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Keywords:

  • gender differences;
  • head circumference;
  • intrauterine growth;
  • ultrasound screening

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Objective

Female fetuses, on average, weigh less than male fetuses at all gestational ages. The purpose of this study was to compare female and male fetuses in terms of intrauterine ultrasound growth measurements and to develop gestational-age-related charts based on a computerized perinatal database.

Methods

This was a retrospective study of unselected women in the second and third trimesters of pregnancy, who had a normal scan at 10–14 weeks. Data analysis was performed using measurements obtained from a mixed-race population of 4234 women, who underwent 5198 ultrasound examinations. The scans were performed by four trained sonographers, according to a standardized protocol. Routine measurements included biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL). The main end-points were sex- and race-specific differences in fetal biometry, which were also used to estimate fetal weight.

Results

The base-line demographic characteristics and risk factors were comparable in female and male fetuses. Significant differences in fetal BPD, HC, AC and estimated fetal weight, but not FL, were seen between male and female fetuses. Centile charts for each of these variables were constructed for both male and female fetuses.

Conclusions

This study suggests that small but consistent sex-related differences in prenatal BPD, HC and AC measurements are established by as early as 15 weeks of gestation. The use of sex-specific nomograms may improve the prenatal assessment of fetal growth as well as the diagnosis of structural abnormalities. Copyright © 2004 ISUOG. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Sonography has transformed the antenatal care of pregnant women and it is regarded as a well-established method of dating the pregnancy1 and monitoring fetal growth2. Ultrasound measurements of biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL) are used to evaluate fetal growth and estimate fetal weight. Several authors have provided practical standards relating these measured values to gestational age3–6, and these are widely used to monitor fetal growth. Other authors have attempted to adjust these tables and equations for physiological variables, such as maternal weight, parental height, ethnic group and parity, and have provided customized antenatal growth charts7. Whilst it is clearly established that birth weight and HC are significantly larger in boys than in girls born both at full term8, 9 and prematurely10, the standard ultrasound reference ranges are not sex-specific.

The aim of this study was to determine potential antenatal gender-related differences in the ultrasound measurements of BPD, HC, AC and FL in uncomplicated singleton pregnancies, the gestational age of which had been confirmed by early ultrasound. We provide sex-specific reference ranges between 15 and 40 weeks of gestation. All measurements were made using standardized methodology, and the data were from a single study, in which interobserver differences were known to be small.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

This was a retrospective study of unselected women in the second and third trimesters of pregnancy. Patients booking for antenatal care in our unit between November 1996 and April 1998 were enrolled into the study. All had a fetal ultrasound examination at 10 to 14 weeks' gestation, confirming a normal singleton pregnancy. All women had an expected date of delivery estimated from the date of their last menstrual period. When this differed by more than 7 days from the due date provided by the 10–14-week scan, gestational age was corrected. The second-trimester fetal anomaly scan and subsequent second- and third-trimester follow-up scans were performed transabdominally by four trained sonographers and all measurements were made using electronic calipers. Routine measurements included BPD (distance from the proximal outer table to the distal outer table of the skull at the level of the thalamus)11, HC (measurement around the calvarium excluding soft tissues)11, lateral cerebral ventricle/hemisphere ratio (V/H ratio), transcerebellar diameter (TCD)11, cisterna magna (CM)11, AC11 and FL11. Reasons for rescanning included: (i) incomplete anatomical check list; (ii) notch(es) in the color Doppler waveform of the uterine arteries; (iii) low-lying placenta (<10 mm clear from the internal os); (iv) a previous history of pre-eclampsia and/or fetal growth restriction or previous fetal abnormality. Pregnancies complicated by signs of fetal abnormalities, oligo- or polyhydramnios, fetal growth restriction or abnormal fetal Doppler measurements were excluded from the study. Pregnancy outcome was obtained from analysis of specifically designed outcome questionnaires and outcome of the newborns from a neonatologist.

Age-related centile charts were calculated using the method of Altman12: the mean HC was modeled by regression against gestational age. The differences between the observed HC and the predicted mean for that age were then calculated. Provided the differences for a given age follow a normal distribution with mean zero, the absolute values of these differences will follow a half normal distribution, whose mean is a simple multiple of the SD of the differences. Regression of absolute difference against age thus enabled us to predict the SD from gestational age. Hence, we obtained the mean and SD of HC as a function of gestational age. Centlie charts were then calculated using the centiles of the normal distribution. The assumption of normal distribution can be checked graphically: the mean must be zero using this method of calculation of the differences. Regressions were performed using the fractional polynomial method of Royston and Altman13, which allows a great variety of curves to be fitted economically. Analyses were carried out using Stata 5.0 (Stata Corporation, College Station, TX, USA). Fetal weight was estimated using the Hadlock formula14.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

