Down syndrome birth weight in England and Wales: Implications for clinical practice

Abstract

The aim of this study was to determine if syndrome-specific birth weight charts were beneficial for babies with Down syndrome in England and Wales. Birth weights of 8,825 babies with Down syndrome born in England and Wales in 1989-2010 were obtained from the National Down Syndrome Cytogenetic Register. Birth weight centiles for 30-42 weeks gestation by sex were fitted using the LMS method and were compared to those for unaffected babies from the UK-WHO growth charts. For babies born with Down syndrome the median birth weight from 37 to 42 weeks was 2,970 g (10th-90th centile: 2,115-3,680) for boys and 2930 g (2,100-3,629) for girls, and the modal age of gestation was 38 weeks, 2 weeks earlier than for unaffected babies. At 38 weeks gestation they were only slightly lighter than unaffected babies (159 g for boys and 86 g for girls). However at 40 weeks gestation the shortfall was much greater (304 g and 239 g, respectively). In neonates with Down syndrome there is little evidence of growth restriction before 38 weeks gestation, so up to this age it is appropriate to use the UK-WHO birth weight charts. Thereafter birth weight is below that of unaffected babies and it should be plotted on the UK Down syndrome growth charts. © 2015 Wiley Periodicals, Inc.

Full text

RESEARCH ARTICLE
Down Syndrome Birth Weight in England and
Wales: Implications for Clinical Practice
Joan K. Morris,
1
* Tim J. Cole,
2
Anna L. Springett,
1
and Jennifer Dennis
3
1
Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom
2
Population, Policy and Practice Programme, UCL Institute of Child Health, London, United Kingdom
3
Down Syndrome Medical Interest Group, Oxford, United Kingdom
Manuscript Received: 27 February 2015; Manuscript Accepted: 24 August 2015
The aim of this study was to determine if syndrome-s pecific birth
weight charts were beneficial for babies with Down syndrome in
England and Wales. Birth weights of 8,825 babies with Down
syndrome born in England and Wales in 1989–2010 were
obtained from the National Down Syndrome Cytogenetic Reg-
ister. Birth weight centiles for 30–42 weeks gestation by sex were
fitted using the LMS method and were compared to those for
unaffected babies from the UK-WHO growth charts. For babies
born with Down syndrome the median birth weight from 37 to
42 weeks was 2,970 g (10th–90th centile: 2,115–3,680) for boys
and 2930 g (2,100–3,629) for girls, and the modal age of gestation
was 38 weeks, 2 weeks earlier than for unaffected babies. At
38 weeks gestation they were only slightly lighter than unaffected
babies (159 g for boys and 86 g for girls). However at 40 weeks
gestation the shortfall was much greater (304 g and 239 g,
respectively). In neonates with Down syndrome there is little
evidence of growth restriction before 38 weeks gestation, so up to
this age it is appropriate to use the UK-WHO birth weight charts.
Thereafter birth weight is below that of unaffected babies and it
should be plotted on the UK Down syndrome growth charts.
Ó2015 The Authors. American Journal of Medical Genetics Part A Published by
Wiley Periodicals, Inc.
Key words: Down syndrome; trisomy 21; birth weight;
gestational age; growth charts
INTRODUCTION
Growth charts show that early in life babies with Down syndrome
gain weight more slowly than unaffected babies [Piro et al., 1990;
McCoy, 1992; Myrelid et al., 2002; Styles et al., 2002]. However
there is a lack of data on their prenatal growth. Since the seminal
paper of Smith and McKeown [1955], using cross sectional birth
weight data as a proxy measure of intrauterine growth in late
pregnancy, only two others [Clementi et al., 1990; Boghossian et al.,
2012] have presented data on the birth weight of babies with Down
syndrome according to gestational age at birth. It is nevertheless a
belief widely held that among those born with Down syndrome
there is an excess of preterm birth and low birth weight
[Cunningham, 2006]. Our study used cross sectional birth weight
data from the National Down Syndrome Cytogenetic Register
(NDSCR) to test this belief and to determine whether syndrome-
specific birth weight charts are necessary for this population.
METHODS
The NDSCR was set up on January 1st 1989, and currently holds
anonymous data on over 33,000 ante- or postnatal diagnoses of
Down syndrome obtained from all clinical cytogenetic laboratories
in England and Wales [Mutton et al., 1991]. It has approval from
the Confidentiality Advisory Group, under Section 251 of the NHS
Act 2006, to collect, process and use data without the need for
individual consent. It also has ethics approval from the Trent
Medical Research Ethics Committee (MREC).
Virtually every baby with clinical features suggesting Down syn-
drome, and any antenatal diagnostic sample from a pregnancy
suspected to have Down syndrome, receives a cytogenetic examination
becausethedefinitivetestfortheconditionisthefindingoftrisomy21.
The data in the register are obtained from all clinical cytogenetic
laboratories in England and Wales, which are requested to send a
completed form for each such diagnosis and its variants. The form
This is an open access article under the terms of the Creative Commons
Attribution License, which permits use, distribution and reproduction in
any medium, provided the original work is properly cited.
Conflict of interest: none.
Correspondence to:
Joan K. Morris, Wolfson Institute of Preventive Medicine, Queen Mary
University of London, Charterhouse Square, London, EC1M 6BQ.
E-mail: j.k.morris@qmul.ac.uk
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 26 September 2015
DOI 10.1002/ajmg.a.37366
How to Cite this Article:
Morris JK, Cole TJ, Springett AL, Dennis J.
2015. Down syndrome birth weight in
England and Wales: Implications for
clinical practice.
Am J Med Genet Part A 167A:3070–3075.
Ó2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. 3070

