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Erschienen in: BMC Pregnancy and Childbirth 1/2008

Open Access 01.12.2008 | Research article

Centile charts for birthweight for gestational age for Scottish singleton births

verfasst von: Sandra Bonellie, James Chalmers, Ron Gray, Ian Greer, Stephen Jarvis, Claire Williams

Erschienen in: BMC Pregnancy and Childbirth | Ausgabe 1/2008

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Abstract

Background

Centile charts of birthweight for gestational age are used to identify low birthweight babies. The charts currently used in Scotland are based on data from the 1970s and require updating given changes in birthweight and in the measurement of gestational age since then.

Methods

Routinely collected data of 100,133 singleton births occurring in Scotland from 1998–2003 were used to construct new centile charts using the LMS method.

Results

Centile charts for birthweight for sex and parity groupings were constructed for singleton birth and compared to existing charts used in Scottish hospitals.

Conclusion

Mean birthweight has been shown to have increased over recent decades. The differences shown between the new and currently used centiles confirm the need for more up-to-date centiles for birthweight for gestational age.
Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1471-2393-8-5) contains supplementary material, which is available to authorized users.

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

SRB and CW carried out the statistical analysis. All authors were co-investigators on the CSO grant and contributed to the initiation of the project and subsequent discussion. All authors have read and approved the final manuscript.

Background

Birthweight is one of the important indicators used to assess the health of an infant at birth. Low birthweight has often been defined as weights less than 2500 grams with birthweights less than 1500 grams classed as very low birthweight. These definitions however do not take into account gestational age. It is important to be able to differentiate between babies who are light because they are premature and those who are small-for-gestational age since the latter may have different health problems to the former. They may be growth restricted and have an increased risk of other complications such as perinatal asphyxia, symptomatic hypoglycaemia, congenital malformations, chronic intra-uterine infection and pulmonary haemorrhage [1]. Large-for-gestational age babies also have related health problems. Identification of small or large for gestational age babies is important for the management of the individual pregnancy and neonate. It is also a valuable aid to epidemiological studies where the aim is to identify risk factors or to assess the management of pregnancies [2].
Small- or large-for-gestational age babies may be identified using centile charts of birthweight by gestational age. Centile reference charts are used to monitor clinical measurements on individuals in the context of population values. Raw centiles can be calculated from appropriate data but the perturbations in these curves are unlikely to reflect the pattern of underlying growth at the population level. It is therefore reasonable to use statistical methods to derive a series of smoothed curves showing how the centiles of a measurement, in this case birthweight, change when plotted against time, in this case gestational age.
In Scotland there have been three sizeable studies resulting in the production of centile charts each based on data collected in Aberdeen [35]. The charts from the most recent of these studies, using data from 17,927 singleton births occurring between 1975–1980, were extensively used as a standard throughout Scotland until relatively recently.
The Information Services Division (ISD) of the Scottish Health Service use and publish birthweight centile charts[6]. ISD collects data on all maternity patients admitted to Scottish hospitals on an SMR02 form. The charts are based on 894,066 live births occurring between 1975 and 1989 and are the most recent published in Scotland.
Increases in birthweight since the formation of these standards have been observed for Scotland [7] England and Wales [8], the United States [9] and Canada [10] There have also been changes in the methods used to calculate gestational age [11]. These changes suggest that the centile charts in present use may now be inaccurate. Therefore, we aimed to produce updated charts using more recent data from 1998–2003.

