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Risk factors for low birth weight: a review

European Journal of Obstetrics & Gynecology and Reproductive Biology, Volume 116, Issue 1, September 2004, Pages 3 - 15

Abstract

Low birth weight (LBW) is one of the main predictors of infant mortality. The global incidence of LBW is around 17%, although estimates vary from 19% in the developing countries (countries where it is an important public health problem) to 5–7% in the developed countries. The incidence in Spain in the decade 1980–1989 was about 5.7%. LBW is generally associated with situations in which uterine malnutrition is produced due to alterations in placental circulation. There are many known risk factors, the most important of which are socio-economic factors, medical risks before or during gestation and maternal lifestyles. However, although interventions exist to prevent many of these factors before and during pregnancy, the incidence of LBW has not decreased.

Keywords: Low birth weight, Risk factors, Epidemiology, Reproductive health.

1. Introduction

Low birth weight is one of the main risk factors for infant morbidity and mortality. When considering a foetus that is small for its gestational age, it is important to differentiate whether this is due to intra-uterine growth restriction (IUGR), prematurity or other constitutional factors. Although prematurity has historically been defined (American Academy of Pediatrics, 1935) as the birth of a live infant weighing 2500 g or less, experience in clinical practice showed that many of these infants were not actually premature, but rather full-term foetuses from a pregnancy in which growth had been limited due to different factors. In 1967 the World Health Organization (WHO) recognized this fact, designating infants weighing 2500 g or less as “low birth weight”.

Thus, it is necessary to begin by defining what is understood by “birth weight”, that is, the first weight of the foetus or infant obtained after birth. This should be measured during the first hour after birth, before the appreciable postnatal loss of weight occurs. With this in mind, and attempting to clarify existing discrepancies, the perinatal definitions currently accepted internationally are those formulated by the “Committee of Annual Reports and Definitions of Terms in Human Reproduction” of the International Federation of Gynecology and Obstetrics (FIGO), adopted by WHO (1982) [1]. It is important to clarify the meaning of three terms that are frequently used interchangeably but are not necessarily synonymous:

  • Low birth weight (LBW). This term refers only to infants born weighing 2500 g or less, regardless of gestational age and the cause of LBW [2]. Three categories can be distinguished:
    • 1.1. Premature or preterm LBW babies (born before 37 complete weeks of gestation or with fewer than 259 days of gestation).
    • 1.2. Term LBW, that is, born between 37 and 42 complete weeks of gestation, or between 259 and 293 days of gestation.
    • 1.3. Postterm LBW, born after 42 weeks or 294 days of gestation.
    LBW infants can be further classified as “very low birth weight” (1000–1499 g) and “extremely low birth weight” (500–999 g).
  • Small-for-gestational-age (SGA). This term is based on a statistical definition, which refers to infants whose weight is less than the lower limit of the confidence interval of the normal curve for weight by weeks of gestation [3].
  • Intra-uterine growth restriction (IUGR). IUGR is currently defined as a process of whatever etiology that can limit the potential for intra-uterine growth of the foetus, resulting in low birth weight.

With reference to the latter two definitions, it is important to clarify that the terms LBW and IUGR do not necessarily reflect the same clinical situations. Some small babies, perfectly healthy and normally formed, are born weighing less than the 10th percentile for their gestational age, while others whose birth weight is higher than this percentile may show signs of growth restriction if they come from a uterine environment that impeded the foetus from reaching its full potential for growth [4].

It can be seen that all the preceding definitions are based on birth weight. The obvious advantage of using this parameter is that it makes it possible to compare specific rates among different countries. It is not so easy, however, to compare foetal growth curves, since they are all based on measurements made in uncomplicated pregnancies in the developed countries. To avoid this bias, similar curves need to be developed based on a country’s level of development, ethnicity, parity and other factors.

2. Incidence and consequences of LBW

The study of LBW is very important, since sub-optimal birth weight may have consequences in the perinatal period, during infancy, and even in adulthood. In the first place, perinatal morbidity and mortality are more frequent in LBW infants than in normal infants; LBW has become the second cause of death in this period, after premature birth [5]. Furthermore, term infants weighing between 1500 and 2500 g at birth have a perinatal mortality rate 5–30 times greater than infants with birth weights between the 10th and 50th percentile, while infants born almost at term weighing less than 1500 g have 70–100 times higher mortality rates [6]. The consequences of LBW on the subsequent development of these infants depend on the specific cause giving rise to the foetal growth restriction, its time of occurrence and the duration of the impairment. It has recently been reported [7] that the intellectual quotient (IQ) of infants with IUGR, at 5 years of age, averages 3.3 points lower than that of normal infants; if they were also premature, the IQ averages 6.7 points lower on intelligence tests. Hack et al. [8] found that children with a small head circumference at birth who do not regain normal growth have a higher risk of having impaired neurological functions. However, infants with intra-uterine growth restriction but with a normal head circumference at birth, or those in whom normal head circumference is rapidly attained, are not likely to suffer subsequent neurological sequelae. They may, however, be slower to develop language abilities and may have problems in school [4]. Finally, several epidemiological studies have suggested that infants born with IUGR, especially those who had a large placenta, have a higher risk of developing hypertension in adulthood [9].

For all these reasons, it is important to know the incidence of LBW babies. The studies that have measured the incidence of this process have yielded variable estimates: from mean values of 25% LBW in countries like India [10] to much lower values, for example, 7.6% in the United States [11], 5–6% in the Scandinavian countries, and 6% in the United Kingdom [12].

In Spain, the incidence of LBW was around 5.7% during the decade 1980–1989. More recent population data from the National Statistics Institute [13] refer to an incidence of nearly 6.1% of LBW in 1998.

