Human Reproduction, Vol.27, No.2 pp. 576–582, 2012
Advanced Access publication on December 19, 2011 doi:10.1093/humrep/der428
ORIGINAL ARTICLE Reproductive epidemiology
Placental weight in singleton
pregnancies with and without assisted
reproductive technology: a population
study of 536 567 pregnancies
C. Haavaldsen 1,2,*, T. Tanbo 3, and A. Eskild 1,2,4
1
Department of Gynecology and Obstetrics, Akershus University Hospital, 1478 Lørenskog, Norway 2Institute of Clinical Medicine, Akershus
University Hospital, University of Oslo, Lørenskog, Norway 3Department of Gynecology, Oslo University Hospital, Rikshospitalet, University
of Oslo, 0424 Oslo, Norway 4Division of Mental Health, Norwegian Institute of Public Health, 0304 Oslo, Norway
*Correspondence address. Tel: +47-67-96-47-72; E-mail: [email protected]
Submitted on August 2, 2011; resubmitted on October 18, 2011; accepted on November 17, 2011
background: Pregnancies conceived by assisted reproductive technology (ART) are at increased risk of adverse outcomes. Previous
studies have suggested increased placental weight and increased placental weight/birthweight ratio in pregnancies associated with adverse
outcomes. We therefore studied the association of ART with placental weight and placental weight/birthweight ratio.
methods: We included all singleton births in the Medical Birth Registry of Norway during the period 1999–2008 (n ¼ 536 567, including
8259 after ART). We divided placental weight and placental weight/birthweight ratio into quartiles, and calculated the proportions of ART
and spontaneous pregnancies in the lowest and the highest quartile by length of gestation. Thereafter, we estimated crude and adjusted odds
ratios (ORs) for being in each quartile of placental weight for ART pregnancies with spontaneous pregnancies as the reference. The analyses
were repeated with ART pregnancies subgrouped into IVF or ICSI.
results: Mean placental weight was 678.9 g in pregnancies conceived by ART, and 673.0 g in pregnancies after spontaneous conception.
ART pregnancies were overrepresented in the highest quartile of placental weight and underrepresented in the highest quartile of birthweight, independent of length of gestation at delivery. Thus, placental weight/birthweight ratio was higher in ART pregnancies. For ART
pregnancies, the OR for being in the highest quartile of placental weight was 1.37 (95% confidence interval 1.30 –1.45) after adjustment
for length of gestation, offspring birthweight, parity, fetal sex, maternal age, pre-eclampsia and diabetes. There was no difference in placental
weight/birthweight ratio between IVF and ICSI pregnancies.
conclusions: We found larger placentas and a higher placental weight/birthweight ratio among pregnancies conceived by ART compared with spontaneous pregnancies, and the difference was independent of length of gestation at delivery and ART method.
Key words: ART / ICSI / IVF / placental weight / placental weight/birthweight ratio
Introduction
The prevalence of infertility is increasing (Lutz et al., 2003; Nyboe
Andersen and Erb, 2006; Skakkebaek et al., 2006), and part of this increase has been explained by a higher maternal age at pregnancy
attempt, higher prevalence of obesity and reduced semen quality.
Consequently, the number of couples undergoing assisted reproductive technology treatment (ART) is rising (Nygren et al., 2011). Pregnancies conceived by ART seem to have a higher risk of
pre-eclampsia (Chen et al., 2009), placenta praevia (Romundstad
et al., 2006), perinatal mortality, preterm delivery and low birthweight
(Helmerhorst et al., 2004; Jackson et al., 2004). It has, however, been
questioned whether the increased risk of adverse outcomes in ART
pregnancies can be explained by the treatment itself or by characteristics of the infertile couple (Ghazi et al., 1991; Romundstad et al.,
2008).
The placenta is essential for the maintenance of pregnancy and fetal
growth. Placental weight may be an indicator of placental function, and
small placentas are more likely to be dysfunctional (Thame et al., 2004;
Salafia et al., 2006). Placental weight is closely correlated to birthweight (Salafia et al., 2008). Since infants conceived by ART have
lower birthweight, we would expect these pregnancies also to have
lower placental weight compared with spontaneously conceived pregnancies. However, in other complicated pregnancies associated with
& The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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577
Placental weight and ART
low birthweight, such as pregnancies with pre-eclampsia (Eskild et al.,
2009) or fetal death, a relative enlargement of the placenta when compared with fetal size has been seen. Since ART pregnancies are at
increased risk of complications, disproportions between placental
weight and birthweight may be more common in these pregnancies.