A total number of 4876 women were enrolled into the study. In 68 (1.4%) women the pregnancy was complicated by fetal or maternal abnormalities and in 12 (0.25%) cases intrauterine death was diagnosed at the time of scanning. These women were excluded from the study. The initial study population therefore comprised 4796 women, of whom 562 (11.7%) were lost to follow-up. Subsequent analyses were therefore performed on 4234 women, who underwent 5198 ultrasound examinations, with 948 of them having two or more examinations. The study group consisted of a mixed-raced population with Caucasians accounting for 48%, Asians for 20%, black Africans 17% and black Caribbeans 15% of the population. Race was categorized according to the race of the mother. The base-line demographic characteristics and risk factors in the study group were in accordance with a low-risk population.

The distribution of HC at each gestational age appeared to be normal. Figure 1 shows histograms for 20, 26, 32 and 37 weeks. These were chosen because there were fairly large numbers of observations at these times and to give an indication of change with gestational age.

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Figure 1. Distribution of fetal head circumference at four gestational ages.

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To test whether there was evidence of a difference in HC between the sexes, HC data were first log transformed. The log transformation was required as the SD of HC measurements clearly increased with increasing fetal size. Multiple regression of log HC against sex and fetal age was carried out, the terms for fetal age being fitted using the fractional polynomial method. The effect of sex was estimated to be 0.0162 (SE, 0.0011; 95% CI, 0.0140–0.0184; P < 0.001). This transforms back to a male : female ratio of 1.016 (95% CI, 1.014–1.019). The effect is small, but highly significant and well-estimated. The corresponding estimates for BPD, AC, and FL are shown in Table 1. There were highly significant effects for BPD and AC, but no evidence of any sex effect for FL. We therefore proceeded to estimate fetal age charts for boys and girls separately for HC, BPD and AC.

Table 1. Male : female (M : F) ratio for head circumference (HC), biparietal diameter (BPD), abdominal circumference (AC), femur length (FL) and estimated fetal weight (EFW) after adjustment for fetal age
 Log M : F ratiotP95% CIM : F ratio
RatioSERatio95% CI
HC0.01620.001114.6< 0.0010.0140 to 0.01841.0161.014 to 1.019
BPD0.01780.001313.8< 0.0010.0153 to 0.02031.0181.015 to 1.021
AC0.01470.00178.7< 0.0010.0114 to 0.01811.0151.011 to 1.018
FL0.00010.00140.01.0− 0.0026 to 0.00281.0000.997 to 1.003
EFW0.03060.00368.6< 0.0010.0236 to 0.03761.0311.024 to 1.038

Figure 2 shows the individual data for HC in males with the centiles fitted; the fit appears to be good. 5.3% of HCs were below the estimated 5th centile and 4.7% were above the 95th centile. Figures 3–6 show the charts for both sexes for HC, BPD, AC and estimated fetal weight.

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Figure 2. Head circumference of males fetuses only plotted against gestational age with centiles fitted.

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Figure 3. Sex-specific centile charts for head circumference. ----, females; ——, males.

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Figure 4. Sex-specific centile charts for biparietal diameter. ----, females; ——, males.

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Figure 5. Sex-specific centile charts for abdominal circumference. ----, females; ——, males.

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Figure 6. Sex-specific centile charts for estimated fetal weight. ----, females; ——, males.

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The male : female ratio on the log and natural scales is shown in Table 1 and details of the regression equations are given in Table 2. Tables 3 to 6 give the mean and SD values of HC, BPD, AC and estimated fetal weight for each sex and at week of gestational age.

Table 2. Regression equation
 VariableCoefficient
Loge head circumference, females
 MeanConstant5.092
g−2− 148.9
g20.001632
g3− 0.00002838
 SDConstant0.03593
g0.00008949
Loge head circumference, males
 MeanConstant− 0.1274
ln(g)1.832
g20.0005069
 SDConstant0.03806
g0.00004988
Loge biparietal diameter, females
 MeanConstant3.400
g−2− 98.52
g20.006263
g2ln(g)− 0.001492
 SDConstant0.04595
g− 0.00005778
Loge biparietal diameter, males
 MeanConstant− 0.6894
ln(g)1.546
g3− 0.000006955
 SDConstant0.05651
g− 0.0003933
Loge abdominal circumference, females
 MeanConstant5.168
g−2− 176.8
g30.0001280
g3ln(g)− 0.00003144
 SDConstant0.04311
g0.0005919
Loge abdominal circumference, males
 MeanConstant− 0.7233
ln(g)2.123
g− 0.03132
 SDConstant0.04024
g0.0007446
Log10 estimated fetal weight, females
 MeanConstant3.011
g−1− 16.97
g30.0001711
g3ln(g)− 0.00004243
 SDConstant0.02181
g0.001112
Log10 estimated fetal weight, males
 MeanConstant6.120
g−0.5− 16.09
 SDConstant0.02023
g0.0008859
Table 3. Mean and SD of head circumference (HC) in female and male fetuses at each week of gestation
Female HCMale HC
GA (weeks)Mean (mm)SD (mm)Frequency (n)GA (weeks)Mean (mm)SD (mm)Frequency (n)
  1. GA, gestational age.