contains details of the date, place of birth, and indications for referral,
maternal age, and family history. Most laboratories send a copy of this
form to the referring physician for confirmation and completion. The
gestational age was estimated from the date of the last menstrual period
(LMP), and was usually confirmed by ultrasound.
Comparisons with other congenital anomaly registers and the
Office for National Statistics show that since its inception the
register has captured data on an estimated 93% of all diagnosed
Down syndrome births and pregnancy terminations for residents
of England and Wales [Savva and Morris, 2009].
Centiles were fitted to the birth weight data with the LMS
method [Cole and Green, 1992] in R (http://www.R-project.org/
) using the gamlss package [Rigby and Stasinopoulos, 2005]. The
Box–Cox–Cole–Green (BCCG) distribution was used with a log
link for the median. In essence the LMS method estimates for each
week of gestation the median birth weight (M) and its coefficient of
variation (S), allowing for non-normality in the distribution by
using a Box–Cox power transformation (L). The sex difference in
median birth weight did not vary with gestation and so was fitted as
a constant, this (due to the log link) corresponding to a constant
percentage difference. The centiles were fitted using data from 28 to
43 weeks of gestation, and are presented from 30 to 42 weeks as
tables of smoothed L, M, and S values by sex. From these values,
centiles C
100a
were derived using the formula
C100a¼Mð1þLSzaÞ1=L
where z
a
is the standard deviation for tail area aunder a Normal
distribution. This leads to approximate 2nd, 9th, 25th, 50th, 75th,
91st, and 98th centiles using the two-thirds of a standard deviation
spacing proposed by Cole [1994].
The birth weight centiles were compared with those for unaf-
fected babies from the revised UK-WHO growth charts [Cole et al.,
2011], which were based on 9,443 babies with gestational age
estimated by date of LMP confirmed by ultrasound.
The secular trend in birth weight was examined using linear
regression of birth weight SD score on year of birth. The association
between gestational age and missing birth weight was estimated
using logistic regression.
RESULTS
33,767 diagnoses of Down syndrome were recorded in the
register from January 1st 1989 to December 31st 2011, from
which 8,825 live births with free trisomy 21 and complete
information on birth weight and gestational age were extracted
(see flow chart in Fig. 1).
Figure 2 shows the distribution of gestational age at birth for
babies with Down syndrome compared to unaffected babies born
in England and Wales in 2010 [Office for National Statistics, 2012],
scaled to adjust for the different sample sizes. The modal gestational
ages were 38 weeks for Down syndrome babies and 40 weeks for
unaffected babies.
Table I gives the sample sizes and fitted LMS parameters for birth
weight by sex and gestational age. The skewness (L) and coefficient
of variation (S) parameters were the same by sex, while median
birth weight (M) was 2.4% (95%CI: 1.7–3.1) less in girls than boys
at all gestations. There was no evidence of a secular trend in birth
weight from 1989 to 2011 (regression coefficient 0.3 g per year, 95%
CI 2g to þ2.6 g).
Tables II and III present the fitted birth weight centiles by sex and
gestational age. At 38 weeks gestation, median weight was 2,567 g
for boys and 2,506 g for girls.
Figure 3 shows the birth weight centiles by gestational age for
babies with Down syndrome compared to unaffected babies. From
30 to 38 weeks median birth weight for Down syndrome babies was
slightly but consistently lower than for unaffected babies. At
38 weeks the difference was 159 g for boys and 86 g for girls. But
after 38 weeks the two median curves diverged, and by 40 weeks the
shortfall was much greater (304 g for boys and 239 g for girls). The
FIG. 1. Flow chart of the selection of free trisomy 21 cases for
inclusion in the analysis. [Color figure can be seen in the online
version of this article, available at http://wileyonlinelibrary.com/
journal/ajmga].
FIG. 2. The distribution of gestational age at birth in babies with
Down syndrome (gray bars) compared to unaffected babies
(dashed line) [Office for National Statistics, 2012].
MORRIS ET AL. 3071