Our aim was to compare placental weight and placental weight/
birthweight ratios in pregnancies obtained by ART with that of spontaneous pregnancies. The two most common ART methods are IVF
and ICSI. IVF is mainly performed in cases of female infertility,
whereas ICSI is mostly performed in couples with male infertility
and a presumably fertile female spouse. Whether birthweight or placental weight differs by ART method is not known. Such knowledge
could give insight into possible differential roles of male and female infertility on offspring growth. Therefore, in separate analyses, we subgrouped the ART pregnancies into IVF and ICSI. All comparisons were
made across gestational length at delivery.
Materials and Methods
The Medical Birth Registry of Norway has registered all births in Norway
since 1967. The notification is compulsory and the registration forms have
remained almost unchanged. Since 1988, voluntary notification to the
Medical Birth Registry of all diagnosed pregnancies after ART has been
performed, and in 2001 the notification of all ART pregnancies conceived
in Norway was made compulsory. Placental weight has been reported to
the Medical Birth Registry since 1999. Our study population included all
singleton births in Norway during 1999 – 2008, a total of 567 176 births.
We excluded 3262 births with gestational length ,22 weeks. Pregnancies
with gestational length above 43 weeks, placental weight ,25 g or above
2500 g, and birthweight ,250 g or above 6500 g, a total of 2237 pregnancies were considered as having outlying values and were also excluded
from our sample. Placental weight, offspring birthweight and gestational
length at delivery were not registered for 25 110 of the remaining pregnancies, thus 536 567 pregnancies could be included in the study.
Placental weight, measured in grams, was the main outcome variable.
The placentas were weighed by a midwife shortly after delivery with membranes and umbilical cord attached. Offspring birthweight was also measured in grams. Placental weight/birthweight ratios were calculated by
dividing placental weight by birthweight in grams. Placental weight, offspring birthweight and placental weight/birthweight ratio were divided
into quartiles based on the population as a whole. Hence, if there is no
difference, 25% of both ART and spontaneous pregnancies are expected
to be in each quartile. The quartiles were calculated separately within categories of gestational length at delivery.
ART treatment was coded yes or no and included IVF, ICSI, the combination of both or other and unspecified methods of ART. We also made
separate analyses with pregnancies after IVF and ICSI.
Gestational length at delivery was based on the estimated date of term
at routine fetal ultrasonographic examination in gestational weeks 17 – 19.
If fetal ultrasonographic examination was not performed, date of term was
based on last menstrual period. In ART pregnancies, date of embryo transfer is known but not reported to the Medical Birth Registry. Thus, the
length of gestation could be estimated by the same means, independent
of method of conception. Gestational length at delivery was grouped
into 2 weeks’ intervals from 28 weeks of gestation. Deliveries at Weeks
22 – 27 were merged into one group because of the limited number of deliveries in ART pregnancies before Week 28.
We calculated mean placental weight, mean birthweight and mean placental weight/birthweight ratio in pregnancies after ART and in pregnancies with spontaneous conception by gestational length at delivery.
Differences in mean placental weight and birthweight were assessed by
Student’s t-test. We also assessed differences in placental weight and
birthweight between the methods of conception after adjustment for
length of gestation by applying linear regression analyses. Pearson’s correlation between placental weight and birthweight in ART and spontaneously
conceived pregnancies was estimated. We also compared the proportions
of pregnancies, spontaneously conceived or conceived by ART, in the
lowest and the highest quartile of placental weight, birthweight and placental weight/birthweight ratio by length of gestation, and differences in proportions were tested by x 2 tests. These analyses were repeated with ART
pregnancies subgrouped as IVF or ICSI.
By applying logistic regression analyses, we estimated crude and
adjusted odds ratios (ORs) for being in each quartile of placental weight
for ART pregnancies, with spontaneous pregnancies as the reference.
