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The contribution of assisted conception, chorionicity and otherrisk factors to very low birthweight in a twin cohort
Anne Lyncha, Robert McDuffie Jrb,*, Janet Stephensc, James Murphyd,Kenneth Fabere, Miriam Orleansf
Objectives To investigate the contribution of assisted conception (assisted reproductive technology andovulation induction), chorionicity and selected maternal risk factors for very low birthweight.
Design Retrospective twin cohort study.
Setting Staff model Colorado Health Maintenance Organization.
Sample Five hundred and sixty-two twin gestations [assisted ¼ 193 (34%); unassisted ¼ 369 (66%)].
Methods Data were collected from a perinatal database and medical record review. Data were analysed usingunivariate and multivariable logistic regression analysis.
Main outcome measure Very low birthweight.
Results Women with assisted twin gestation were more likely to be older, nulliparous, non-smokers, married,have a prior history of a miscarriage and a dichorionic placentation. There was no difference in thedistribution of low and very low birthweight, discordant growth or preterm delivery between assisted andunassisted twin gestations. Significant risk factors for very low birthweight were: a prior preterm birth (oddsratio, OR, 3.8, 95% confidence interval, CI, 2, 7), monochorionicity (OR 3, 95% CI 2, 4.7), nulliparity (OR2, 95% CI 1.3, 3), cigarette smoking (OR 1.8, 95% CI 1, 3) and prior miscarriage (OR 1.6, 95% CI 1, 2).Monochorionicity was significantly associated with adverse perinatal outcomes.
Conclusion Assisted conception did not play a significant role in the occurrence of very low birthweight inthis cohort. A history of preterm birth and a monochorionic twin gestation were the leading risk factors forvery low birthweight. Associated risk factors for very low birthweight were nulliparity, cigarette smokingand a prior miscarriage.
INTRODUCTION
The recent epidemic of multiple births in the United
States is one of the main contributory factors to the upward
trend in the number of low birthweight (<2500 g) or very
low birthweight (<1500 g) babies. Multiple births are
associated with a disproportionate amount of perinatal mor-
bidity and mortality1. One of the reasons for the increased
frequency of multiple births is the more widespread avail-
ability of infertility treatments, which include assisted
reproductive technologies and ovulation induction2. We
have estimated, that the proportion of multiple births, in
our Colorado Health Maintenance Organization due to one
of these forms of assisted conception is 33%3.
The increase in multiple births has prompted investiga-
tion into the possible association between assisted concep-
tion and adverse perinatal outcomes in twin cohorts4 – 14.
These studies have produced conflicting results, perhaps
due to differences in study population characteristics,
definition of assisted conception and study methods. Twin
placentation15,16 and other events in the maternal social and
prenatal history are known risk factors for adverse neonatal
outcomes17,18. However, in many existing studies adjust-
ment for these risk factors has not been included in the data
analysis. The main purpose of this study was to examine
the association between assisted conception (assisted repro-
ductive technology and ovulation induction) and very low
birthweight in twins, adjusting for chorionicity of the
placenta and other maternal risk factors. Very low birth-
weight was chosen as the main outcome of this study
because of its established importance as a predictor of not
BJOG: an International Journal of Obstetrics and GynaecologyApril 2003, Vol. 110, pp. 405–410
D RCOG 2003 BJOG: an International Journal of Obstetrics and Gynaecology
doi:10.1016/S1470-0328(03)02942-2 www.bjog-elsevier.com
aClinical Research Unit, Kaiser Permanente, Denver,
Colorado, USAbDepartment of Obstetrics and Gynecology, Kaiser
Permanente, Denver, Colorado, USAcDepartment of Pathology, Exempla Saint Joseph Hospital,
Denver, Colorado, USAdDivision of Biostatistics, National Jewish Medical and
Research Center, Denver, Colorado, USAeDepartment of Reproductive Endocrinology, Kaiser
Permanente, Denver, Colorado, USAfDepartment of Preventive Medicine and Biometrics,
University of Colorado Health Sciences Center, Denver,
Colorado, USA
* Correspondence: Dr R. McDuffie Jr, Department of Obstetrics and
Gynecology, 20th Street Medical Campus, 2045 Franklin Street, Denver,
Colorado 80205, USA.
only adverse neonatal events19 but also of developmental
problems later in life20.