Methods

Data on singleton births occurring between 1980 and 2003 were obtained from ISD's SMR02 (maternity) data collection system. This includes information on the birthweight, gestational age and sex of the infant. The parity of the mother is also recorded. Gestational age at birth was reported in completed weeks and is a clinician's estimate of gestation at birth based on an ultrasound dating scan and date of last menstrual period.
In order to adequately represent the population of all singleton births, the only exclusions made were lethal congenital anomalies and obvious outliers which included any birthweights less than 250 grams. Outliers were identified using Tukey's methodology [12]. This calculates the interquartile range and identifies as outliers any values more than twice the interquartile range below the first quartile or above the third quartile. This method assumes a symmetric distribution which is not the case for birthweights at most gestational ages. However the values of L obtained in each of the groups for each suggests only a slight degree of skewness at most gestational ages. The number of birthweights omitted as possible outliers was small and inspection of the omitted birthweights suggests that most of these could be explained by transcription errors.
The mean birthweight of all singletons born in each year between 1980–2003 was calculated. This confirmed the reported increase in birthweight over this period. This increase is marked over the period from 1980–1997 but appears to level off from 1998 onwards and therefore the most recent years for which complete data were available, namely 2002 and 2003, were used as a basis from which to construct new centile charts. For births occurring at gestations between 31 and 42 weeks a two year period gives sufficient data, however for the extremes of gestational age the data was supplemented by births from 1998 to 2001.
Centiles were calculated using the LMS method [13] which uses the Box-Cox power transformation to obtain normally distributed data within each group. This involves estimating three sets of values for each gestational age group, namely, L the power transformation used to achieve normality, M the median birthweight and S the coefficient of variation of the data. L, M and S are estimated for each gestational age and then smoothed curves are fitted using cubic splines to these to give L(t), M(t) and S(t) where t is the gestational age. The extent of the smoothing is expressed in terms of the degrees of freedom used for the fit. The 100αth centile for the appropriate sex and parity group is then given by
C100α (t) = M(t) [1+L(t)S(t)Z α ]1/L(t)
where Z α is the α % point of the normal distribution.
For a particular infant, with birthweight y, a z-score can be calculated using the formula
z = [ y M ( t ) ] L ( t ) 1 L ( t ) S ( t ) MathType@MTEF@5@5@+=feaafiart1ev1aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xI8qiVKYPFjYdHaVhbbf9v8qqaqFr0xc9vqFj0dXdbba91qpepeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGacaGaaiaabeqaaeqabiWaaaGcbaGaeeOEaONaeyypa0tcfa4aaSaaaeaadaWadaqaamaalaaabaGaeeyEaKhabaGaeeyta00aaeWaaeaacqqG0baDaiaawIcacaGLPaaaaaaacaGLBbGaayzxaaWaaWbaaeqabaGaeeitaW0aaeWaaeaacqqG0baDaiaawIcacaGLPaaaaaGaeyOeI0IaeGymaedabaGaeeitaW0aaeWaaeaacqqG0baDaiaawIcacaGLPaaacqqGtbWudaqadaqaaiabbsha0bGaayjkaiaawMcaaaaaaaa@4526@
Four sets of charts were constructed defined by the sex of the baby, male or female, and the parity of the mother, nulliparous or multiparous. Centiles were calculated using the software LMS ChartMaker. Other analysis was carried out using SAS, version 9.1

Results

The mean birthweight for each of the years from 1980 to 2003 is shown in Figure 1 and confirms the previously reported increase in birthweight.
There were 98,904 records of singleton births occurring in 2002 and 2003. These were supplemented by information on 1,883 singleton births from 1998–2001 for gestational ages of 30 weeks or less or 43 weeks. Excluding lethal congenital anomalies and omitting outliers gave a total of 100,133 records. Applying Tukey's method resulted in 0.4% of the observations being omitted as outliers. Figures 2a and 2b show plots of birthweight against gestational age with and without the outliers for the subgroup girls, parity 1 or more. Table 1 gives the numbers of births used in constructing the centiles, and the percentage of outliers omitted together with the overall mean birthweight and standard deviation based on the data for 2002–2003 only.
Table 1
Summary of Data by Sex and Parity Groupings
Group
Total Numbers
2002–2003 Data
Sex of infant
Parity
Number of births used
Percentage of outliers
Mean(St.Dev) Birthweight (with outliers omitted)
Male
0
23419
0.37
3376 (603.33)
 
1 or more
27924
0.43
3494 (603.03)
Female
0
21948
0.39
3266 (570.94)
 
