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• W1993552120 abstract "That was the parting farewell wish in the graduation card given to me by one of my professors on completing fellowship training more than 20 years ago. If only he had known! The fate of a short femur length has certainly taken various twists and turns since my fellowship year. Two papers in this issue of the Journal continue to expand our knowledge of short femur length, while at the same time touch on a number of related issues of fetal abnormalities, abnormal biochemistry, the potential value of uterine artery Doppler and prediction of adverse outcome1, 2. A short femur length is seen most commonly in normal fetuses and it is natural to assume that ethnicity or parental height might influence this. Even during the time of my residency and fellowship, when performing obstetric ultrasound in a racially diverse city such as San Francisco, it was apparent that shorter femur lengths were more likely among certain ethnic groups, particularly Asians. Studies have confirmed that fetuses of Asian mothers have shorter femurs and those of black mothers have longer femurs compared with fetuses of white mothers3. These ethnic differences were not confirmed by the current study of Weisz et al.2 and it is possible that other factors, such as maternal and paternal height, are more important than ethnicity alone in influencing fetal femur length4, 5. At the time of my fellowship, it was recognized only that a short femur may be seen with skeletal dysplasias. Certainly skeletal dysplasias are a concern when short femurs are identified, although from a practical perspective this is less of a diagnostic problem during the second trimester, especially if it is an isolated finding. If a serious skeletal dysplasia is present, the femur length is usually very short in the second trimester. Milder forms of skeletal dysplasia may present with slightly short femur length, but the most likely of these—heterozygous achondroplasia—is not usually apparent until after 20 weeks. Even in this situation and, even in the setting of advanced paternal age, as I personally experienced as a prospective parent of twins, a short femur length is more likely to be seen in a normal fetus. A slightly short femur length, and more so a short humerus length, were subsequently noted to increase to some extent the risk for fetal Down syndrome6, 7. Femur length correlates well with height and it is well known that patients with Down syndrome tend to be shorter than average, so this association was not unexpected. The risk of fetal Down syndrome with short femur length alone is small, with a likelihood ratio estimated at 1.5 when it is an isolated finding8. With incorporation of the nasal bone as part of a genetic sonogram, this risk may be even less. Therefore, other risk factors, such as those detected during first-trimester screening, are much more important than is short femur length for assessing the risk for fetal Down syndrome. Nevertheless, when a short femur is identified, it is important to search for additional findings that may indicate an underlying fetal abnormality. In the study by Papageorghiou et al.1, among fetuses with short femur length and additional abnormalities, over half (26 of 46) had skeletal dysplasias (n = 16) or fetal aneuploidy (n = 10). While this re-emphasizes the importance of fetal abnormalities in the setting of a short femur, there were no cases of fetal abnormalities when short femur was isolated, confirming the low risk when this is an isolated finding. By the early 1990s it had become apparent that some fetuses affected with growth restriction due to placental dysfunction can present primarily with a short femur length, in contrast to the more typical presentation of a disproportionately small abdominal circumference9, 10. This presentation was usually observed in the third or late second trimester. Accumulative experience suggested that a moderate to marked degree of femur shortening may be seen in some fetuses with growth restriction and the degree of reduced length overlaps with that observed in fetuses with skeletal dysplasias9-11. Even in fetuses with markedly short femur length (Z-score of − 4 or less), Papageorghiou et al.1 found that about half of those affected had growth restriction and half had skeletal dysplasia. The two studies published in this month's issue of the Journal contribute to our knowledge of short femur length in association with growth restriction and other placenta-related complications (hypertension, preterm delivery, placental abruption and fetal demise). What these two studies contribute is the concept that routine detection of short femur length during the second trimester can help to identify those fetuses at risk of subsequently developing growth restriction and other placenta-related complications. Furthermore, the studies indicate the importance of correlation with other variables, including pregnancy proteins and Doppler studies. These studies further support the