METHODS
The study was approved by the Kaiser Foundation
Institutional Review Board. The cohort of twins was drawn
from a study population of all women (n ¼ 33,949) who
delivered after 20 weeks of gestation, between January 1994
and December 2001 at Exempla Saint Joseph Hospital and
Boulder Community Hospital in Colorado. During the study
period of seven years, 564 sets of twins were delivered. Two
mothers delivered two sets of twins. In order to assure
independence in the data analysis, the second set of births
from each of these mothers was removed from the data set.
We used a retrospective study design to answer the
study’s research questions. The primary exposure was
assisted conception with either assisted reproductive tech-
nology (defined as procedures that involved handling
of human oocytes or embryos) or ovulation induction
(treatment with clomiphene citrate or human menopausal
gonadotrophins) in the absence of assisted reproductive
technology. The main outcome was very low birthweight
(<1500 g). Data as to whether a pregnancy was assisted
or spontaneous and on risk factors (Tables 1–3) were
obtained from Colorado Kaiser Permanente Perinatal
Database (described elsewhere3,21). Medical records were
also reviewed to add new variables to the database and
to establish that there was no misclassification of the
category of conception (i.e. assisted vs unassisted). In
addition, 20% of the medical records were reviewed by
another member of the research team for quality assurance
purposes. If discrepancies were found, they were discussed
and resolved. Placentation was classified as monochorionic
(monochorionic diamniotic or monochorionic monoam-
niotic) or dichorionic. We assumed that all twins who were
of the opposite sex (n ¼ 72) were dichorionic diamniotic.
We reviewed postnatal placental pathology on the remain-
ing 490 sets of twins to determine their chorionicity.
Pathology on the placenta was missing for one set of twins.
Information regarding birthweight and gestational age at
delivery were obtained from the perinatal database. Gesta-
tional age was determined for all subjects relying primarily
on first and second trimester ultrasound but also menstrual
dates. From the birthweights, we distinguished low birth-
weight (<2500 g) from very low birthweight (<1500 g).
Intrauterine twin growth curves described by Min et al.22.
were used to classify the birthweight as less than or greater
than the fifth centile for gestational age. We noted if there
was evidence of discordant growth, here defined as greater
than a 25% difference in weight between a twin pair. Three
categories of preterm birth (less than 37, 32 and 28 weeks)
were examined. Labour onset was either spontaneous,
medically induced (for maternal or fetal complications) or
none (an elective caesarean delivery).
The data were analysed in several stages using SAS 8.2
(SAS Institute, Cary, North Carolina). First, we determined
the general clinical characteristics of the cohort. Second,
we investigated if there was any statistically significant
difference in the frequency of selected maternal character-
istics, monochorionicity, selective fetal reduction and neo-
natal outcomes between mothers with assisted and
unassisted conception. Third, using very low birthweight
as the main outcome variable, we initially studied if as
compared with spontaneously conceived twins there was an
association between assisted reproductive technology,
human menopausal gonadotrophin and clomiphene citrate
with very low birthweight. We then determined the overall
contribution of the grouped variable, assisted conception
and other risk factors for very low birthweight.
The relative risk (RR) was used as a measure of as-
sociation to test the relationship between the primary
exposure and risk factors for very low birthweight. The
relative risk was defined as the cumulative incidence of
very low birthweight among mothers with the exposure
divided by the cumulative incidence of very low birth-
weight among mothers without the exposure. The incidence
of very low birthweight in the subjects exposed to a
selected risk factor was compared with the incidence of
very low birthweight among those not exposed. Measures
of association between dichotomous variables were tested
using the m2 or Fisher’s Exact Test. Differences in means
of continuous variables were tested using the Student t test.
Statistics are presented with 95% confidence intervals (CI)
( P < 0.05).
In the final stage of the analysis, we conducted a multi-
variable logistic regression. This was used to estimate the
odds ratios (OR) of assisted conception for very low birth-
weight adjusted for other covariates. The odds ratio was
used as an approximation of the relative risk. Each explan-
atory variable was entered separately into the logistic
model to determine its independent (unadjusted) effect on
very low birthweight. A full model was then constructed
with the combined variable (assisted conception), risk
factors identified from the univariate analysis as associated
with the outcome and potential confounders.