15114.603.72  10  15116.734.15  10
16128.326.37  13  16128.558.62  17
17139.565.40  24  17142.976.72  17
18153.357.25  73  18155.626.84  81
19167.967.57  77  19169.288.93  65
20176.907.55 454  20179.777.20 486
21187.257.79 222  21190.388.52 260
22199.248.39 178  22201.498.68 185
23209.128.56  53  23214.869.51  51
24221.9910.42  79  24227.979.73  87
25231.567.77  35  25241.248.64  42
26243.5411.18  32  26247.767.99  49
27255.4910.46  39  27260.1112.68  41
28263.4210.52  85  28270.2911.12  89
29275.5412.02  40  29281.5312.42  65
30282.9714.16  61  30290.2910.52  61
31291.2012.78  70  31296.0312.15  81
32300.139.74 149  32302.8011.67 134
33305.5812.09 110  33308.7811.93 109
34312.1711.34 198  34315.4712.34 190
35315.2613.51 111  35320.6213.70 119
36321.5813.10 122  36326.9412.42 146
37324.5513.81 108  37331.0812.99 102
38327.2312.62  81  38334.7214.77  69
39330.9411.33  42  39335.5413.28  33
Total2466Total2589
Table 4. Mean and SD of biparietal diameter (BPD) in female and male fetuses at each week of gestation
Female BPDMale BPD
GA (weeks)Mean (mm)SD (mm)Frequency (n)GA (weeks)Mean (mm)SD (mm)Frequency (n)
  1. GA, gestational age.

1533.111.63  16  1533.202.42  17
1636.421.92  15  1636.532.95  27
1739.651.88  24  1739.791.48  18
1842.882.06  75  1844.012.01  84
1946.992.45  77  1947.552.91  66
2049.312.44 457  2050.322.43 486
2152.482.53 221  2153.062.78 259
2255.432.72 178  2256.282.81 185
2358.442.95  52  2359.672.96  51
2462.303.26  79  2463.443.29  87
2564.232.75  35  2567.432.98  42
2667.633.95  31  2668.993.08  49
2771.653.64  39  2772.924.39  41
2873.703.89  84  2875.963.32  88
2976.833.70  40  2978.764.73  66
3079.714.36  61  3081.773.51  61
3181.593.99  70  3183.913.60  80
3284.453.28 149  3285.803.37 134
3386.423.63 109  3388.033.76 109
3488.383.64 197  3489.623.77 189
3589.954.52 111  3590.914.06 119
3691.403.83 122  3692.793.74 146
3792.493.96 108  3794.343.93 102
3893.224.03  81  3895.974.23  69
3995.353.66  42  3996.053.98  33
Total2473Total2608
Table 5. Mean and SD of abdominal circumference (AC) in female and male fetuses at each week of gestation
Female ACMale AC
GA (weeks)Mean (mm)SD (mm)Frequency (n)GA (weeks)Mean (mm)SD (mm)Frequency (n)
  1. GA, gestational age.

1597.295.89   9  1597.594.43   9
16109.926.24  12  16109.266.67  17
17118.796.32  24  17121.715.31  18
18130.478.96  73  18132.367.27  84
19144.489.12  77  19146.509.45  65
20152.998.97 451  20155.858.98 482
21162.819.08 221  21165.499.58 258
22174.139.92 176  22174.5110.45 184
23183.0710.97  53  23188.7210.25  51
24193.8913.47  78  24200.0613.09  87
25205.5210.26  35  25212.879.86  42
26217.5517.54  32  26218.5511.94  49
27228.0517.29  39  27234.1215.94  40
28237.6416.95  85  28243.4713.72  89
29248.4417.28  40  29255.3416.61  65
30259.2417.44  61  30265.5812.51  61
31272.3216.90  70  31273.2316.96  81
32281.3814.39 149  32283.0815.89 134
33291.4519.07 110  33293.8218.75 109
34300.4717.57 197  34303.3619.31 190
35308.4421.59 111  35311.9622.68 119
36317.6722.30 122  36323.4823.89 146
37324.3120.84 108  37328.4825.16 102
38332.1624.23  81  38336.1324.81  69
39344.5920.69  48  39340.6621.02  53
Total2462Total2604
Table 6. Mean and SD of estimated fetal weight (EFW) in female and male fetuses at each week of gestation
Female EFWMale EFW
GA (weeks)Mean (g)SD (g)Frequency (n)GA (weeks)Mean (g)SD (g)Frequency (n)
  1. GA, gestational age.