idea that all pregnancies can be screened for placental-related adverse outcome at the time of a routine ultrasound examination. Weisz et al.2 found that isolated short femur observed during the second trimester helps to predict low birth weight and small-for-gestational age (SGA) fetuses. Similarly, Papageorghiou et al.1 found that, among 83 cases with isolated short femur length during the second trimester, severe growth restriction subsequently developed in 40% (n = 33). They defined severe growth restriction as an abdominal circumference below the 5th percentile, abnormal umbilical artery Doppler, and delivery before 37 weeks. Those pregnancies with severe growth restriction were also more likely to develop pre-eclampsia and result in intrauterine death; fetal demise occurred in a third of these cases. Papageorghiou et al.1 also found that the addition of uterine artery Doppler was more predictive of adverse outcome than was short femur alone. At the time of diagnosis and excluding false positives, over half (39 of 56 cases) of fetuses with short femur length had abnormal uterine artery Doppler, and there was abnormal uterine artery Doppler in 90% of those which subsequently developed severe growth restriction. The majority (27 of 39) of patients with this combination of findings had an adverse outcome. Also, an increased risk of hypertension and adverse outcome was noted among patients with abnormal uterine artery Doppler, even when subsequent umbilical artery Doppler was normal. While there were no cases of pre-eclampsia or placental abruption in those with normal uterine artery Doppler, others have found that short femur may be associated with SGA fetuses, despite normal uterine and umbilical artery Doppler12. These and other data confirm the importance of uterine artery Doppler in identifying patients at risk for developing pre-eclampsia and other adverse outcomes. We owe credit to Stuart Campbell and colleagues, who proposed this idea from pioneering work that began more than 20 years ago but which continues today13, 14. A number of other studies15-18 have now confirmed that abnormal uterine artery Doppler during the second as well as the first trimester can identify patients at risk for developing pre-eclampsia as well as other placenta-related adverse outcomes. Furthermore, uterine artery Doppler has been found to be more effective than maternal risk factors, including race, nulliparity, high body mass index and personal or family history of pre-eclampsia. Pre-eclampsia affects about 2% of pregnancies, but more severe disease requiring delivery before 34 weeks occurs in just 0.5% of pregnancies. Uterine artery Doppler suffers from low predictive values, but it has been found to be more effective in detecting those patients who develop more severe disease and who could benefit from earlier detection. Smith et al.18 also reported that abnormal uterine artery Doppler was a good predictor (sensitivity, 58%; specificity, 95%) of stillbirth up to 32 weeks but a poor predictor of later stillbirth (sensitivity, 7%). A number of other studies have also correlated adverse pregnancy outcome with abnormal levels of biochemical analytes. Low levels of pregnancy-associated plasma protein-A (PAPP-A) have been associated with an increased risk of fetal loss, growth restriction, preterm birth, pre-eclampsia and placental abruption. Furthermore, the risk increases inversely with the level of PAPP-A19-23. Weisz et al.2 found that short femur length is associated with low PAPP-A levels, consistent with other observations noting correlations between femur length and PAPP-A levels. PAPP-A has now been correlated closely with fetal growth, especially growth of long bones, in laboratory and clinical studies24-29. This is consistent with studies which suggest that PAPP-A represents a protein produced by human fibroblasts that helps activate an insulin-like growth factor (IGF). IGFs are required for normal prenatal and postnatal growth and can be modulated by a family of IGF binding proteins (IGFBPs) in a complicated and highly regulated system25-27. PAPP-A appears to increase specifically the activity of IGFBP-425. Other evidence from animal models suggests that PAPP-A is involved in the regulation of bone development27. As supportive evidence, maternal serum PAPP-A levels in the first trimester are associated with the length of fetal long bones22, 28, 29. Weisz et al.2 also found that isolated short femur length was highly associated with lower levels of PAPP-A but not with levels of other analytes. In another recent study, Peterson and Simhan22 found that first-trimester PAPP-A levels correlate well with birth weight, and suggest that this observation warrants further evaluation for possible screening. In the second trimester, elevated levels of alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG) and inhibin-A as well as decreased levels of estriol have been associated with adverse fetal outcome, including fetal loss30, 31. The risk appears to increase with the number