RESULTS
During the study period, 562 sets of twins were delivered
after 20 weeks of gestation. There were 369 (66%) unas-
sisted twin births. One hundred and ninety-three (34%) of
the twin gestations received some form of assisted concep-
tion. Sixty-nine (12%) resulted from assisted reproductive
technology, 94 (17%) from clomiphene citrate and 30 (5%)
from human menopausal gonadotrophin. Four hundred and
thirty-two women in the cohort were white (77%), 62
(11%) were Hispanic, 50 (9%) were African American
and 18 (3.3%) were from other races. Stratified into
assisted and unassisted groups, Table 1 demonstrates the
406 A. LYNCH ET AL.
D RCOG 2003 Br J Obstet Gynaecol 110, pp. 405–410
distribution of risk factors and outcomes between the two
groups. Compared with unassisted twin pregnancies, we
found a higher frequency of older, nulliparous mothers
among the assisted group. In contrast, fewer women with
assisted conceptions were African American, single or
smoked cigarettes. With regard to the maternal prenatal
history, we found the incidence of prior preterm birth did
not differ between the groups. However, a significantly
higher incidence of prior miscarriage was found among
mothers with assisted conceptions. No unassisted preg-
nancy was selectively reduced from a higher order gesta-
tion. In contrast, 18 (9%) of the assisted pregnancies had
been selectively reduced. The incidence of monochorioni-
city was significantly lower among the assisted twin gesta-
tions. Using women with spontaneous onset of labour as the
referent group, we found a significantly higher number of
women with assisted pregnancies had a medically induced
labour [64 (38%) vs 96 (29%), RR 1.3, 95% CI 1, 1.7].
Table 1. Comparison of maternal risk factors and outcomes among assisted (n ¼ 193) and unassisted twin pregnancies (n ¼ 369). Values are given as n (%)
and RR [95% CI].
Risk factors and outcomes Incidence exposure or outcomes RR [95% CI]
Assisted conception Unassisted conception
Maternal characteristics
Age �35 years 75 (39) 43 (12) 3.3 [2.4, 4.6]
African American 2 (1) 48 (13) 0.08 [0.02, 0.3]
Nulliparity 136 (70) 121 (33) 2.1 [1.8, 2.6]
Marital status (single) 6 (3) 88 (24) 0.1 [0.06, 0.3]
Cigarette smoking 10 (5) 62 (17) 0.3 [0.2, 0.6]
Maternal prenatal history
Prior preterm delivery 9 (5) 26 (7) 0.7 [0.3, 1.4]
Miscarriage 65 (34) 79 (21) 1.6 [1.2, 2.1]
Characteristics of this pregnancy
Monochorionic placentation* 8 (4) 112 (30) 0.1 [0.07, 0.3]
Selective fetal reduction 18 (9) –
Pregnancy outcomes
Low birthweight 113 (59) 218 (59) 1.0 [0.9, 1.1]
Very low birthweight 20 (10) 47 (13) 0.8 [0.5, 1.3]
Birthweight <5th centile for gestational age 11 (6) 18 (5) 1.2 [0.6, 2.4]
Discordant growth 17 (9) 33 (9) 1.0 [0.6, 1.7]
Delivery
<37 weeks 104 (54) 206 (56) 1.0 [0.8, 1.1]
<32 weeks 15 (8) 43 (12) 0.7 [0.4, 1.2]
<28 weeks 8 (4.2) 19 (5.2) 0.8 [0.4, 1.8]
RR ¼ relative risk, or the incidence in the exposed group divided by incidence in the unexposed group; CI ¼ confidence interval.
* Missing placental pathology on one subject.
Table 2. The relative risk of assisted conception and other selected risk factors for very low birthweight. Values are given as n (%) and RR [95% CI].
