds ratios and 95% CI with FET as reference]
Group

APH

PP

PA

PPH

.............................................................................................................................................................................................
Stimulated cycle: fresh embryo transfer
(N 4058)

314 (7.7)

122 (3.0)

46 (1.1)

417 (10.3)

Unstimulated cycle: FET (N 2045)

105 (5.1)

OR (95% CI), P-value

1.55 (1.231.94), ,0.001

1.41 (1.00 1.99), 0.05

2.59 (1.29 5.18), 0.007

0.94 (0.80 1.12), 0.52

Ad OR (95% CI), P-value

1.53 (1.221.93)*, ,0.001

1.37 (0.96 1.95)*, 0.08

2.56 (1.25 5.27)* 0.01

0.94 (0.78 1.22)$, 0.49

44 (2.2)

9 (0.4)

221 (10.8)

APH, antepartum haemorrhage; PA, placental abruption; PP, placenta praevia; PPH, primary post-partum haemorrhage, FET, frozen thawed embryo transfer.
*Adjusted for age, year of birth, country of birth Asia and Middle East, marital status, parity, any miscarriages or terminations of pregnancy, vertex presentation, tertiary and private hospital
status (Model 2).
$
Adjusted for age, year of birth, country of birth Asia and Middle East, marital status, parity, any miscarriages or terminations of pregnancy, vertex presentation, tertiary and private hospital
status, pre-eclampsia, APH, PP, PA, premature rupture of membranes, induced labour, Caesarean section (Model 2).

Infertility diagnosis: endometriosis and ovulatory disorders

PP and post-partum haemorrhage were increased with endometriosis.
Adding the other IVF/ICSI factors to the models did not change the
OR greatly: PP 1.7 (1.22.4) and post-partum haemorrhage 1.3
(1.1 1.6). Post-partum haemorrhage was also moderately strongly
associated with ovulatory disorders and this continued after adding
the other IVF/ICSI factors to the model [OR 1.3 (1.1 1.6)].

Hormone treatment
Post-partum haemorrhage was less frequent when hCG was used for
luteal phase support. Adding the other IVF/ICSI covariates did not
change the OR greatly [0.7 (0.6 0.9)].
Analysing only the frozen embryo transfer results showed strong
evidence (P , 0.001) for an increase in post-partum haemorrhage
with FET in articial cycles compared with natural cycles [OR 2.2
(95% CI 1.6 2.9), Adjusted OR 1.8 (1.3 2.6)]. There were 93 postpartum haemorrhages following 458 FET in articial cycles (20.3%) and
221 post-partum haemorrhages in 2045 FET in natural cycles (10.8%).

Factors within the IVF/ICSI group without strong evidence of an

association with the haemorrhagic complications
Other factors analysed, including number of previous oocyte collections or ETs, types of ovarian stimulation and drugs used, source of
sperm, overnight culture of embryos, maternal height, smoking and
obesity (for which data were incomplete), showed no evidence of
association with APH, PP or post-partum haemorrhage (P . 0.1).

Discussion
This large, multi-centre study shows increased rates of obstetric haemorrhage in mothers of singleton ART babies. Our results add to information in national and international studies (Dickey, 2007; Halliday,
2007; Anderson et al., 2008). It has been hitherto uncertain
whether the increases in these complications are caused by factors
intrinsic to the ART procedures or factors related to the characteristics of the ART-seeking population. We have interrogated our data