Down syndrome babies showed greater variation than the unaf-
fected babies at all gestations, but particularly before 34 weeks when
the centiles are positively skew, with a much wider gap between the
91st and 98th centiles than between the 2nd and 9th. This corre-
sponds to the L value being well below one at early gestations.
Figure 4 shows the distribution of birth weight at 38 weeks
gestation for babies with Down syndrome compared to unaffected
babies, with good agreement.
DISCUSSION
Our study shows that babies with Down syndrome born near
to term (39–41 weeks) were lighter than unaffected babies
(Fig. 3). However the modal age at delivery was 38 weeks
gestation (Fig. 2). This concurs with findings by Smith and
McKeown [1955] and it was also shown though not mentioned
by Clementi et al. [1990] and Boghossian et al. [2012]. Hence
this is the first time in 60 years that attention has been drawn
to the fact that modal gestational age in Down syndrome is
38 weeks, when mean birth weight was within 150 g of that for
unaffected babies (Fig. 2). Hence there was little evidence
of significant growth restriction in the first 38 weeks of pre-
gnancy. After 38 weeks babies with Down syndrome were in-
creasingly lighter than unaffected babies on average, suggesting
that they were postmature and that intrauterine growth was
slowing.
TABLE I. Sample Sizes and LMS Parameters for Birth Weight in Down Syndrome by Sex and Gestational Age (n ¼8,825)
Gestational age
Number of births M
(weeks) Boys Girls Boys Girls L S
28 11 10 960 937 0.12 0.266
29 16 19 1132 1105 0.03 0.253
30 26 23 1319 1288 0.06 0.243
31 29 27 1518 1482 0.15 0.237
32 73 41 1719 1678 0.23 0.233
33 84 54 1915 1869 0.31 0.228
34 117 85 2113 2063 0.39 0.220
35 192 156 2333 2277 0.47 0.206
36 414 298 2567 2506 0.55 0.189
37 693 525 2800 2733 0.62 0.174
38 1219 921 3019 2947 0.69 0.162
39 822 824 3164 3088 0.76 0.153
40 797 809 3251 3174 0.83 0.150
41 204 207 3304 3225 0.89 0.151
42 55 56 3318 3239 0.96 0.152
43 8 10 3300 3221 1.02 0.153
M, Median: L, skewness; S, coefficient of variation.
TABLE II. Birth Weight (g) Centiles for Boys With Down Syndrome According to Gestational Age
Gestational age (weeks) 2nd 9th 25th 50th 75th 91st 98th
28 574 679 806 960 1149 1380 1665
29 685 809 957 1132 1341 1590 1887
30 805 951 1121 1319 1550 1819 2131
31 929 1098 1294 1518 1775 2068 2402
32 1049 1245 1467 1719 2003 2322 2678
33 1170 1390 1638 1915 2222 2561 2934
34 1304 1548 1817 2113 2437 2789 3170
35 1476 1739 2024 2333 2665 3020 3399
36 1682 1958 2253 2567 2899 3250 3618
37 1893 2181 2483 2800 3131 3476 3835
38 2092 2389 2698 3019 3350 3692 4044
39 2232 2534 2845 3164 3491 3826 4168
40 2302 2612 2929 3251 3580 3913 4252
41 2325 2647 2974 3304 3638 3976 4316
42 2317 2649 2983 3318 3655 3993 4332
43 2289 2627 2964 3300 3636 3971 4305
3072 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