Risk factor Incidence of very low birthweight RR [95% CI]
Exposed Unexposed
Maternal age �35 years 30 (13) 95 (11) 1.2 [0.8, 1.7]
African American 16 (16) 109 (11) 1.5 [0.9, 2.4]
Marital status (single) 29 (15) 96 (10) 1.5 [1.0, 2.2]
Cigarette smoking 26 (18) 99 (10) 1.8 [1.2, 2.7]
Nulliparity 65 (13) 60 (10) 1.3 [0.9, 1.8]
Previous miscarriage 39 (14) 86 (10) 1.3 [0.9, 1.9]
Previous preterm delivery 17 (24) 108 (10) 2.4 [1.5, 3.7]
Any assisted conception 36 (9) 89 (12) 0.8 [0.5, 1.1]
Selective fetal reduction 2 (6) 123 (11) 0.5 [0.1, 1.9]
Monochorionicity* 48 (20) 77 (9) 2.3 [1.6, 3.2]
RR ¼ relative risk, or the incidence in the exposed group divided by incidence in the unexposed group; CI = confidence interval.
* Missing placental pathology on one set of twins.
ASSISTED CONCEPTION AND VERY LOW BIRTHWEIGHT 407
D RCOG 2003 Br J Obstet Gynaecol 110, pp. 405–410
We found no significant difference in the frequency of
elective caesarean section delivery between the assisted
and the unassisted group [23 (18%) vs 34 (12%), RR 1.4,
95% CI 0.9, 2.3]. The mean [SD] gestational age at delivery
of twins who experienced spontaneous labour, medically
induced labour or an elective caesarean section was 35 [4]
(range 20.2–40.6), 37 [2] (range 27–40.4) and 37 [2] (range
27.1–39.2) weeks, respectively. There was no significant
difference ( P ¼ 0.6) in the mean birthweights between the
assisted, 2326 [619] (range 315–3775 g), and unassisted,
2313 [641] (range 100–3930 g), births. Similarly, there was
no significant ( P ¼ 0.4) difference in the mean gestational
age at delivery between the assisted, 36 [3] (range 20.2–40.2
weeks), and unassisted, 36 [3] (range 20.2–40.6 weeks),
groups. Table 1 shows no significant difference in the
incidence of pregnancy outcomes between the assisted and
unassisted twin pregnancies. Among the 345 women who
had a spontaneous preterm (<37 weeks) birth, 70 (66%) had
assisted conceptions and 156 (65%) had unassisted concep-
tions (RR 1, 95% CI 0.9, 1.2).
In comparison with spontaneously conceived twins, we
found no association between assisted reproductive tech-
nology (RR 0.8, 95% CI 0.5, 1.4), human menopausal
gonadotrophin (RR 0.7, 95% CI 0.3, 1.7) and clomiphene
citrate (RR 0.8, 95% CI 0.5, 1.3) with very low birthweight.
Because the trend and the association of these exposures
with very low birthweight were similar, we grouped the
methods of assisted conception together into one variable
(i.e. assisted conception) for further analysis. Table 2 shows
the relative risk of assisted conception and other maternal
risk factors for very low birthweight. Assisted conception
was not associated with very low birthweight. Further, no
association was found between assisted conception and
very low birthweight appropriate for the 5th centile for
gestational age (RR 0.9, 95% CI 0.5,1.1) and very low
birthweight less than the 5th centile for gestational age (RR
0.9, 95% CI 0.4, 1.9). A monochorionic placentation and a
past history of a preterm delivery were the most significant
risk factors for the delivery of a very low birthweight baby.
Other significant risk factors associated with very low
birthweight were maternal cigarette smoking and a single
marital status. The relative risk of nulliparity, African
American race, history of miscarriage and maternal age
greater than 35 years for very low birthweight was
increased. However, in the univariate analysis, these asso-
ciations did not reach statistical significance. Eighteen
(3%) of the twin pregnancies resulted from a selective fetal
reduction from a higher order gestation. Thirteen selective
fetal reductions occurred among conceptions following
assisted reproductive technology. Selective fetal reduction
was not associated with very low birthweight (Table 2).
Table 3 is the fully adjusted multivariable logistic
regression model. Adjusted for the covariates in the model,
assisted conception was not associated with very low
birthweight. In contrast there was a significant association
of monochorionicity, nulliparity, cigarette smoking,
prior preterm birth and prior miscarriage for very low
birthweight.