to address this question and examined possible mechanisms for

these adverse outcomes.
The GIFT women were different because this group was small in
number, younger, treated earlier and more often married than the
IVF/ICSI group. They also had less Caesarean sections probably
related to the increasing rate of Caesarean section over the time of
the study. The GIFT method of treatment has become less popular
over time with improvements in the results of IVF. Although they
had less post-partum haemorrhage than the IVF/ICSI group, they
had the same or higher rates of APH, PP and PA (Table II). The signicance of this is that in contrast to IVF and ICSI, embryos are not
formed in vitro with GIFT. The oocytes and sperm are introduced
into the outer end of the uterine tube and fertilization and early
embryo cleavage occurs in vivo. GIFT was also usually used in
couples with unexplained infertility. The fact that APH is not less frequent with GIFT than with IVF and ICSI indicates that it is not the fertilization and embryo manipulation within the laboratory that is
responsible for the increased frequency of APH in the IVF/ICSI
group. Furthermore, the adverse APH results with GIFT are also evidence that it is not the trans-cervical embryo transfer with low placement of embryos into the uterus that increases the risk of APH and
particularly PP, as previously suggested (Smithers et al., 2003;
Romundstad et al. 2006). In contrast, as IVF/ICSI and GIFT are
both undertaken during a stimulated cycle, factors common to both
procedures such as ovarian stimulation, or anaesthesia and surgery
for oocyte collection may be implicated in the adverse outcomes.
The non-ART group had fewer of the haemorrhages than the IVF/
ICSI group. From these data there is inconclusive evidence of
increased rates of obstetric haemorrhages related to infertility;
however, it is likely this group of patients had less severe infertility
than did those in the IVF/ICSI group. It is possible but unlikely that
some of these patients may have conceived by ART interstate or overseas. As this would bias this groups results towards more haemorrhages, we conclude there appears to be adverse effects of IVF/ICSI
increasing the haemorrhagic complications separate from the
infertility.
Having conrmed higher frequencies of APH and post-partum
haemorrhage with ART, we were interested to determine if the differences in characteristics between subjects in the IVF/ICSI and general
population groups would account for some or all of the effect.

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 24, 2014

oocytes collected (,6 oocytes 51/897, 5.7%; 6 9 oocytes 93/1220,

7.6%; 1013 oocytes 77/947, 8.1%; .13 oocytes 100/1163, 8.6%,
P 0.009).

272

involved. Oocyte number is related to the dose of FSH used and the
ovarian responsiveness of the woman. Estradiol and progesterone
levels at the time of implantation in fresh embryo transfer cycles
would be expected to be associated with oocyte number. It may be
that excessive ovarian hormone levels with multiple follicular developments interfere with the endometrium during implantation and increase
the risk of APH and PA. We have recently shown that the endometrial
protein, pregnancy associated plasma protein A (PAPP-A) is low in pregnancies after fresh embryo transfer in stimulated cycles (Amor et al.,
2009). PAPP-A is a zinc binding matrix metalloproteinase. PAPP-A
helps regulate extracellular matrix remodelling. This is vital in angiogenesis and the establishment of placentation during the early weeks of
pregnancy. Our nding of increased APH after fresh embryo transfer
in stimulated ART cycles suggest that the high estradiol and progesterone concentrations, as a result of multiple folliculogenesis, produce suboptimal angiogenesis and placentation.
The diagnosis of endometriosis was associated with more PP and
post-partum haemorrhage. Although PP was also associated with
higher PPH, there was evidence that the effect of endometriosis
increased the risk of both complications. We recently reported
other potential obstetric consequences of endometriosis for ART:
ovarian endometriosis is associated with approximately doubled
rates of preterm birth and small for gestational age babies (Fernando
et al., 2009).
The less frequent post-partum haemorrhage with luteal phase hCG
also suggests a disturbance of endometrial function around the time of
implantation is involved in increasing PPH. In addition it suggests that
improved management of luteal phase support in ART patients may
have a benecial effect. With FET there was more PPHs with the articial cycles. This may be related directly to the hormone treatment
being less effective in preparing the endometrium for implantation
compared with natural cycles or, alternatively, the ovulatory disorder
in the patients requiring articial cycles may be responsible. Ovulatory
disorders were also associated with increased post-partum
haemorrhage.
The strengths of this study are the large study population and
detailed information available on the treatments from the three infertility services and birth outcomes from the State PCDU database. The
results of IVF/ICSI patients were compared with those of population
controls, GIFT and non-ART conceptions in infertile women. Independent midwives, not ART clinic staff, recorded all obstetric data and this
should minimize ascertainment bias. During the study period relatively
low numbers of embryos were transferred, the multiple pregnancy
rate was less that 20% and there were few vanishing twins. The analysis of singleton births only and the high usage of FET is different from
most other data for this time with higher multiple pregnancy rates. We
could therefore study the inuence of ovarian stimulation by comparing fresh embryo transfer with FET in a natural or non-stimulated
cycle. We also assessed the effects of different methods of stimulation
and a marker of the effect of stimulation: the number of oocytes collected before a fresh embryo transfer. To avoid the problem of analysis of subsequent pregnancies in the same woman and the high within
subject correlations with repeated complications in subsequent pregnancies, for each woman only the rst birth within the study period
was analysed.
There are a number of limitations. The quality of the data is variable.
For example, there were inevitable time-related changes over the