1 or more
26842
0.37
3369 (570.79)
Tables 2, 3, 4, 5 give the centiles for the groups: boys parity 0, boys parity 1 or more, girls parity 0 and girls parity 1 or more respectively. The tables also give the number of births used and the fitted values of L. M and S for each gestational age for each group, as well as the degrees of freedom used in fitting the cubic splines.
Table 2
Centiles for Boys, Nulliparous
Gestational Age
No.
L d.f. = 5
M d.f. = 12
S d.f. = 6
3rd
5th
10th
25th
50th
75th
90th
95th
97th
24
65
1.30
658
0.245
326
372
440
546
658
764
856
910
944
25
59
1.34
759
0.240
379
432
510
632
759
879
982
1042
1080
26
101
1.38
851
0.235
430
490
577
712
851
982
1095
1160
1202
27
105
1.41
958
0.229
494
561
656
805
958
1101
1224
1295
1341
28
128
1.43
1103
0.222
585
659
766
932
1103
1263
1400
1479
1530
29
143
1.44
1271
0.214
696
778
896
1081
1271
1449
1601
1689
1745
30
160
1.43
1446
0.205
823
911
1039
1239
1446
1640
1807
1904
1966
31
86
1.41
1643
0.196
976
1068
1204
1419
1643
1855
2037
2143
2211
32
105
1.38
1848
0.187
1142
1239
1382
1609
1848
2075
2272
2387
2460
33
121
1.34
2065
0.178
1326
1425
1574
1812
2065
2308
2519
2643
2722
34
213
1.27
2286
0.169
1521
1622
1774
2021
2286
2543
2768
2901
2986
35
341
1.17
2510
0.161
1729
1830
1983
2235
2510
2779
3018
3159
3250
36
586
1.05
2744
0.153
1950
2050
2204
2461
2744
3026
3278
3428
3526
37
1051
0.93
2959
0.145
2159
2259
2412
2671
2959
3250
3513
3671
3774
38
2447
0.84
3162
0.137
2363
2461
2613
2871
3162
3457
3726
3889
3996
39
4459
0.77
3341
0.130
2546
2643
2794
3050
3341
3638
3910
4075
4182
40
6421
0.74
3510
0.125
2711
2809
2960
3217
3510
3809
4083
4250
4359
41
5906
0.76
3664
0.120
2859
2957
3110
3369
3664
3964
4238
4405
4514
42
867
0.83
3736
0.116
2935
3034
3187
3445
3736
4031
4299
4461
4567
43
55
0.92
3764
0.112
2976
3074
3225
3479
3764
4050
4309
4465
4566
Table 3
Centiles for Boys, Multiparous
Gestational Age
No.
L d.f. = 4
M d.f. = 15
S d.f. = 8
3rd
5th
10th
25th
50th
75th
90th
95th
97th
24
61
1.24
628
0.229
339
378
436
529
628
723
806
855
886
25
59
1.23
756
0.224
418
463
531
640
756
868
966
1024
1061
26
71
1.22
866
0.218
490
540
615
736
866
991
1101
1166
1207
27
72
1.21
996
0.212
578
633
716
851
996
1137
1260
1333
1380
28
111
1.20
1147
0.207
679
740
833
984
1147
1305
1444
1526
1579
29
122
1.18
1308
0.203
788
856
959
1126
1308
1484
1640
1732
1791
30
153
1.15
1483
0.200
907
982
1096
1281
1483
1681
1856
1959
2026
31
62
1.10
1676
0.196
1044
1125
1249
1453
1676
1897
2093
2209
2284
32
100
1.05
1859
0.192
1183
1269
1400
1618
1859
2099
2314
2442
2525
33
135
0.98
2065
0.187
1344
1434
1573
1806
2065
2325
2560
2701
2792
34
209
0.90
2284
0.181
1520
1614
1760
2007
2284
2565
2821
2975
3076
35
312
0.82
2523
0.178
1708
1807
1961
2224
2523
2828
3108
3278
3389
36
679
0.75
2792
0.172
1927
2031
2194
2473
2792
3121
3425
3610
3731
37
1448
0.70
3063
0.160
2181
2287
2452
2737
3063
3400
3711
3902
4027
38
3940
0.69
3313
0.144
2457
2560
2721
2997
3313
3639
3940
4124
4245
39
6247
0.70
3480
0.130
2663
2762
2916
3179
3480
3788
4072
4245
4358
40
7809
0.73
3649
0.123
2831
2931
3086
3349
3649
3955
4236
4407
4519
41
5665
0.76
3793
0.120
2962
3063
3221
3489
3793
4102
4386
4557
4670
42
629
0.79
3856
0.120
3005
3110
3272
3546
3856
4172
4460
4634
4748
43
40
0.83
3866
0.123
2987
3095
3263
3547
3866
4190
4486
4665
4781
Table 4
Centiles for Girls, Nulliparous
Gestational Age
No.
L d.f. = 4
M d.f. = 12
S d.f. = 6
3rd
5th
10th
25th
50th
75th
90th
95th
97th
24
55
1.43
604
0.254
270
319
389
496
604
704
789
838
869
25
56
1.35
682
0.252
320
372
446
562
682
794
891
947
983
26
78
1.27
779
0.249
382
437
517
645
779
907
1018
1084
1125
27
69
1.19
888
0.246
453
511
598
738
888
1033
1160
1235
1283
28
118
1.12
1018
0.241
540
602
696
850
1017
1181
1327
1413