DISCUSSION
In this cohort of 562 twin births, we found no association
between assisted reproductive technology, human meno-
pausal gonadotrophin or clomiphene citrate and very low
birthweight. A prior history of preterm birth, monochorionic
placentation, nulliparity, cigarette smoking and a prior
miscarriage were significant risk factors for very low birth-
weight (Table 3). There was no difference in the distribution
of other neonatal outcomes (Table 1) between assisted and
unassisted twin pregnancies.
In agreement with the results of this study, Fitzsimmons
et al.8 found no difference in mean birthweights and
gestational age at delivery among multiple births resulting
from assisted reproductive therapy (assisted reproductive
technology or clomiphene citrate) and spontaneously con-
ceived multiple birth controls. This group of Canadian
researchers did, however, report an increase in perinatal
mortality among spontaneously conceived twins8. Agusts-
son et al.4 studied 69 assisted twin pregnancies and 453
natural conceptions from Iceland and Scotland. A similar
gestational age and birthweight at delivery was found
among the assisted and unassisted group. Another study
from a twin cohort found no difference in duration of
gestation, birthweight or other outcomes among 1241 twins
from assistance (in vitro fertilisation and intracytoplasmic
sperm injection) compared with natural twin gestations7.
Using logistic regression models that controlled for mater-
nal characteristics and placental membranes, a multicentred
American, collaborative study of 2523 spontaneous and
415 assisted twin pregnancies suggests as association
between assisted conception and low birthweight but
not very low birthweight11. Another recent study from
the United States found the risk of term and preterm
low birthweight among twins conceived with assisted
Table 3. Multivariable logistic regression analysis showing the crude and
adjusted odds ratios of assisted conception, placentation and other risk
factors for very low birthweight. Values are given as OR [95% CI].
Risk factor OR 95% CI
Crude Adjusted
Maternal age > 35 years 1.2 1.3 [0.8, 2.2]
Marital status (single) 1.6 1.3 [0.8, 2.2]
Nulliparity 1.3 2.0 [1.3, 3]
Cigarette smoking 2.0 1.8 [1, 3]
African American 1.6 1.7 [0.9, 3]
Prior miscarriage 1.4 1.6 [1, 2]
Prior preterm birth 2.8 3.8 [2, 7]
Assisted conception 0.8 1.0 [0.6, 1.6]
Monochorionicity 2.6 3.0 [2, 4.7]
OR ¼ odds ratios; CI ¼ confidence interval.
408 A. LYNCH ET AL.
D RCOG 2003 Br J Obstet Gynaecol 110, pp. 405–410
reproductive technology was similar to that of the general
population of twins23.
Other authors have however, found an association
between assisted conception and adverse pregnancy out-
comes. Moise et al.13 included very low birthweight as an
outcome in their study of the association between in vitro
fertilisation and perinatal outcomes among dizygotic twins
using univariate and multivariable analysis. Twenty in vitro
fertilisation pregnancies were matched on maternal age,
parity and ethnicity to 40 pairs of spontaneous twins. In
this small study, there was a significantly higher frequency
of prematurity, lower average birthweight and a higher
very low birthweight rate among in vitro fertilisation
compared with unassisted twins13. Other studies from
Israel6 and Italy14 described similar results. Data from a
multicentred Dutch study9 reported a lower mean birth-
weight, a higher low birthweight rate and more discordance
in birthweights among 96 in vitro fertilisation twins
compared with 96 matched controls. In agreement with
this study, Lambalk and van Hooff10, also found less
favourable obstetric outcomes among assisted (in vitro
fertilisation or ovulation induction) compared with spon-
taneous twins. Bernasko et al.5 reported an increased
frequency of discordant growth and low birthweight among
assisted reproductive technology compared with spontane-
ously conceived twins.
The incidence of dichorionic twinning is related to
factors that increase double ovulation such as older
mothers, increasing parity, genetic factors and ovulation
induction24. One of the major strengths of this study was
the careful differentiation of placental chorionicity. Mono-
chorionicity was found less frequently among assisted
compared with unassisted twin gestations (Table 2). As
shown by this and other studies16, monochorionicity was an
important independent risk factor for adverse perinatal
outcomes. As seen in Tables 2 and 3, compared with
dichorionic twins, monochorionic twins were more than
twice as likely to be born very low birthweight. As we
continue to gather data and expand this cohort, we hope to
further evaluate the role of monochorionicity as a con-
founder or effect modifying variable. Other authors have
also recognised the important effect of this covariate by
either restricting their twin studies to dizygotic twins10
or adjusting for this covariate using logistic regression
analysis11. Maternal age, nulliparity, marital status, race,
smoking status and a prior miscarriage were identified as
significant confounding variables. Table 3 demonstrates the
importance of inclusion of these covariates into the
adjusted analysis. For example, nulliparity, which was a
borderline significant risk factor for very low birthweight in
the univariate analysis (Table 2), became a significant risk
factor in the logistic regression analysis (Table 3).