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 24, 2014

Although we matched the general population group and the IVF/ICSI

subjects by age of mother and date of birth, this left some important
differences between the two groups particularly in gravidity and parity.
Also the IVF/ICSI group delivered by Caesarean section more often.
Adjusting for confounding left the ORs for APH either unchanged or
increased (Table III). In contrast, for post-partum haemorrhage, the
ORs decreased with adjustments for the other factors particularly
parity, Caesarean section and other maternal complications
(Table III). Thus some of the higher frequency of post-partum haemorrhage after IVF/ICSI is explained by differences in the characteristics
of women having these treatments from those in the general community, particularly their lower parity and higher use of Caesarean
section. However, there remained some evidence of a small excess
of post-partum haemorrhage related to some other aspect of IVF/
ICSI.
Having conrmed an increase in the obstetric haemorrhages specic
to IVF/ICSI, we then analysed the IVF/ICSI group on its own to
explore which factors were related to the higher frequencies of the
haemorrhages. We found that APH, PP and PA were higher with
fresh embryo transfer than with FET, and within the fresh embryo
transfer treatments, APH increased with the numbers of oocytes collected. PP and post-partum haemorrhage were increased in subjects
with endometriosis. Post-partum haemorrhage was also more frequent in women with ovulatory disorders, but less frequent when
hCG had been used for luteal phase support. Post-partum haemorrhage was more frequent with FET treatments in articial cycles
than with FET in natural cycles. It is possible that some of these
new ndings may be statistically signicant by chance alone and they
need conrmation by analysis of separate datasets. Also it is difcult
to know if these signicant associations reect direct mechanisms or
result from a peripheral relationship. For example the luteal phase
hCG and FET in articial cycle effects maybe more related to the
characteristics of the patients having these treatments than to the
treatments themselves. However, if these ndings are true there
may be important implications and some speculation on the possible
mechanisms, is useful for further studies.
There was a greater risk of APH after fresh embryo transfer in a stimulated cycle than FET in a natural cycle (Tables IV and V). This increase in
APH in general with fresh embryo transfer in stimulated cycles is particularly interesting. Differences in outcome of singleton births after fresh
embryo transfer and FET have been noted for birthweight, preterm
birth, perinatal death and some birth defects (Sutcliffe et al., 1995; Wennerholm et al., 1998; Aytoz et al., 1999; Kallen et al., 2005a; Olson et al.,
2005; Belva et al., 2008; Shih et al., 2008). These differences are intriguing, as they must result from either embryonic effects, with cryopreservation improving the outcomes by exerting some selective effect for
better embryos, or adverse effects occurring in the mother in fresh
embryo transfer cycles that are not present with FET. The latter may
be related to ovarian stimulation and oocyte collection.
Anaesthesia or monitored conscious sedation for oocyte collection
seems unlikely to explain the differences observed between stimulated
and natural ART cycles. The initial half-life of anaesthetic medicines
such as propofol is only 24 min: embryo transfer is typically 25
days after anaesthesia. Moreover, anaesthetic agents are not thought
to act on the endometrium.
The increase in APH following fresh embryo transfer with the number
of oocytes is a particularly important indicator that ovarian stimulation is

Healy et al.

273

Increased obstetric haemorrhage after ART

Authors Roles
All authors have contributed to the conducting of this study. The
manuscript has been seen and approved by all authors. D.L.H.,
H.W.G.B. and J.H. were the senior investigators involved in study
design, method investigations, data analysis and preparation of the
manuscript. S.B., A.J., D.R. and C.G. were involved in method investigation, data checking and analysis and review of the manuscript.
J.M.T. was involved in data provision.