1468
29
102
1.06
1173
0.234
648
715
818
987
1173
1357
1522
1620
1684
30
157
1.01
1339
0.226
770
842
952
1136
1339
1543
1726
1836
1907
31
50
0.97
1515
0.216
904
980
1097
1294
1514
1735
1935
2055
2133
32
88
0.94
1709
0.206
1057
1138
1263
1473
1709
1947
2163
2293
2377
33
118
0.92
1927
0.195
1233
1319
1451
1675
1927
2181
2412
2551
2642
34
161
0.91
2160
0.183
1429
1519
1659
1894
2159
2428
2672
2819
2914
35
303
0.89
2399
0.172
1640
1734
1879
2123
2399
2678
2932
3086
3186
36
462
0.87
2633
0.161
1855
1950
2099
2350
2633
2920
3182
3340
3443
37
955
0.85
2851
0.150
2066
2162
2312
2565
2851
3142
3407
3567
3672
38
2183
0.80
3062
0.140
2280
2376
2524
2776
3062
3353
3619
3780
3886
39
4240
0.73
3230
0.131
2464
2557
2702
2949
3230
3518
3783
3944
4049
40
6223
0.65
3371
0.125
2610
2702
2845
3091
3371
3661
3928
4091
4198
41
5718
0.57
3514
0.121
2754
2845
2987
3232
3514
3806
4078
4244
4354
42
760
0.49
3590
0.117
2845
2934
3073
3313
3590
3879
4148
4314
4424
43
52
0.41
3630
0.113
2909
2994
3128
3360
3630
3912
4176
4339
4447
Table 5
Centiles for Girls, Multiparous
Gestational Age
No.
L d.f. = 4
M d.f. = 14
S d.f. = 8
3rd
5th
10th
25th
50th
75th
90th
95th
97th
24
65
1.14
630
0.247
326
366
426
524
630
734
826
881
916
25
59
1.11
720
0.245
377
422
489
599
719
837
942
1004
1044
26
101
1.09
832
0.244
442
492
568
694
832
968
1089
1161
1208
27
105
1.06
958
0.241
517
573
659
802
958
1114
1253
1335
1389
28
128
1.04
1073
0.235
595
656
748
902
1072
1242
1394
1484
1543
29
143
1.01
1222
0.225
706
770
870
1037
1222
1407
1574
1673
1738
30
160
0.96
1406
0.214
846
916
1023
1204
1406
1609
1793
1903
1975
31
86
0.92
1580
0.203
989
1061
1174
1365
1580
1798
1996
2115
2193
32
105
0.87
1759
0.193
1137
1213
1331
1531
1759
1990
2201
2329
2412
33
121
0.82
1956
0.184
1301
1381
1505
1716
1956
2202
2427
2564
2654
34
213
0.77
2188
0.177
1488
1572
1704
1930
2188
2453
2698
2847
2945
35
341
0.72
2442
0.173
1684
1775
1917
2161
2442
2732
3000
3164
3272
36
586
0.68
2687
0.169
1877
1973
2125
2386
2687
2999
3289
3466
3583
37
1051
0.65
2932
0.161
2092
2192
2349
2620
2932
3256
3558
3742
3864
38
2447
0.63
3176
0.146
2347
2446
2601
2868
3176
3495
3792
3974
4094
39
4459
0.62
3352
0.132
2556
2652
2801
3057
3352
3656
3939
4111
4225
40
6421
0.64
3498
0.126
2706
2802
2951
3206
3498
3799
4077
4247
4359
41
5906
0.69
3625
0.122
2824
2921
3072
3330
3625
3927
4205
4375
4486
42
867
0.73
3673
0.122
2855
2954
3109
3373
3673
3979
4260
4431
4543
43
55
0.78
3669
0.126
2821
2924
3085
3359
3668
3983
4271
4446
4560
The z-scores resulting from the LMS models fitted should be normally distributed within each grouping. This was verified by obtaining normal probability plots of the z-scores overall and for each gestational age. The plot for girls, parity 1 or more is given in Figure 3. Table 6 gives the observed percentage of z-scores by centiles groupings for the same group.
Table 6
Percentage of observations (observed and expected) within centile bands
Centiles
Expected Percentage
Observed Percentage
Less than 3rd
3
3.1
Between 3rd and 5th
2
1.9
Between 5th and 10th
5
4.8
Between 10th and 25th
15
14.9
Between 25th and 50th
25
25.5
Between 50th and 75th
25
25.1
Between 75th and 90th
15
14.5
Between 90th and 95th
5
5.0
Between 95th and 97th
2
2.0
Above 97th
3
3.2
In order to assess the goodness of fit of the models, the new centiles were plotted against the observed centiles for each group. Figure 4 shows this plot for the 3rd, 50th and 97th centiles for girls, parity 1 or more. Figure 5 shows the 3rd, 10th, 25th, 50th, 75th, 90th and 97th centiles superimposed on the actual birthweights for the same groups. For comparison Figure 6 shows the new centiles compared to the currently used ISD centiles again for the 3rd, 50th and 97th centiles