Many authors have found higher elective caesarean
delivery rates among iatrogenic compared with unassisted
gestations. It has been suggested that babies from assisted
conception may be delivered early because of overconcern
by the obstetrician and parents for the outcome of these
anxiously awaited births25. In this staff model Colorado
Health Maintenance Organization, all mothers with mul-
tiple gestations receive a systematic level of organised
prenatal care from a team of obstetricians and other
maternal–fetal medicine specialists. This may explain the
similar rates of elective caesarean section among the
assisted and unassisted groups. The frequency of medically
induced labours was higher among assisted compared with
unassisted twin gestations. However, women with med-
ically induced labours delivered at a later gestational age
than women who had a spontaneous onset of labour.
We were unable to fully explore the clinical implication
of nulliparity and other risk factors because of several
limitations of the study. Nulliparity was significantly asso-
ciated with very low birthweight and was found more
frequently among mothers who had assisted pregnancies
(Tables 1 and 2). Similarly, we found a higher frequency of
a history of prior miscarriage among women with assisted
conception. It is possible that some of the risk associated
with these variables may be related to other factors in the
woman’s infertility history. These factors were not exam-
ined in this study. Analysis of selective fetal reduction was
also limited by low numbers in the outcome group. Like-
wise, the limited representation of African American
women among the assisted group of twin conceptions did
not allow full evaluation of the contribution of this risk
factor to very low birthweight in this cohort. We were also
unable to investigate if the effect of assisted conception on
very low birthweight was modified by chorionicity because
of low numbers of very low birthweight babies among
assisted twin gestations with a monochorionic placentation.
Preliminary analysis of the possible association between
assisted conception and birthweight less than the 5th centile
for gestational age was limited by small numbers and also
by the utilisation of intrauterine growth curves22 that were
not adjusted for Denver’s altitude (5280 ft above sea level).
CONCLUSION
Although this study did not find an association between
assisted conception and very low birthweight, research
efforts continue to follow this cohort to identify adverse
sequelae related to not only the method of conception but
also their plurality.
Acknowledgements
The authors thank Kimberly Bischoff MSHA for her
careful management of the perinatal database and Michelle
Perri for her help in obtaining pathology records. Grant
support was from the Agency for Health Care Research and
Quality (RO3 HS10700-01).
ASSISTED CONCEPTION AND VERY LOW BIRTHWEIGHT 409
D RCOG 2003 Br J Obstet Gynaecol 110, pp. 405–410
References
1. Ventura SJ, Martin JA, Curtin SC, Mathews TJ. Births: final data for
1997. Natl Vital Stat Rep 1999;47:1– 94.
2. Keith L, Oleszezuk J. Iatrogenic multiple birth, multiple pregnancy
and assisted reproductive technologies. Int J Gynaecol Obstet 1999;
64:11 –25.
3. Lynch A, McDuffie R, Murphy J, Faber K, Leff M, Orleans M.
Assisted reproductive interventions and multiple birth. Obstet Gynecol
2001;97:195 –200.
4. Agustsson T, Geirsson RT, Mires G. Obstetric outcome of natural and
assisted conception twin pregnancies is similar. Acta Obstet Gynecol
Scand 1997;76:45– 49.
5. Bernasko J, Lynch L, Lapinski R, Berkowitz RL. Twin pregnancies
conceived by assisted reproductive techniques: maternal and neonatal
outcomes. Obstet Gynecol 1997;89:368– 372.
6. Daniel Y, Ochshorn Y, Fait G, Geva E, Bar-Am A, Lessing JB.
Analysis of 104 twin pregnancies conceived with assisted reproduc-
tive technologies and 193 spontaneously conceived twin pregnancies.
