Ultrasound estimation of gestational age in late pregnancy in low-income countries: made to measure or off-the-peg?
Authors: Gordon CS Smith, Annettee Nakimuli
Journal: The Lancet Global Health (2020)

Gestational age is one of the most important features of a pregnancy when making clinical decisions. In particular, the management of delivery, such as the timing of a caesarean section before labour or when to induce labour, is crucially informed by knowledge of gestational age. Overestimation of gestational age could lead to iatrogenic premature birth, whereas underestimation of gestational age could increase the risk of post-term stillbirth. Consequently, most pregnant women in high-income countries are offered an ultrasound scan at the end of the first trimester, when gestational age can most accurately be assessed by measuring the crown-rump length (CRL). Delivering this service necessitates women being identified as pregnant at an early stage and being appropriately referred, and that ultrasound is available to all pregnant women in the first trimester. Obstacles to the delivery of this service include geographical, economical, and societal issues, and the capacity of health-care services. These obstacles are common and frequently coexist in low-income countries. Consequently, many women will present for clinical care in late pregnancy and without having undergone gestational age dating by ultrasound in the first half of pregnancy. For example, one study showed that only 29% of women in Uganda had their first antenatal care visit during the first trimester.1UBOS and ICF Uganda Demographic and Health Survey 2016. Uganda Bureau of Statistics and International Classification of Functioning, Disability and Health, Kampala, Uganda and Rockville MD, USA2018Google Scholar Given its fundamental importance in clinical decision making, attempts to estimate gestational age have to be made when gestational age dating in early pregnancy has not been done. Sometimes, attempts to estimate gestational age in late pregnancy can be made without imaging modalities, for instance, by obtaining a reliable menstrual history. However, in many cases, such information is absent, and a best guess of gestational age is attempted with a late pregnancy ultrasound, despite knowing that these estimates will be much less accurate than those from a first trimester ultrasound. The widespread use of injectable depot medroxyprogesterone acetate as a contraceptive in low-income countries also contributes to the uncertainty of the menstrual history, as amenorrhoea is a commonly associated side-effect of this drug. The aim of the study by the WHO Alliance for Maternal and Newborn Health Improvement (AMANHI) late pregnancy dating study group,2The WHO Alliance for Maternal and Newborn Health Improvement late pregnancy dating study groupPerformance of a late pregnancy biometry for gestational age dating in low-income and middle-income countries: a prospective, multicountry, population-based cohort study from the WHO Alliance for Naternal Newborn Health Improvement (AMANHI) study group.Lancet Glob Health. 2020; 8: e545-e554Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar published in The Lancet Global Health, was to prospectively evaluate and improve the accuracy of the ultrasound scan in estimating gestational age in late pregnancy (ie, after 24 weeks' gestation) in low-income and middle-income countries (LMICs). This study,2The WHO Alliance for Maternal and Newborn Health Improvement late pregnancy dating study groupPerformance of a late pregnancy biometry for gestational age dating in low-income and middle-income countries: a prospective, multicountry, population-based cohort study from the WHO Alliance for Naternal Newborn Health Improvement (AMANHI) study group.Lancet Glob Health. 2020; 8: e545-e554Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar which had many strengths in its design, recruited a large number of pregnant women from Bangladesh, Pakistan, and Tanzania, and quantified the accuracy of gestational age estimates from late pregnancy ultrasound scans (in which standard fetal biometry measurements and transcerebellar diameter measurements were taken) when compared with the gold-standard first trimester CRL measurement of gestational age. Subsequent modelling analyses were done to identify improved gestational age prediction formulas for third trimester ultrasonography in these settings. One of the remarkable findings of the analysis was how well existing ultrasound biometry formulas, which were derived in high-income settings performed. The Hadlock formula,3Hadlock FP Deter RL Harrist RB Park SK Estimating fetal age: computer-assisted analysis of multiple fetal growth parameters.Radiology. 1984; 152: 497-501Crossref PubMed Scopus (412) Google Scholar which was derived in a study done in Texas (USA) in the early 1980s involving a population of 361 pregnant women scanned between 14 and 42 weeks' gestation, estimated gestational age to within 1 day of the novel AMANHI parsimonious combination formula at ultrasound scans done at 24+0−29+6 weeks' gestation. Notably, the Hadlock formula3Hadlock FP Deter RL Harrist RB Park SK Estimating fetal age: computer-assisted analysis of multiple fetal growth parameters.Radiology. 1984; 152: 497-501Crossref PubMed Scopus (412) Google Scholar also showed similar limits of agreement to the INTERGROWTH-21st formula.2The WHO Alliance for Maternal and Newborn Health Improvement late pregnancy dating study groupPerformance of a late pregnancy biometry for gestational age dating in low-income and middle-income countries: a prospective, multicountry, population-based cohort study from the WHO Alliance for Naternal Newborn Health Improvement (AMANHI) study group.Lancet Glob Health. 2020; 8: e545-e554Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 4Papageorghiou AT Kemp B Stones W et al.Ultrasound-based gestational-age estimation in late pregnancy.Ultrasound Obstet Gynecol. 2016; 48: 719-726Crossref PubMed Scopus (89) Google Scholar This result is surprising, given that the INTERGROWTH-21st study was a huge multinational effort with a complex and purposeful sampling protocol. However, there was evidence that the calibration of the Hadlock formula3Hadlock FP Deter RL Harrist RB Park SK Estimating fetal age: computer-assisted analysis of multiple fetal growth parameters.Radiology. 