Discussion

Centile charts of birthweight for gestational age are a valuable tool in many epidemiological studies as well as providing important information to clinicians as to which babies may be at higher risk of neonatal or postnatal morbidity [14]. It is therefore essential that the charts used are representative of the population to which they are applied. A number of standards are available based on births occurring in various European countries; mostly using data from the 1980s and the 1990s [15].
There are clear differences between the centiles calculated here from recent data and those in current use in Scotland which are based on data from 1975–1989. For term babies the median birthweight in all sex and parity groupings is shown to be higher than it was previously. This increase in birthweight is also reflected in the other centiles. For babies born at very low gestational ages the median birthweight is now less than it was, possibly reflecting the increased survival rate in pre-term births [16]. The centiles for lower gestational ages are also much closer together than in the existing charts. One possible explanation for such a marked difference at lower gestations in particular may be poor estimation of gestational age, particularly in the 1970s, as was found in data for England and Wales analysed by Milner and Richards in 1974 [17].
In recent years a number of centiles charts [18] have been constructed using the method developed by Gardosi [19]. This method aims to give a fetal weight standard and requires only data for term births from the population of interest. Whilst it is desirable in principle to look at fetal weights the assumptions which are being made with this method cannot be substantiated with reference to our data which consists only of actual birthweights. It is therefore not possible to assess the goodness of fit of the centiles calculated in this way.
As well as modelling the median birthweight the LMS method also models the coefficient of variation S and the power L which is used to transform the birthweights to achieve normality. Within each of the sex and parity groupings it is seen that the coefficient of variation decreases with increased gestational age showing that the birthweights are more variable at lower gestational ages. This contrasts with the assumption used in Gardosi's methodology for fetal weights that the coefficient of variation is constant.
It is important in constructing charts of this type to test the adequacy of the model fitted both with reference to the raw data used to construct the charts and to the assumptions on which the model relies [20, 21].
Comparing the new centiles to the empirical centiles suggests that the LMS method is a reasonable fit to the data. It can be shown that, in general, the standard errors of empirical centiles are larger than those for the centiles calculated using the normal distribution. The latter method is therefore more efficient. This is only true if the assumption of normality is reasonable which is not the case for birthweight and therefore some transformation of the data is required. A value of 1 for L indicates no transformation required with a value less than 1 adjusting for positive skewness and a value greater than 1 for negative skewness. For each sex and parity grouping the values of L suggest that the birthweights are negatively skewed for low gestational ages and positively skewed for higher gestational ages. The values of L suggest the extent of skewness at each gestational age is not high.
Normal probability plots of the z-scores for each grouping and for each gestational age within each grouping show that the LMS method has largely succeeded in achieving normality. There is some suggestion in the plot of heavier tails however the percentages in the tails are close to what is expected.
An important question in constructing centile charts of any data is which cases to include in the calculations and which to omit. Many previous studies into centile charts have used live births only because of the difficulty of accurately assessing the gestational age of stillbirths. The argument in the past has been that a baby which is stillborn may have died some time before delivery and therefore the weight may not be a true reflection of the gestational age at which delivery occurs. This is not often the case now. Fetal death is almost always recognized very quickly, and most women prefer to be delivered as soon as possible once it is realized that this has happened. This was argued by Tin[16] looking at the problems of estimating centiles for babies born before 32 weeks gestational age, In this paper it was suggested that not all stillbirths should be excluded, arguing that by doing so centiles at gestational ages less than 28 weeks have been largely overestimated.