There is a relatively high rate of spontaneous fetal loss in Down
syndrome pregnancies [Savva et al., 2006] with 3.3% of birth s being
stillborn. The gestational-age-adjusted weight of stillborn babies
was less than that of live births (data not shown), indicating that
birth weight of live births is a biased measure of intrauterine
growth, with the smaller fetuses being excluded. However, as
the proportion of stillbirths did not alter from 38 to 42 weeks
gestation, ignoring them would not explain the observed diver-
gence in birth weight. So there is probably some intrauterine
growth restriction amongst fetuses with Down syndrome at all
gestations, but compared to unaffected fetuses it is greater from
38 weeks gestation.
The birth weight charts for US babies with Down syndrome
derived by Boghossian et al. [2012] gave similar results to ours (e.g.,
at 38 weeks gestation median birth weight for boys was 3,048 g vs.
2,947 g in this study and for girls 3,092 g vs. 3,019 g). Median birth
weight for unaffected babies is greater in North America than
England and Wales, so a larger difference might have been
expected. Against that, Boghossian only included babies admitted
to hospital at birth or dying before admission; this might be
expected to be a “sicker” population, biasing the weight centiles
downwards, which might explain why the differences between the
studies were small.
Heart anomalies are also relevant, as 44% of babies with Down
syndrome have a heart anomaly [Morris et al., 2014]. Babies with
heart anomalies are 100–200g lighter than unaffected babies born at
the same gestational age [Rosenthal et al., 1991; Rosenthal, 1996].
This will account for some but not all of the difference in birth
weight, and the observation of growth restriction after 38 weeks
gestation remains relevant.
Smith and McKeown [1955] questioned whether the low birth
weight of those with Down syndrome was due to shorter gestation
or slower prenatal growth. In a study hampered by small numbers
(n ¼103) their difference in birth weight at 38 weeks was greater
than in our study 0.6 Lb (272 g). On this basis they concluded
that there must be some intrauterine growth restriction prior to
38 weeks. They did however record placental weights and found
these to be similar to those in their control population. Hence they
suggested that the apparent growth restriction was likely to be due
to a “lowered growth capacity of the foetus rather than inability of
the intrauterine environment to support its growth”. However
studies of first trimester growth restriction and aneuploidy using
crown rump measurements [Bahado-Singh et al., 1997; Schemmer
et al., 1997] have shown that those with Down syndrome grow
normally in the first trimester. Our own data suggest that from
30-38 weeks the average intrauterine growth of those with Down
syndrome differs little from that of other babies. Hence intrauterine
growth restriction appears to be confined to gestations beyond
38 weeks.
In unaffected babies, slowing of intrauterine growth after the
modal gestational age of 40 weeks is considered a surrogate marker
for incipient postmaturity and signals a need for enhanced obstetric
vigilance and possible intervention. For babies with Down
syndrome, slowing of intrauterine growth appears to occur from
the modal gestational age of 38 weeks, hence there may be an earlier
onset of incipient postmaturity in this population and enhanced
vigilance may be necessary from this time.
Strengths and Weaknesses
Direct measures of intrauterine growth in late pregnancy are not
available for babies with Down syndrome. Hence in our study and
those of others [Clementi et al., 1990; Smith and McKeown, 1995;
Boghossian et al., 2012] cross sectional birth weight data is used as a
proxy measure. A strength of the study is the large sample size
derived from a national register over 22 years with an estimated
ascertainment rate of 93%. There was no evidence of a trend in
birth weight over this time. A weakness is that 36% of the 13,940
live births recorded in the register had missing data for gestational
age and/or birth weight. The register receives information from
TABLE III. Birth Weight (g) Centiles for Girls With Down Syndrome According to Gestational Age
Gestational age (weeks) 2nd 9th 25th 50th 75th 91st 98th
28 560 662 786 937 1121 1347 1625
29 668 790 934 1105 1309 1552 1842
30 786 928 1094 1288 1513 1776 2080
31 906 1072 1263 1482 1733 2019 2344
32 1024 1215 1432 1678 1955 2266 2614
33 1142 1357 1599 1869 2169 2500 2864
34 1273 1511 1774 2063 2378 2722 3094
35 1441 1697 1976 2277 2601 2948 3318
36 1641 1911 2199 2506 2830 3172 3532
37 1848 2128 2424 2733 3056 3393 3744
38 2042 2332 2634 2947 3270 3604 3948
39 2179 2473 2777 3088 3408 3734 4068
40 2247 2550 2859 3174 3494 3820 4150
41 2270 2584 2903 3225 3552 3881 4213
42 2262 2586 2912 3239 3568 3898 4229
43 2234 2564 2893 3221 3549 3876 4202
MORRIS ET AL. 3073

