Fetal growth standards: the NICHD fetal growth study approach in context with INTERGROWTH-21st and the World Health Organization Multicentre Growth Reference Study

Abstract

Three recently completed longitudinal cohort studies have developed intrauterine fetal growth charts, one in the United States and two international. This expert review compares and contrasts the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies, INTERGROWTH-21st and World Health Organization Multicentre Growth Reference Study conclusions in light of differences in aims, sampling frames, and analytical approaches. An area of controversy is whether a single growth reference is representative of growth, regardless of ethnic or country origin. The INTERGROWTH and World Health Organization Fetal studies used a similar approach as the World Health Organization Multicentre Growth Reference Study for infants and children, the aim of which was to create a single international reference for the best physiological growth for children aged 0-5 years. INTERGROWTH made the same assumption (ie, that there would be no differences internationally among countries or racial/ethnic groups in fetal growth when conditions were optimal). INTERGROWTH found differences in crown-rump length and head circumference among countries but interpreted the differences as not meaningful and presented a pooled standard. The World Health Organization Multicentre Growth Reference Study was designed to create a pooled reference, although they evaluated for and presented country differences, along with discussion of the implications. The Eunice Kennedy Shriver National Institute of Child Health and Human Development Study was designed to assess whether racial/ethnic-specific fetal growth standards were needed, in recognition of the fact that fetal size is commonly estimated from dimensions (head circumference, abdominal circumference, and femur length) in which there are known differences in children and adults of differing racial/ethnic groups. A pooled standard would be derived if no racial/ethnic differences were found. Highly statistically significant racial/ethnic differences in fetal growth were found resulting in the publication of racial/ethnic-specific derived standards. Despite all 3 studies including low-risk status women, the percentiles for fetal dimensions and estimated fetal weight varied among the studies. Specifically, at 39 weeks, the 50th percentile for estimated fetal weight was 3502 g for whites, 3330 g for Hispanics, 3263 g for Asians, and 3256 for blacks in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Study, compared with 3186 g for INTERGROWTH and 3403 g for World Health Organization Multicentre Growth Reference Study. When applying these standards to a clinical population, it is important to be aware that different percentages of small- and large-for-gestational-age fetuses will be identified. Also, it may be necessary to use more restrictive cut points, such as the 2.5th or 97.5th, for small-for-gestational-age or large-for-gestational-age fetuses, respectively. Ideally, a comparison of diagnostic accuracy, or misclassification rates, of small-for-gestational-age and large-for-gestational-age fetuses in relation to morbidity and mortality using different criteria is necessary to make recommendations and remains an important data gap. Identification of the appropriate percentile cutoffs in relation to neonatal morbidity and mortality is needed in local populations, depending on which fetal growth chart is used. On a final point, assessment of fetal growth with a one-time measurement remains standard clinical practice, despite recognition that a single measurement can indicate only size. Ultimately, it is knowledge about fetal growth in addition to other factors and clinical judgment that should trigger intervention.

Trial registration: ClinicalTrials.gov NCT00912132.

Keywords: estimated fetal weight; fetal growth; small for gestational age; ultrasound reference; ultrasound standard.

Figure 1. Cohort profiles for the three studies

Legend: Main differences among the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies^, , INTERGROWTH-21^st (INTERGROWTH)^, , and World Health Organization Multicentre Growth Reference Study (WHO Fetal).^, NICHD and WHO Fetal calculated EFW from HC, AC and FL using the Hadlock 1985 formula, while INTERGROWTH created a new formula based on only HC and AC.

Figure 2. Estimated fetal weight comparison among the three studies

Legend: Distribution of estimated fetal weight (EFW) by race/ethnicity and gestation, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Study – Singletons, INTERGROWTH-21^st and World Health Organization Multicentre Growth Reference Study (WHO Fetal) for 24 to 40 weeks of gestation (panel a) and 36 to 40 weeks of gestation (panel b). Estimated 3^rd, 50^th, and 97^th percentiles for fetal weight by study; note that values are the 2.5^th and 97.5^th for the WHO Fetal Study. Also, NICHD and WHO Fetal calculated EFW from HC, AC and FL using the Hadlock 1985 formula, while INTERGROWTH created a new formula based on only HC and AC.

Figure 3. Head circumference comparison among the three studies

Legend: Distribution of head circumference, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Study – Singletons, INTERGROWTH-21^st and World Health Organization (WHO Fetal). Estimated 5^th, 50^th, and 95^th percentiles for head circumference by race/ethnicity and gestation, and study.

Figure 4. Abdominal circumference comparison among the three studies

Legend: Distribution of head circumference, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Study – Singletons, INTERGROWTH-21^st and World Health Organization (WHO Fetal). Estimated 5^th, 50^th, and 95^th percentiles for abdominal circumference by race/ethnicity and gestation, and study.

Figure 5. Femur length comparison among the three studies

Legend: Distribution of head circumference, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Study – Singletons, INTERGROWTH-21^st and World Health Organization (WHO Fetal). Estimated 5^th, 50^th, and 95^th percentiles for femur length by race/ethnicity and gestation, and study.

Figure 6. Comparison of estimated fetal weight formulas

Using the NICHD Fetal Growth Study – Singleton standard data, we compared the two estimated fetal weight (EFW) formulas calculated using the Hadlock 1991 formula from HC, AC and FL (add ref) and IG-21 formula based on HC and AC (add ref). EFW was calculated using the Hadlock formula: Log₁₀ weight = 1.326 − 0.00326 AC × FL + 0.0107 HC + 0.0438 AC + 0.158 FL and INTERGROWTH-21^st formula: Log(EFW) = 5.084820 − 54.06633×(AC/100)³ − 95.80076×(AC/100)³×log(AC/100) + 3.136370 ×(HC/100), and plotted across gestation.

Figure 7. Estimated fetal weight comparison between NICHD and Hadlock 1991

Legend: Distribution of estimated fetal weight (EFW) by race/ethnicity and gestation, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Study – Singletons, and Hadlock 1991 (add ref) for 24 to 40 weeks of gestation (panel a) and 36 to 40 weeks of gestation (panel b). Estimated 3^rd, 50^th, and 97^th percentiles for fetal weight by study.