Acknowledgements
The authors thank Obi Ukoumunne, Odette Taylor, Gillian Wheatley
and Associate Professor James King at the Perinatal Data Collection
Unit for assistance. We acknowledge the nancial support from the
BUPA Foundation and the Fertility Society of Australia.

Funding
J.H. Senior Research Fellowship is funded by the National Health &
Medical Research Council (436904).

References
Amor DJ, Xu JX, Halliday J, Francis L, Healy DL, Breheny S, Baker HW,
Jaques A. Pregnancies conceived using assisted reproductive
technologies (ART) have low levels of pregnancy associated protein-A
(Papp-A) leading to a high rate of false positive results in rst
trimester screening for Down syndrome. Hum Reprod 2009;
24:1330 1338.
Anderson AN, Goossens V, Ferraretti AP, Bhattacharya S, Felberbaum R,
de Mouzon J, Nygren KG, (ESHRE) EI-mECESoHRaE. Assisted
reproductive technology in Europe, 2004: results generated from
European registers by ESHRE. Hum Reprod 2008;23:756 771.
Aytoz A, Van den Abbeel E, Bonduelle M, Camus M, Joris H, Van
Steirteghem A, Devroey P. Obstetric outcome of pregnancies after
the transfer of cryopreserved and fresh embryos obtained by
conventional in-vitro fertilization and intracytoplasmic sperm injection.
Hum Reprod 1999;14:2619 2624.
Belva F, Henriet S, Van den Abbeel E, Camus M, Devroey P, Van der Elst J,
Liebaers I, Haentjens P, Bonduelle M. Neonatal outcome of 937 children
born after transfer of cryopreserved embryos obtained by ICSI and IVF
and comparison with outcome data of fresh ICSI and IVF cycles. 2008;
23:2227 2238.
Daniel Y, Ochshorn Y, Fait G, Geva E, Bar-Am A, Lessing JB. Analysis of
104 twin pregnancies conceived with assisted reproductive technologies
and 193 spontaneously conceived twin pregnancies. Fertil Steril 2000;
74:683 689.
Dickey R. The relative contribution of assisted reproductive technologies
and ovulation induction to multiple births in the United States 5 years
after the Society for Assisted Reproductive Technology/American
Society for Reproductive Medicine recommendation to limit the
number of embryos transferred. Fertil Steril 2007;88:1554 1561.
Fernando S, Breheny S, Jaques AM, Halliday JL, Baker G, Healy D. Preterm
birth, ovarian endometriomata, and assisted reproduction technologies.
2009;91:325 330.
Halliday J. Outcomes of IVF conceptionsare they different? Best Pract Res
Clin Obstet Gynaecol 2007;21:67 81.
Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in
singletons following in vitro fertilization: a meta-analysis. Obstet
Gynecol 2004;103:551 563.
Kallen B, Finnstrom O, Nygren KG, Olausson PO. In vitro fertilization
(IVF) in Sweden: risk for congenital malformations after different IVF
methods. Birth Defects Res A Clin Mol Teratol 2005a;73:162 169.
Kallen B, Finnstrom O, Nygren KG, Olausson PO, Wennerholm U. In vitro
fertilization (IVF) in Sweden: obstetric characteristics, maternal
morbidity & mortality. BJOG 2005b;12:1529 1535.
McCullagh P, Nelder JA. Generalized Linear Models, 2nd edn. London:
Chapman and Hall, 1989.
Olson CK, Keppler-Noreuil KM, Romitti PA, Budelier WT, Ryan G,
Sparks AE, Van Voorhis BJ. In vitro fertilization is associated with an
increase in major birth defects. Fertil Steril 2005;84:1308 1315.
Perri T, Chen R, Yoeli R, Merlob P, Orvieto R, Shalev Y, Ben-Rafael Z,
Bar-Hava I. Are singleton assisted reproductive technology
pregnancies at risk of prematurity? J Assist Reprod Genet 2001;
18:245 249.
Riley M, Grifn O. Validating a statewide data collection: differences in
information technology resources between hospitals. Health Inf Manag
1997;27:67 68.
Romundstad LB, Romundstad PR, Sunde A, von During V, Skjaerven R,
Vatten LJ. Increased risk of placenta previa in pregnancies following
IVF/ICSI; a comparison of ART and non-ART pregnancies in the
same mother. Hum Reprod 2006;21:2353 2358.