cytogenetic laboratories and then contacts the referral clinicians for
further information. For some cytogenetic laboratories it is not
possible to contact the referral clinicians and therefore the missing
information is unlikely to be a source of bias as it is missing for
administrative reasons. There was no association between gesta-
tional age and missing birth weight (P¼0.2). Mode of delivery was
also unavailable and it may be that growth restriction was an
indication for induced delivery before 38 weeks. However this is
unlikely because mean birth weight was similar to that for unaf-
fected babies up to 38 weeks. Detailed information on other
associated anomalies (particularly heart anomalies) was not
available.
Implications for Perinatal Clinical Practice
Timing of elective delivery. Marlow has recently challenged
the accepted view that for the general population the optimum time
for delivery is 37–41 weeks gestation (full term) [Marlow, 2012]. He
provides evidence of increased morbidity and mortality among
those born in early term (37–38 weeks), agreeing with Clark that for
the general population perinatal risk is a continuum for adverse
outcomes that is minimal at 39–41 weeks of gestation [Clark and
Fleischman, 2011]. Our findings suggest that in Down syndrome
the optimum time for delivery may be earlier than for other babies,
though there is currently no other evidence to support this. We
suggest nevertheless that clinicians should be mindful of this
possibility when a foetus with Down syndrome is still in utero
at 40–41 weeks. In this situation they may wish to consider
induction of labour. However, they need to balance this against
the early weight gain/loss in newborns with DS, for which there is
very little robust information.
There is a need for information about the associations between
gestational age at delivery and short and long-term outcome
measures in babies with Down syndrome. Some of this might
be available by linking existing cohorts and registers.
Preterm Birth Weight Charts for Babies With
Down Syndrome
The widely used UK-WHO growth charts include a birth weight
chart for 32–42 weeks gestation [Cole et al., 2011]. Our findings
show that median birth weight for those with Down syndrome is
only slightly less than for UK-WHO until 38 weeks gestation.
However the centile lines are further apart, so there is a greater
chance of Down syndrome babies being small or large for dates. We
FIG. 3. Birth weight centiles for boys and girls: Down syndrome
(black lines) compared with revised UK-WHO growth charts
(gray lines) [Cole et al., 2011].
FIG. 4. The distribution of birth weight at 38 weeks in babies
with Down syndrome (grey bars) compared to unaffected babies
(dashed line) [Office for National Statistics, 2012].
3074 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

suggest that birth weights of preterm babies with Down syndrome
should be plotted on the UK-WHO charts up to 38 weeks gestation,
and for later gestations at age 0 on the 2011 edition of the UK Down
syndrome growth charts [Styles et al., 2002] (http://www.dsmig.
org.uk/publications/growthchart.html). The distribution of birth
weight in this study was similar to that of Styles et al (medians 3.06
and 3.00 kg respectively).
CONCLUSION
The modal age at delivery in babies with Down syndrome is
38 weeks. For gestations up to 38 weeks their median birth weight
is similar to that for unaffected babies, but after 38 weeks their
median birth weight rises less fast than for unaffected babies. This
may have implications for perinatal clinical practice.
ACKNOWLEDGMENTS
We would like to thank Haiyan Wu for ensuring the accuracy of the
data from the NDSCR.
FUNDING
TJC was funded by UK Medical Research Council grant MR/
M012069/1.
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