of abnormal quad-screen markers, as well as the degree of deviation from normal. Weisz et al.2 found that the combination of a short femur length and early growth restriction, defined as an abdominal circumference below the 5th percentile, was associated with elevated AFP, β-hCG and inhibin-A, although the number of cases was small. Although many of the currently known associations between serum markers and adverse obstetric outcome are highly significant, the sensitivities, positive likelihood ratios and positive predictive values still tend to be low. Therefore, it would be reasonable to alter patient monitoring only for more marked deviations of analytes, or in combination with other analytes or risk factors or by combining both first- and second-trimester serum markers32-36. It has been suggested that further monitoring occur when PAPP-A levels are less than 0.3 multiples of the median (MoM), corresponding to the 1st percentile (the 5th percentile corresponds to 0.41 MoM.)37 Other management strategies include recommending increased surveillance for patients with inhibin-A > 2 MoM, or those with two or more abnormal quad screen markers. The cumulative data suggest that abnormal uterine artery Doppler combined with abnormal biochemical results is more predictive than is either one alone for identifying patients at high risk of adverse outcome including pre-eclampisa, fetal demise and placental abruption32-36. As noted by the two papers in this issue of the Journal, short femur length appears to be an additional risk factor, particularly when it is associated with a small abdominal circumference, for identifying fetuses which will develop growth restriction and suffer adverse outcome. It is likely that ultrasound, Doppler and biochemical values could be combined to develop a ‘risk profile’ for all patients, just as we now combine ultrasound findings and biochemical values to determine the risk of fetal aneuploidy. Indeed, a growing number of studies have combined ultrasound findings with biochemical results, suggesting that this strategy will prove to be effective in screening for pre-eclampsia and other adverse outcomes32-36. This may include a combination of first-trimester ultrasound (Doppler), second-trimester ultrasound including Doppler, and first-trimester and/or second-trimester biochemistry. In addition to the standard biochemical markers used for aneuploidy screening, a growing number of other markers have shown promise in screening for early pre-eclampsia and adverse outcome38-41. Again, these appear to be more effective when combined with Doppler studies. For example, ADAM12s has been found to be effective in the detection of pre-eclampsia and was even more effective when combined with uterine artery Doppler40. Similarly, maternal serum placental protein 13 (PP-13) may be useful in the first trimester for identification of patients at risk for adverse outcome, especially when combined with Doppler studies37, 41. Once we have more effective screening methods for identification of patients at risk for placenta-related complications, the major challenge is what can be done about it? In addition to closely monitoring these patients for development of pre-eclampsia and/or fetal growth restriction, it is likely that more effective treatment strategies will develop. Although antioxidants have not been proved to be useful42, a recent publication suggests that a significant reduction (nearly three-fold) in development of pre-eclampsia may result from administering multivitamins containing folic acid in the second trimester43. This and other treatment strategies deserve further study. Returning to my farewell wish, we know that not all of our femur lengths will be long, but at least we now have a better idea of what this means and what else to look for when we see it. We know that we need to search carefully for other abnormalities, to exclude skeletal dysplasias as well as aneuploidy. As the two studies in this issue of the Journal show, we also know to consider the more common possibility that the pregnancy is at risk for adverse outcome due to placenta-related complications. We need to search for other findings that may indicate an increased risk for adverse outcome, such as a smaller abdominal circumference. We then need to perform uterine artery Doppler, and we should also correlate the ultrasound findings with biochemical values from the first and/or second trimester. This information will better help us to identify those patients at risk for non-fetal adverse outcomes. We should also expect to see further advances in the combination of ultrasound findings with biochemical markers for detection of patients at risk of developing early severe pre-eclampsia and other placenta-related complications. Ultimately, these efforts are likely to lead to more effective treatment strategies." @default.
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• W1993552120 title "May all your femurs be long!" @default.
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