Fertil Steril 2000;74:683– 689.
7. Dhont M, De Sutter P, Ruyssinck G, Martens G, Bekaert A. Perinatal
outcome of pregnancies after assisted reproduction: a case-control
study. Am J Obstet Gynecol 1999;181:688 –695.
8. Fitzsimmons BP, Bebbington MW, Fluker MR. Perinatal and neona-
tal outcomes in multiple gestations: assisted reproduction versus spon-
taneous conception. Am J Obstet Gynecol 1998;179:1162–1167.
9. Koudstaal J, Bruinse HW, Helmerhorst FM, Vermeiden JP, Willem-
sen WN, Visser GH. Obstetric outcome of twin pregnancies after in-
vitro fertilization: a matched control study in four Dutch university
hospitals. Hum Reprod 2000;15:935– 940.
10. Lambalk CB, van Hooff M. Natural versus induced twinning and
pregnancy outcome: a Dutch nationwide survey of primiparous dizy-
gotic twin deliveries. Fertil Steril 2001;75:731– 736.
11. Luke B, Anderson E, Misiunas, et al. Do outcomes differ in spon-
taneous vs. assisted-conceived twins? Society for Maternal Fetal
Medicine New Orleans January 2002. Am J Obstet Gynecol 2001;
185(6, Suppl):S7 (abstract).
12. Minakami H, Sayama M, Honma Y, et al. Lower risks of adverse
outcome in twins conceived by artificial reproductive techniques
compared with spontaneously conceived twins. Hum Reprod 1998;
13:2005– 2008.
13. Moise J, Laor A, Armon Y, Gur I, Gale R. The outcome of twin
pregnancies after IVF. Hum Reprod 1998;13:1702– 1705.
14. Zuppa AA, Maragliano G, Scapillati ME, Crescimbini B, Tortorolo G.
Neonatal outcome of spontaneous and assisted twin pregnancies. Eur
J Obstet Gynecol Reprod Biol 2001;95:68– 72.
15. Minakami H, Honma Y, Matsubara S, Uchida A, Shiraishi H, Sato I.
Effects of placental chorionicity on outcome in twin pregnancies. A
cohort study. J Reprod Med 1999;44:595 –600.
16. Dube J, Dodds L, Armson BA. Does chorionicity or zygosity predict
adverse perinatal outcomes in twins. Am J Obstet Gynecol 2002;
186:579– 583.
17. Lumley J. The prevention of preterm birth: unresolved problems and
work in progress. Aust Paediatr J 1988;24:101– 111.
18. Goldenberg RL, Mayberry SK, Copper RL, Dubard MB, Hauth JC.
Pregnancy outcome following a second-trimester loss. Obstet Gynecol
1993;81:444– 446.
19. Hack M, Friedman H, Fanaroff AA. Outcomes of extremely low birth
weight infants. Pediatrics 1996;98:931 –937.
20. Hack M, Flannery DJ, Schluchter M, Cartar L, Borawski E, Klein N.
Outcomes in young adulthood for very-low-birth-weight infants.
N Engl J Med 2002;346:149 –157.
21. Lynch A, McDuffie Jr R, Murphy J, Faber K, Orleans M. Preeclamp-
sia in multiple gestation: the role of assisted reproductive technologies.
Obstet Gynecol 2002;99:445 –451.
22. Min SJ, Luke B, Gillespie B, et al. Birth weight references for twins.
Am J Obstet Gynecol 2000;182(5):1250–1257 (May).
23. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS.
Low and very low birth weight in infants conceived with use of
assisted reproductive technology. N Engl J Med 2002;346:731– 737.
24. Benirschke K. Multiple gestation: incidence, etiology and inheritance.
In: Creasy RK, Resnik R, editors. Maternal Fetal Medicine, 4th edi-
tion. Philadelphia, Pennsylvania: WB Saunders, 1999:585– 592.
25. Tanbo T, Dale PO, Lunde O, Moe N, Abyholm T. Obstetric outcome
in singleton pregnancies after assisted reproduction. Obstet Gynecol
1995;86:188 –192.
Accepted 16 January 2003
410 A. LYNCH ET AL.
D RCOG 2003 Br J Obstet Gynaecol 110, pp. 405–410
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