Adjustments were made for gestational length at delivery, birthweight,
parity, offspring sex, maternal age, pre-eclampsia and diabetes mellitus,
as reported to the Medical Birth Registry (Salafia et al., 2008; Eskild
et al., 2009; Haavaldsen et al., 2011).
In the logistic regression analyses, birthweight was divided into categories of 500 g. Maternal age at delivery was divided into intervals of 5 years.
Parity was defined as the number of previous deliveries after 16 weeks of
gestation, and categorized as 0 or ≥1. Pre-eclampsia was defined as blood
pressure ≥140/90 mmHg and proteinuria with dipstick ≥1 after 20
weeks of gestation. Diabetes included types I and II diabetes mellitus, unspecified diabetes, gestational diabetes or the use of antidiabetic medication during pregnancy.
We used the Statistical Package for the Social Sciences (SPSS,
version 16.0) for all statistical analyses. The study was approved by the Advisory Committee for the Medical Birth Registry of Norway and the Norwegian Data Inspectorate.
Results
In our study sample of 536 567 singleton pregnancies, 8259 pregnancies (1.5%) were conceived by ART. Of the ART pregnancies, 4557
pregnancies were conceived by IVF (55.2%), 3192 pregnancies were
conceived by ICSI (38.6%), 88 pregnancies were conceived by the
combination of IVF and ICSI or other methods of ART (1.1%) and
for 422 ART pregnancies the method was not specified (5.1%).
Mean placental weight and mean placental weight/birthweight ratio
were higher, while mean birthweight was lower in ART pregnancies
when compared with pregnancies after spontaneous conception
(Table I). Mean gestational length was 276.6 days (SD 16.3) in ART
pregnancies and it was 278.6 days (SD 13.7) in spontaneous pregnancies (Student’s t-test P , 0.001). The differences in placental weight
and birthweight in ART and spontaneous pregnancies remained after
adjustment for length of gestation at delivery. The adjusted regression
coefficient for ART was 12.5 (P , 0.001) with placental weight as the
dependent variable, and it was 255.9 (P , 0.001) with birthweight as
the dependent variable. The estimated correlations between placental
weight and birthweight were higher in ART pregnancies compared
with spontaneous pregnancies at almost any length of gestation at delivery (Table II).
Pregnancies conceived by ART and spontaneously conceived pregnancies were similarly distributed in the lowest quartile of placental
weight independent of length of gestation at delivery (Fig. 1A). In
the highest quartile of placental weight, however, ART pregnancies
were overrepresented throughout pregnancy (Fig. 1B). In gestational
weeks 40 –41, 28.3% of the pregnancies conceived by ART were in
0.19 (0.04)a
0.18 (0.03)a
0.19 (0.03)a
0.19 (0.04)a
0.20 (0.04)a
0.22 (0.04)a
0.24 (0.05)
0.27 (0.07)
0.30 (0.10)
0.39 (0.15)
Table II Pearson’s correlation of placental weight and
birthweight according to gestational length at delivery
in pregnancies with ART or spontaneous conception
in 536 567 pregnancies during 1999–2008 in Norway.
0.20 (0.04)
Differences in mean placental weight, birthweight and placental weight/birthweight ratio have been assessed by Student’s t-test and are ,0.05.
673.0 (152.0)
678.9 (159.8)
528 308
8259
Total
a
3560.6 (588.4)
3451.0 (646.6)
0.19 (0.03)
537
42–43
Correlation
placental weight/
birthweight ART
Correlation placental
weight/birthweight
spontaneous
conception
........................................................................................