1984; 152: 497-501Crossref PubMed Scopus (412) Google Scholar was imperfect for the AMANHI setting. The Hadlock formula3Hadlock FP Deter RL Harrist RB Park SK Estimating fetal age: computer-assisted analysis of multiple fetal growth parameters.Radiology. 1984; 152: 497-501Crossref PubMed Scopus (412) Google Scholar tended to systematically underestimate gestational age. This degree of underestimation was greater at the ultrasound scans done at 30+0−36+6 weeks' gestation and among infants who were ultimately born small-for-gestational-age. A plausible explanation for this observed pattern is that a greater proportion of women in the AMANHI study population had late-onset fetal growth restriction. Therefore, infants born in LMICs in the AMANHI study2The WHO Alliance for Maternal and Newborn Health Improvement late pregnancy dating study groupPerformance of a late pregnancy biometry for gestational age dating in low-income and middle-income countries: a prospective, multicountry, population-based cohort study from the WHO Alliance for Naternal Newborn Health Improvement (AMANHI) study group.Lancet Glob Health. 2020; 8: e545-e554Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar were smaller than expected on the basis of the Hadlock formula.3Hadlock FP Deter RL Harrist RB Park SK Estimating fetal age: computer-assisted analysis of multiple fetal growth parameters.Radiology. 1984; 152: 497-501Crossref PubMed Scopus (412) Google Scholar Analysis of individual ultrasound parameters showed that transcerebellar diameter and head circumference did not systematically underestimate gestational age, even when reference ranges derived from high-income countries were used. This observation probably reflects the fetal adaptive response of so-called, brain sparing, which prioritises the cerebral circulation (among some other organs) during periods of acute and chronic stress.5Giussani DA The fetal brain sparing response to hypoxia: physiological mechanisms.J Physiol. 2016; 594: 1215-1230Crossref PubMed Scopus (201) Google Scholar Compared with the other combination formulas, the novel AMANHI parsimonious combination formula showed the highest degree of agreement with crown-rump length measurements for estimating gestational age. However, one weakness of this formula is that it was tested on the same population from which it was derived. This can lead to an overly optimistic assessment of accuracy because of model overfitting. Although the researchers used cross-validation to address this issue, they did not use a method for optimism adjustment that included at least 200 repetitions, which is recommended.6Smith GC Seaman SR Wood AM Royston P White IR Correcting for optimistic prediction in small data sets.Am J Epidemiol. 2014; 180: 318-324Crossref PubMed Scopus (221) Google Scholar In addition, the external validity of the model depends on it being applied to a similar population of pregnant women. The model was fitted to best describe the associations within that study population, and it might be less well calibrated when used in other LMIC populations with different characteristics. Therefore, the finding that the novel AMANHI formula outperformed the Hadlock formula2The WHO Alliance for Maternal and Newborn Health Improvement late pregnancy dating study groupPerformance of a late pregnancy biometry for gestational age dating in low-income and middle-income countries: a prospective, multicountry, population-based cohort study from the WHO Alliance for Naternal Newborn Health Improvement (AMANHI) study group.Lancet Glob Health. 2020; 8: e545-e554Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar and INTERGROWTH-21st formula4Papageorghiou AT Kemp B Stones W et al.Ultrasound-based gestational-age estimation in late pregnancy.Ultrasound Obstet Gynecol. 2016; 48: 719-726Crossref PubMed Scopus (89) Google Scholar should ideally be validated in other populations. So, what should happen next? Implementation of the novel AMANHI formula might be somewhat premature, given the aforementioned issues. However, one approach could be to abandon the use of combination formulas altogether and use the TCD as a single parameter for estimating gestational age from 24 weeks' gestation onwards. This parameter did not systematically underestimate gestational age, even in infants ultimately born small-for-gestational-age. Additionally, compared with the Hadlock formula3Hadlock FP Deter RL Harrist RB Park SK Estimating fetal age: computer-assisted analysis of multiple fetal growth parameters.Radiology. 1984; 152: 497-501Crossref PubMed Scopus (412) Google Scholar and INTERGROWTH-21st formula,4Papageorghiou AT Kemp B Stones W et al.Ultrasound-based gestational-age estimation in late pregnancy.Ultrasound Obstet Gynecol. 2016; 48: 719-726Crossref PubMed Scopus (89) Google Scholar the TCD was only slightly less accurate in estimating gestational age at 24+0 to 29+6 weeks' gestation and was slightly more accurate at 30+0 to 36+6 weeks' gestation. GCSS reports grants from GlaxoSmithKline Research and Development and Sera Prognostics, personal fees from Roche Diagnostics and GlaxoSmithKline, and non-financial support from Illumina and Roche Diagnostics, outside the submitted work. GCSS is one of three named co-inventors of a pending UK patent for a method to determine risk of fetal size abnormalities. AN declares no competing interests. Performance of late pregnancy biometry for gestational age dating in low-income and middle-income countries: a prospective, multicountry, population-based cohort study from the WHO Alliance for Maternal and Newborn Health Improvement (AMANHI) Study GroupIncorporation of TCD and the use of new formulas in late pregnancy ultrasound scans could improve the accuracy of gestational age estimation in both appropriate-for-gestational-age and small-for-gestational-age infants in LMICs. Given the high rates of small-for-gestational-age infants in LMICs, these results might be especially relevant. Validation of this new formula in other LMIC populations is needed to establish whether the accuracy of the late pregnancy ultrasound can be narrowed to within approximately 2 weeks. Full-Text PDF Open Access