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

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