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 24, 2014

15 years of data collection, with differences in approach to diagnosis

and procedures with the evolution of ART. There were not many
women with PA. There was no information on covariates such as
maternal weight or smoking during pregnancy in the general population group and this was also incomplete in the IVF/ICSI group.
Another problem with these data is that we have no information of
previous pregnancy complications particularly previous Caesarean
section, which increases the risk of PP in subsequent pregnancies.
We were not able to analyse these factors. Nevertheless, as 78% of
the IVF/ICSI patients were primiparous (Table I), we might have
expected to see a higher rate of past Caesarean sections in the
general population group thereby producing more PP cases: we
observed the opposite. Thus it is not possible to treat the results as
if they were from a clinical trial with random placement of couples
in separate treatment groups or from a hypothesis based study, and
conclusions on cause and effect need to be guarded.
In conclusion, all the obstetric haemorrhages are more frequent
after IVF/ICSI than in the general population. For post-partum haemorrhage, some of the increase is related to the IVF/ICSI patients
having fewer previous pregnancies and using Caesarean section
more. As these complications are less frequent in non-ART conceptions in infertile women, the mechanism of the increase must
involve some aspects of the IVF/ICSI treatment. As APH is not less
frequent with GIFT, embryology procedures and embryo placement
through the cervix do not appear to be important. Exploratory analysis
of factors in the IVF/ICSI group suggests events around the time of
implantation are responsible for the increase in subsequent obstetric
haemorrhages. The increased APH with fresh embryo transfer and
with greater numbers of oocytes collected, and the protective effect
of hCG luteal phase support and the adverse effect of ovulatory disorders and articial cycles for FET on PPH all indicate that suboptimal
endometrial function around the time of implantation is critical.

274
Schieve LA, Cohen B, Nannini A, Ferre C, Reynolds MA, Zhang Z, Jeng G,
Macaluso M, Wright VC, Massachusetts Consortium for Assisted
Reproductive Technology Epidemiologic Research (MCARTER). A
population-based study of maternal and perinatal outcomes associated
with assisted reproductive technology in Massachusetts. Matern Child
Health J 2007;11:517 525.
Shevell T, Malone FD, Vidaver J, Porter TF, Luthy DA, Comstock CH,
Hankins GD, Eddleman K, Dolan S, Dugoff L et al. Assisted
reproductive technology and pregnancy outcome. Obstet Gynecol
2005;106:1039 1045.
Shih W, Rushford DD, Bourne H, Garrett C, McBain JC, Healy DL,
Baker HW. Factors affecting low birthweight after assisted
reproduction technology: difference between transfer of fresh and
cryopreserved embryos suggests an adverse effect of oocyte
collection. Hum Reprod 2008;23:1644 1653.
Smithers PR, Halliday J, Hale L, Talbot JM, Breheny S, Healy DL. High
Frequency of Cesarean section, antepartum hemorrhage, placenta

Healy et al.

previa, and preterm delivery in in vitro fertilization twin pregnancies.

Fertil Steril 2003;80:666 668.
Sutcliffe AG, DSouza SW, Cadman J, Richards B, McKinlay IA,
Lieberman B. Minor congenital anomalies, major congenital
malformations and development in children conceived from
cryopreserved embryos. Hum Reprod 1995;10:3332 3337.
Tayor R. Automatic Record Linkage. Sydney: The McGraw-Hill Companies
Inc., 1998, 184 187.
Wennerholm UB, Albertsson-Wikland K, Bergh C, Hamberger L,
Niklasson A, Nilsson L, Thiringer K, Wennergren M, Wikland M,
Borres MP. Post-natal growth and health in children born after
cryopreservation as embryos. Lancet 1998;351:1085 1090.
World Health Organisation. WHO Recommendations for the Prevention of
Postpartum Haemorrhage. Geneva, Switzerland: WHO Press, 2007.
Submitted on May 20, 2009; resubmitted on September 10, 2009; accepted on
October 1, 2009

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 24, 2014