TT Lao

Abstract

Fetal growth is conventionally assessed by the size of the infant at birth, and a small-for-gestational age (SGA) infant is usually regarded as having in-utero growth restriction (JUGR), despite the realisation that low birthweight does not equate to IUGR. The recent finding that the placental weight to birthweight ratio (placental ratio) is increased in low birthweight and term SGA infants may provide a simple method to identify the infants with IUGR. The cause of this increase in the placental weight relative to the birthweight is thought to be placental hypertrophy as a means to compensate for the nutritional deficiency that causes the growth restriction. Nevertheless, an increased placental ratio is also found in other conditions that may not be associated with a difference in the birthweight, such as mild gestational diabetes mellitus, and anaemia due to both iron deficiency and thalassaemia trait. As well, an increased placental ratio is also associated with maternal smoking and living at high altitude. From these observations, it appears that an increased placental ratio reflects not only IUGR as such, but also the placental adaptation to environmental factors that cause fetal growth disturbance.

Introduction

The assessment of fetal growth has generally been an imprecise exercise. In daily practice, this is largely inferred from the infant outcome in the form of birthweight, crown heel length, with or without other additional anthropometric measurements, especially in uncomplicated pregnancies where serial ultrasound measurements have not been performed. Thus the birthweight percentile ranking has been the most commonly utilised parameter of fetal growth, so that a small-for-gestational age (SGA) infant would usually be regarded as having in-utero growth restriction (IUGR). The choice of using birthweight to define fetal growth is largely a matter of convenience, since birthweight is always available and is probably the most objective measurement compared to other parameters. But it has also been realised for some time that SGA does not equate to IUGR,^1-4 and fetal growth restriction could also have occurred in infants who are appropriate-for-gestational age (AGA), but who have not achieved their maximum growth velocity for various reasons. However, the majority of these cases would be missed because the infant birthweight is within the normal range. It has been reported that an increase in placental weight to birthweight ratio (placental ratio) is an indication of IUGR,⁵ the relatively higher placental weight is thought to represent placental hypertrophy in order to compensate for the inadequate supply of nutrients. This observation has recently been confirmed in a study performed in Hong Kong, in which the SGA infants had a significantly increased placental ratio.⁶ Nevertheless, an increased placental ratio can be associated with other conditions, which will be described later, and its use as an indicator of fetal growth restriction per se remains to be confirmed in prospective studies. In the following discussion, the factors influencing placental weight and ratio, and the relationship between an increased placental ratio and clinical conditions will be described.

What Constitutes the Placental ratio?

The placental ratio is calculated by dividing the placental weight by the birthweight. Because there is no correction for the gestational age and actual placental weight and birthweight, the same ratio can be obtained from a big infant with a big placenta, as well as from a small infant with a small placenta. Furthermore, an increased ratio could either be the result of small infant with a normal-sized placenta, or an average-sized infant with a big placenta. ft is therefore important that in order to have a meaningful interpretation of the placental ratio, one has to take into consideration the gestational age and the actual birthweight or birthweight percentile.

Placental Ratio and Fetal Growth

While the placenta is often weighed after delivery as a matter of routine in many delivery suites, little attention is usually paid to the relationship between placental weight and clinical complications, the common exception being when there is suspicion of retained placental tissue in the uterus and the low placental weight may provide a clue. Similarly, there have been few studies on the placental weight and ratio, when compared with studies on placental histology and architecture. Nevertheless, it has been demonstrated that the placental ratio is higher in the preterm infant, attributed to the higher rate of placental growth relative to fetal growth prior to term, and the placental ratio is inversely correlated with gestational age.⁷ It may be for this reason that little attention has been drawn to the possible association between IUGR and an increased placental ratio until now, because in many cases the growth restricted infants were labeled as having low birthweight, a description that was often applied also to preterm infants, with no distinction being made either in the gestational age or birthweight percentile ranking.

The recent surge in interest in the placental ratio is related to the studies reported by Barker and colleagues^5,8 on the correlation between an increased placental ratio and the occurrence of cardiovascular complications in adulthood, and that the cause of the increased placental ratio was IUGR.^5,8 Since the data on placental weight and birthweight for these studies were extracted from birth registries in the 1920s, there is always the concern that the cases might have included low birthweight infants who were actually preterm, and both the increased occurrence of cardiovascular complications and the increased placental ratio were due to causes other than IUGR. Nevertheless, a recent study from Tsan Yuk Hospital on uncomplicated singleton pregnancies resulting in SGA infants at term confirmed that the placental ratio was indeed significantly increased compared with the pregnancies resulting in appropriate-for-gestational age (AGA) infants.⁶ This finding supports the suggestion that placental hypertrophy may be an adaptation to maternal nutritional deficiency, and fetal growth is sacrificed to maintain placental function.⁵ The findings of Barker et al5 also suggest that apart from low birthweight infants, the infants with birthweight that were low relative to what is expected from the placental weight may also be interpreted as a sign of fetal growth failure, and the disproportionate placental size is an adaptation to maternal malnutrition. Thus an increased placental ratio may also be a marker of JUGR in the AGA infants. Support for this hypothesis has recently been presented. In this study on AGA infants, those with a high placental ratio had significantly lower mean birthweight but higher placental weight, and the maternal gestational weight gain was significantly lower, despite a significantly higher pre-pregnant weight⁹ As gestational weight gain has been shown to be one of the determinants of birthweight and predictors of intrauterine growth restriction.^10,11 these observations therefore provide an indirect evidence of restricted fetal growth in these AGA infants.