a
3939.6 (483.0)
a
3903.6 (492.4)
0.19 (0.03)
3683
40–41
40 165
750.6 (159.7)
723.4 (149.3)
a
3746.5 (460.0)a
705.5 (149.2)
2854
38–39
246 443
660.9 (143.3)
671.9 (145.8)
727
187 020
694.4 (145.0)a
3687.0 (470.3)
0.20 (0.04)
3469.7 (457.4)
3410.4 (458.8)
0.21 (0.04)
623.0 (152.1)
636.7 (159.3)
a
3075.1 (493.3)
3014.5 (508.6)
0.23 (0.05)
36–37
36 724
a
a
2571.5 (493.4)
2502.0 (463.4)
564.7 (146.8)
575.2 (149.0)
206
34–35
9439
492.4 (150.0)
511.9 (132.7)
88
32–33
3723
422.0 (142.8)
439.1 (156.5)
69
30–31
1854
359.9 (135.3)
354.2 (118.4)
304.6 (121.8)
47
1778
48
28–29
1162
291.3 (131.9)
a
a
0.25 (0.05)
2059.5 (489.8)
2052.7 (398.9)
0.28 (0.07)
1603.9 (478.7)
1612.2 (496.5)
0.30 (0.07)
794.3 (411.9)
1220.8 (475.4)
818.2 (585.9)
1171.2 (254.7)
0.41 (0.15)
Gestational
weeks
22–27
Grams (SD)
Grams (SD)
Grams (SD)
Grams (SD)
................................................................. .......................................................................
..........................................................................................................................................................................................................................................................
Weeks
n
ART
n spontaneous
conception
Mean placental
weight ART
Mean placental weight
spontaneous conception
Mean
birthweight
ART
Mean birthweight
spontaneous conception
Mean ratio
ART
Mean ratio
spontaneous
conception
Haavaldsen et al.
Gestational
length
Table I Mean placental weight, birthweight and placental weight/birthweight ratio in pregnancies with ART or spontaneous conception, according to gestational
length in 536 567 pregnancies during 1999–2008 in Norway.
578
22–27
0.694
0.592
28–29
0.722
0.664
30–31
0.718
0.648
32–33
0.609
0.657
34–35
0.613
0.655
36–37
0.684
0.651
38–39
0.617
0.615
40–41
0.604
0.588
42–43
0.618
0.575
Total
0.664
0.634
the highest quartile of placental weight. The corresponding figure for
spontaneously conceived pregnancies was 24.9% (x 2 test P ¼ 0.005).
The distribution of birthweight in ART pregnancies differed from the
distribution of placental weight. ART pregnancies were overrepresented in the lowest quartile and underrepresented in the highest
quartile of birthweight across gestational length. In deliveries in gestational weeks 40 –41, 30.2% of the pregnancies conceived by ART
were in the lowest quartile of birthweight (Fig. 2A), whereas 21.0%
were in the highest quartile (Fig. 2B). Thus, in pregnancies conceived
by ART, the proportion of pregnancies with a large placenta relative to
birthweight was increased throughout pregnancy. In deliveries in gestational weeks 40–41, 32.1% were in the highest quartile and only
19.5% were in the lowest quartile of placental weight/birthweight
ratio (Fig. 3). The corresponding figures for pregnancies with spontaneous conception were 24.9 and 25.1% (x 2 tests P , 0.001).
Comparing ART pregnancies with spontaneous pregnancies, the
OR for being in the highest quartile of placental weight was 1.12
[95% confidence interval (CI) 1.07– 1.18] (Table III). The association
increased after adjustment for length of gestation, offspring birthweight, parity, fetal sex, maternal age, pre-eclampsia and diabetes
(OR 1.37, 95% CI 1.30– 1.45). The adjusted OR associated with
ART for having a placenta in the lowest quartile was 0.73 (95% CI
0.69 –0.78).
We also examined possible differences between IVF and ICSI pregnancies and found a difference in both mean placental weight and
birthweight. Mean placental weight in IVF was 674.6 g and in ICSI
683.1 g. Mean birthweight was 3430.1 g in IVF and 3474.4 g in ICSI.
However, there was also a difference in length of gestation at delivery
between IVF and ICSI pregnancies (276.1 days in IVF versus 277.2 days
in ICSI), and after adjustment for gestational length in linear regression
analyses, the differences in placental weight and birthweight between
IVF and ICSI pregnancies were no longer significant. The adjusted regression coefficient for ICSI with IVF as reference was 4.6 (P ¼ 0.18)
with placental weight as the dependent variable, and it was 14.6 (P ¼
Placental weight and ART
579
Figure 2 The proportion of pregnancies in the lowest (A) and
Figure 1 The proportion of pregnancies in the lowest (A) and
highest (B) quartile of placental weight in pregnancies with ART or
spontaneous conception by length of gestation at delivery. All singleton pregnancies in Norway during 1999 – 2008 (n ¼ 536 567).