For babies born within ten weeks of term the difference in centiles including and excluding stillbirths are negligible because the numbers of stillbirths are relatively small. Omitting stillbirths at low gestations of 24–27 weeks gestation causes bias in the centiles possibly because very small babies at any specified gestation are much more likely to be treated as "effectively" stillborn than larger babies of the same gestation when pregnancy ends as soon as this.
Information on ethnicity is poorly recorded on the SMR02 forms therefore no attempt was made to produce separate centiles for different ethnic groups. From the 2001 census it is known that the minority ethnic population was just over 100,000 in that year which is 2% of the total population of Scotland. The percentage is similar for women of child bearing age. Ethnicity is not therefore a major consideration for the Scottish data.
Other studies have followed the convention of excluding babies with major congenital malformations [22] and this has been used in this study. However with such a large data set the exclusion has made little difference to the centiles. Other studies [1, 23] have also identified outliers at each gestational age using the criterion outlined by Tukey. From visual inspection of the charts with and without the outliers, it is clear that the points identified in this study are most likely to be due to transcription errors. The excluded points do not therefore raise any concerns about the accuracy with which gestational age is measured.
Other factors are known to have a significant effect on birthweight and a number of customised charts have been developed in recent years. It can be desirable to take into account physiological factors such as the height of the mother which contribute to the natural variation in birthweights but not potential risk factors such as whether or not the mother smokes. The distinction between the two types of factor may not always be clear cut however. For example height and weight of the mother may in part be determined by risk factors such as social deprivation or nutrition. There is therefore an important role in epidemiological studies into adverse perinatal outcomes for charts such as the ones described here which will allow both the effect of infant's size and the size of the mother to be separated.

Conclusion

The differences shown between the new centiles and the current published centiles confirm the need to have centiles appropriate for the population for which the charts are to be used. Use of inappropriate centiles may result either in small-for-dates babies not being identified or too many babies being flagged as small-for-dates. After consistent increases in mean birthweight from 1980 until the mid 1990s, mean birthweight has stabilised over recent years making the new charts appropriate for current use. It is however important that the distribution of birthweight continues to be monitored on a regular basis.

Acknowledgements

This work was funded by the Chief Scientists Office. We thank Edmund Hey for his contribution and valuable comments. Dr. Gray is funded by a core grant from the Department of Health in England to the National Perinatal Epidemiology Unit. The views expressed in this paper are those of the authors and do not necessarily reflect the views of the Department of Health.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

SRB and CW carried out the statistical analysis. All authors were co-investigators on the CSO grant and contributed to the initiation of the project and subsequent discussion. All authors have read and approved the final manuscript.
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Metadaten
Titel
Centile charts for birthweight for gestational age for Scottish singleton births
verfasst von
Sandra Bonellie
James Chalmers
Ron Gray
Ian Greer
Stephen Jarvis
Claire Williams
Publikationsdatum
01.12.2008
Verlag
BioMed Central
Erschienen in
BMC Pregnancy and Childbirth / Ausgabe 1/2008
Elektronische ISSN: 1471-2393
DOI
https://doi.org/10.1186/1471-2393-8-5

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