Other Conditions Associated with An Increased Placental Ratio

Anaemia and iron deficiency

An increased placental size has been known to be associated with severe maternal anaemia for some time, the best example in this part of the world is the big bulky placenta found in association with fetal haemoglobin Bart's disease. However, the big bulky placenta in this condition may be due as much to placental oedema as to hypertrophy. Nevertheless, an increased placental ratio has been demonstrated in pregnancies complicated by maternal anaemia.¹² This has been attributed to iron deficiency, which could be interpreted as part of the manifestation of maternal malnutrition.¹³ However, a recent local study has indicated that an increased placental ratio is found not only in pregnancies with iron deficiency anaemia, but also in pregnancies with anaemia due to maternal thalassaemia trait,¹⁴ and in the absence of any difference in birthweight. This observation suggests that while iron deficiency, which could manifest as overt maternal anaemia, is a cause of the increased placental ratio, anaemia per se has also a similar effect since those mothers with anaemia due to thalassaemia trait did not have iron deficiency as shown by their high serum ferritin levels. The mechanism of placental hypertrophy in the case of anaemia could be related to hypoxaemia, as an increased placental ratio is also found in association with maternal smoking¹⁵ as well as residence at high altitudes¹⁶ as described later. It is important to realise that in cases of maternal anaemia, the increased placental ratio may not be associated with decreased birthweight as shown in the local study.¹⁴

Gestational diabetes mellitus

One of the causes of gestational diabetes mellitus is the production of placental hormones that leads to maternal insulin resistance, and the placental size has been shown to be increased both in gestational and pre-gestational diabetic pregnancies in previous studies.^7,17,18 But an increased placental size could be related to the concomitant increase in fetal size, and it is not clear if a disproportionally bigger placenta is found in gestational diabetes mellitus. Recently, another local study¹⁹ has demonstrated that while the birthweight of the infants were similar, the placental weight and ratio were significantly increased in diet treated gestational diabetic mothers, the vast majority of whom carried in fact the diagnosis of impaired glucose tolerance as defined by the World Health Organisation criteria.²⁰ Furthermore, the placental ratio was found to be a function of the degree of glucose intolerance as regression analysis confirmed a significant correlation between the placental ratio and the 2 hour postprandial value of the oral glucose tolerance test. This observation would suggest that the development of gestational diabetes mellitus is related, at least partially, to a disproportionally big placenta, and the increased placental ratio found in these cases may not reflect IUGR.

Other conditions

Increased placental ratio has also been found in association with maternal smoking¹⁵ and residence at high altitudes,¹⁶ both of which are conditions that tend to be associated with low birthweight infants as well. Although there may not be malnutrition in the usual sense, the common factor is fetal hypoxaemia in these situations, and the mechanism for the placental hypertrophy is probably similar to that for maternal anaemia unrelated to iron deficiency.

The Clinical Implications of An Increased Placental Ratio

From the literature on placental ratio, it would appear that an increased placental ratio represents an adaptative process by the feto-placental unit in an unfavourable maternal environment. When there is a limitation imposed on fetal growth velocity due to nutritional deficiencies, the placenta may undergo hypertrophy in an attempt to compensate. As well, placental hypertrophy may occur in response to fetal or placental hypoxaemia. This hypothesis is not incompatible with the case of gestational diabetes mellitus where the increased maternal glucose level could have enhanced fetal and placental growth initially, but the subsequent treatment could have restricted fetal growth in a manner similar to idiopathic JUGR. In these situations, an increased placental ratio would be a sign of fetal growth disturbance, rather than growth restriction in the conventional sense.

It is also possible that using the placental ratio as a marker, infants with possible in-utero growth disturbance can be identified so that their postnatal growth and future health status can be monitored. This may provide, in the long run, a means to prevent or reduce the risk of some diseases in adulthood, especially those related to the cardiovascular system. However, prospective studies with long term follow up assessment will be necessary to establish the clinical application of the placental ratio.

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