0.17) with birthweight as the dependent variable. In both IVF and ICSI
pregnancies, we found similar distributions of placental weight/birthweight ratios across delivery weeks as for ART pregnancies as a
whole, with underrepresentation in the lowest and overrepresentation
in the highest quartile (Fig. 4A and B).
Discussion
In this study, comparing 8259 pregnancies after ART with more than
half a million spontaneous pregnancies, we found significantly
increased placental weights and increased placental weight/birthweight ratios in ART pregnancies. These differences were observed independent of length of gestation at delivery. In pregnancies conceived
by IVF or ICSI, we found the same patterns as for ART pregnancies as
a whole.
We have no reason to believe that the methods of placental weighing have differed by mode of conception. However, mode of delivery
may influence placental weighing procedures, and mothers after ART
are more often delivered by Caesarean section than mothers with
spontaneous pregnancies (Helmerhorst et al., 2004), accounting for
highest (B) quartile of birthweight in pregnancies with ART or spontaneous conception by length of gestation at delivery. All singleton
pregnancies in Norway during 1999 – 2008 (n ¼ 536 567).
21.9 and 14.6%, respectively of the deliveries in our study. In supplementary data analyses, we included Caesarean delivery in multivariable
analyses; however, the association of ART with placental weight
remained unchanged.
Also, differences in the prevalence of placenta praevia between
ART pregnancies and spontaneously conceived pregnancies may
have confounded our results (Tanbo et al., 1995; Romundstad et al.,
2006). A low placentation in the uterine cavity has been associated
with intrauterine growth restriction (Newton et al., 1984), however,
data are conflicting (Ananth et al., 2001; Harper et al., 2010) and
the association with placental weight is not known. Inclusion of adjustment for placenta praevia in multivariable analyses did not alter the association of ART with high placental weight.
High maternal age and pre-eclampsia have been related to a high
placental weight/birthweight ratio, while low parity and female offspring have been associated with low placental weight (Naeye,
1987; Dombrowski et al., 1994; Thompson et al., 2007; Eskild et al.,
2009; Dean et al., 2010; Haavaldsen et al., 2011). When we made
adjustments for these factors, the association between ART and a
large placenta was strengthened, and our findings were thus
supported.
580
Haavaldsen et al.
Figure 3 The proportion of pregnancies in the lowest and highest
quartile of placental weight/birthweight ratio in pregnancies with ART
(n ¼ 8259).
Table III The crude and adjusted odds ratio for being
in each quartile of placental weight among all women
giving birth in Norway during 1999– 2008 (n 5 536 567).
Quartiles
Crude OR (95% CI)
Adjusted OR (95% CI)a
........................................................................................
First quartile
0.96 (0.91– 1.01)
0.73 (0.69–0.78)
Second quartile
0.96 (0.91– 1.01)
0.96 (0.92–1.02)
Third quartile
0.96 (0.91– 1.01)
1.03 (0.98–1.09)
Figure 4 The proportion of pregnancies in the lowest (A) and
Fourth quartile
1.12 (1.07– 1.18)
1.37 (1.30–1.45)
highest (B) quartile of placental weight/birthweight ratio in pregnancies with IVF, ICSI or spontaneous conception. All singleton pregnancies in Norway during 1999 – 2008 (n ¼ 536 567).
Spontaneously conceived pregnancies were used as the reference.
a
Adjusted for length of gestation, offspring birthweight, parity, fetal sex, maternal
age, pre-eclampsia and diabetes.
Previous studies on placental weight in ART pregnancies are scarce.
One study, including 45 singleton ART pregnancies and 45 spontaneously conceived pregnancies, reported higher placental weight and
placental weight/birthweight ratio in pregnancies conceived by ART
(Daniel et al., 1999). Two other studies including 50 and 70 ART pregnancies respectively, found no significant difference in placental weight
between ART and non-ART pregnancies (Jauniaux et al., 1990; Gavriil
et al., 1993). Previous comparisons of obstetric outcomes between
IVF and ICSI have shown virtually similar results by the two
methods, however, only a limited number of pregnancies were
included (Hourvitz et al., 2005; Ombelet et al., 2005; Buckett et al.,
2007).