15 129 10   8  15 132 10   9
16 164 18  11  16 159 20  15
17 195 21  23  17 202 18  17
18 244 31  71  18 249 24  80
19 312 38  76  19 317 40  64
20 356 41 445  20 366 40 480
21 419 47 218  21 429 52 255
22 497 60 172  22 500 62 183
23 572 71  52  23 613 71  51
24 686109  78  24 727104  87
25 792 82  35  25 854 89  42
26 926141  30  26 935110  49
271065166  39  271137199  39
281215192  83  281289186  87
291395217  40  291478229  65
301585260  61  301655181  61
311796259  70  311830274  80
321975228 147  322016249 134
332192317 109  332243322 109
342385305 196  342468324 188
352583404 110  352661441 118
362798441 122  362938471 146
372959433 107  373085529 102
383175480  81  383290559  69
393258433  42  393443486  33
Total2426Total2563

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Birth weight is a useful indicator of health, which reflects the normality of the pregnancy and is correlated with infant morbidity and mortality. It is well known that female fetuses, on average, weigh less than do male fetuses at all gestational ages15. There is a discrepancy in length and HC at birth between boys and girls, although placental weight is not biased by the sex of the newborn. It has therefore been argued that the anthropometric differences at birth are caused by expression of a sexual bias in metabolism and physiology in the fetus. The speculations arising from this are supported by the experimental manipulation of the sex ratio in animals by maternal nutrition16 and data suggesting an impact of maternal nutritional status on the sex ratio at birth in humans17. These data imply that the sex of the fetus itself is independently responsible for the gender differences in fetal growth rates rather than the responsibility lying with the capacity of the maternal system to feed the fetus. For the fetal sex to be a determinant of the pregnancy in terms of weight, length and HC, it seems to be necessary for this sex difference to be expressed at an early stage, especially as the development of the head is an early feature of fetal development. The male/female difference in birth weight is an example of biologically based variation because all other factors affecting birth weight and survival are equally distributed among males and females. For instance, amongst all liveborn, full-term, singleton infants born in the United States of America, on average, white male infants are 135 g heavier than are white female infants, and black male infants are 125 g heavier than are black female infants15. As there are no obvious reasons, other than biologically based determinants, that can explain this sex difference, it seems likely that this difference is already established prenatally. Earlier studies demonstrated that male fetuses have significantly larger BPDs compared with females in the second trimester18 and Moore et al.19 described a significant difference in head growth trajectories between male and female fetuses in a small group (n = 108) of normal pregnancies. They considered this to be a relevant cause of error in dating pregnancies by fetal BPD measurement. Parker et al.20 studied 96 pregnant European women with uncomplicated pregnancies from 16 weeks onwards and found a slower rate of growth in female fetuses compared with male fetuses. This difference became statistically significant by 28 weeks of gestation and increased towards term. Empirically, there are significant birth-weight variations among race and ethnic groups21 and FL has been reported to be significantly greater in black fetuses than it is in white fetuses22.

In a racially mixed population with different socioeconomic characteristics we were able to detect small but consistent sex differences in BPD, HC and AC with male fetuses being larger from as early as 15 weeks of gestation. The impact of these findings on the sonographic estimation of gestational age in an individual pregnancy is not great, but in a large population, a small shift in the gestational age distribution might significantly affect rates of prematurity, intrauterine growth restriction and postdatism23. Furthermore, in a variety of high-risk pregnancies complicated by processes affecting the developing fetus, such as intrauterine infection, fetal irradiation or maternal alcoholism, sex-specific growth charts may facilitate the monitoring of intrauterine growth. The prenatal diagnosis of microcephaly, which largely depends on accurate fetal head and brain measurements, remains an ongoing challenge to the sonographer. As demonstrated in a recent case of genetic microcephaly24, the additional use of sex-specific growth charts may make a fall in the growth velocity obvious at an earlier stage, potentially reducing the rate of false-negative diagnoses in these cases.

In conclusion, our data suggest that the use of sex-specific nomograms may improve the prenatal assessment of fetal growth and might provide valuable additional information in high-risk cases.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References