Pregnancies after ART differ from natural conception in many ways.
First of all, infertile couples have an increased risk of adverse pregnancy outcome independent of the ART treatment itself (Ghazi
et al., 1991; Romundstad et al., 2008). Hence, factors associated
with the infertility may explain our findings.
ART treatment, both IVF and ICSI, includes stimulation with exogenous FSH for development of multiple follicles. Such stimulation
results in supraphysiological levels of pre-ovulatory estradiol and
elevated levels of estadiol and progesterone from multiple corpora
lutea during the luteal phase. Endometrium exposed to such high
levels is less receptive to implantation of the embryo than the endometrium in natural cycles (Bourgain and Devroey, 2003). An indication
of sub-optimal endometrial receptivity after multifollicular development is the higher birthweight in offspring after ART with transfer of
cryopreserved/thawed embryos. In such pregnancies, the women
are not treated with FSH for induction of multifollicular growth
(Pelkonen et al., 2010; Henningsen et al., 2011). Survival of an implanting embryo in a non-optimal endometrium may necessitate a compensatory growth of the placenta. Both IVF and ICSI pregnancies in our
study had higher placental weight/birthweight ratios than spontaneous
pregnancies. This finding suggests common factors associated with
both male and female infertility to be associated with placental
growth. Changes in the endometrium, as a consequence of multifollicular development in response to FSH treatment, may be one such
common factor. The stable difference between ART and spontaneous
pregnancies independent of gestational length at delivery in our study,
suggests that the differences in growth may be caused very early in
pregnancy and not by conditions that occur in the later part of
pregnancy.
581
Placental weight and ART
An alternative explanation is that only ‘the best fit’ embryos result in
a viable pregnancy after ART. It is possible that mainly pregnancies
with a high correlation between placental and birthweight are successful in ART pregnancies, whereas in spontaneously conceived pregnancies also sub-optimal endometrial or placental function may result in a
live born offspring. Also in pregnancies of women with high age, a high
correlation between placental and birthweight has been reported
(Haavaldsen et al., 2011). In these pregnancies, as in ART pregnancies,
there is a high miscarriage rate and thereby a stronger selection of
embryos to a successful pregnancy.
The means of oocyte fertilization and culturing the preimplantation
embryo in vitro may also affect pregnancy outcome. Stimulation of multiple follicles with FSH, embryo culture in vitro and the culture media
used have all been shown to alter methylation of imprinted genes in
the oocytes, spermatozoa and embryos (Lucifero et al., 2004;
Fauque et al., 2007; Sato et al., 2007; Market-Velker et al., 2010),
and different media for culturing preimplantation embryos result in different birthweights (Dumoulin et al., 2010). Therefore, epigenetic
changes caused by ART resulting in differential growth of the fetus
and the placenta are plausible (Tilghman, 1999; Tycko and Morison,
2002).
Transfer of multiple embryos may result in a singleton pregnancy
with an early vanishing twin. In singleton births with a vanishing
twin, the birthweight is lower than in singletons with no vanishing
twin (Pinborg et al., 2005). Whether the placental anlage from the
vanishing twin undergoes early necrosis or is present during the
remaining pregnancy is unknown. We studied singleton pregnancies
only and had no information on the number of transferred embryos.
The frequency of twins following double embryo transfer varies
between 10 and 47% (Pinborg et al., 2005). During the study
period, there has been a change in recommended treatment from
double to elective single embryo transfer. Nevertheless, a significant
proportion of the singleton pregnancies in our study may have been
the result of double embryo transfer.
Conclusions
We found larger placentas and higher placental weight/birthweight
ratios in pregnancies conceived by ART when compared with spontaneously conceived pregnancies. When IVF and ICSI pregnancies
were studied separately, the same pattern was seen as for ART pregnancies in general.
Authors’ roles
C.H. analysed the data and wrote the manuscript. T.T. contributed to
the interpretation of the results and writing of the manuscript. A.E.
had the original idea for the study. She contributed to the statistical
analysis and the writing of the manuscript.
Funding
We have received no external funding for this study.
Conflict of interest
None declared.
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