3. Etiology of LBW: risk factors

A variety of factors influence foetal growth, although they can be grouped into several general categories: factors originating from the foetus itself, maternal factors, placental factors and, finally, factors produced from the interaction of these factors. It should also be pointed out that LBW is usually associated with situations in which there is interference with placental circulation due to alteration of the mother-placenta-foetus interchange and, therefore, with intra-uterine malnutrition. Although progress in obstetrical and neonatal care has improved the prognosis for low birth weight infants, the best strategy to reduce its consequences is primary prevention, by identifying and avoiding the risk factors that give rise to this condition. In accordance with the Committee to Study the Prevention of Low Birth Weight [14], the risk factors for LBW can be classified into the large groups described below.

3.1. Socio-demographic risk factors

3.1.1. Constitutional factors

There are clear genetic and constitutional influences that act on foetal growth; it is estimated that 40% of birth weight is due to heredity and the remaining 60% to environmental factors [4]. Thus, small mothers, especially those weighing less than 45 kg, are more likely to have small babies. Ounsted and Ounsted [15] observed a significant association between infant birth weight and the mother’s birth weight. The influence of the mother’s birth weight is greater than that of the father’s, although both the maternal and paternal influences are about equal on the subsequent weight in childhood and adulthood. Certain chromosomal factors also have an influence on birth weight. The Y chromosome is a special case: term male infants weigh between 150 and 200 g more than females. There are other chromosomal anomalies that result in foetal growth retardation, among them, trisomy 21, trisomy 18 and Turner’s syndrome. Infants with trisomy 13 or 18 frequently have IUGR, with a mean birth weight of 2600 and 2240 g, respectively [4]. Turner’s syndrome is also associated with mild growth retardation, with mean birth weight equal to about 85% of normal birth weight. Other chromosomal pathologies such as deletions, duplications or translocations exert a variable effect on foetal growth depending on the chromosome affected and the genetic material that is decompensated.

3.1.2. Maternal age

A large number of epidemiological studies have noted that the incidence of low birth weight increases in the extremes of women’s reproductive life; that is, between 15 and 19 years [16], [17], and [18] and between 35 and 40 years of age [19], [20], and [21]. In explaining these facts, in the case of adolescence, it is important to ask if there are intrinsic biological factors responsible for these results, or if pregnancy at this time of life is a marker for social disadvantage, which may produce these differences regardless of age. In fact, it is seen that most adolescent mothers are single, with low incomes, inadequate prenatal care and lower antenatal maternal weight [22]. These circumstances are commonly accompanied by significantly increased tobacco consumption and low cultural level [23]. At the other extreme, it is widely accepted that women older than 35 years have a higher incidence of pregnancy complications, including LBW, although there is some debate about the latter. Some authors suggest that the risk is related, not with age itself, but rather with complications of other processes such as the larger number of chronic diseases (hypertension, diabetes) [23], or increased vascular arteriosclerotic disorders at the level of the myometrium, which are more frequent at older ages [24].

3.1.3. Ethnicity

It is well known that black women have a higher incidence of LBW than white women [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], and [29], although it is difficult to find studies that are strictly comparable, with stratification by social class and socio-economic level. Some investigators who have studied this subject conclude that genetic and environmental factors have a joint influence, and it is difficult to separate the effects of one from the other [30]. Bearing this in mind, the weight of specific racial factors on foetal growth cannot be evaluated until the different ethnic groups have lived together under comparable conditions for at least two or three generations, to obviate the confounding effect of poverty and lower income [31]. Recent studies comparing the problem in African–American women with respect to those of Anglo Saxon origin also highlight the importance of other factors on the incidence of LBW, such as differences in vitamin D levels during pregnancy depending on the latitude of the area of residence; such differences are also found in black women despite their higher concentrations of skin pigmentation [30].

3.1.4. Marital status

Another important risk factor for LBW is marital status, which is interrelated with other factors such as socio-economic level, age, culture and race. Thus, it has already been seen that LBW babies are frequently children of single mothers [32] and [33], which is directly related with younger maternal age, often adolescence [16] and [17], or of couples in which the father is absent during the pregnancy [34]. Holt et al. [35] carried out a study to evaluate the importance of a change in the mother’s marital status between two births. They found that women who were married during the first pregnancy had a lower incidence of LBW than single mothers did, but if they were separated during the second pregnancy, the relative risk (RR) of low birth weight increased (RR=1.4) in comparison to those who remained married. Conversely, among women whose marital status changed from single to married between pregnancies, the risk of LBW decreased (RR=0.8). Another study [36] found more adverse perinatal effects among women who suffered a marital break-up, with a frequency that was even higher than among single mothers.

3.1.5. Educational level

Some studies suggest the possibility of an important relation between maternal educational level and foetal birth weight [37], [38], [39], and [40], with an increased risk of prematurity and LBW associated with decreasing educational level of the mother.

3.1.6. Socio-economic level

Socio-economic level is one of the factors most closely related with the health status of populations. With regard to the problem that is the subject of this study, it is a proven fact that unfavourable socio-economic conditions increase the incidence of LBW [41] and [42]. When analyzing this association, it is important to highlight the strong relation that exists with other factors such as maternal malnutrition, low educational level, smoking, alcohol consumption, drug abuse and stress [43], [44], and [45]. It is also important to emphasize that when we speak of socio-economic level, we are also talking about inequalities in the access to health care. Authors who have investigated this subject maintain that when the differences or difficulties in obtaining adequate health care are mitigated, the incidence of LBW decreases among the Afro-American population in the United States with regard to other population groups [46].

3.2. Medical risks before pregnancy

3.2.1. Chronic hypertension

Chronic hypertension refers to any hypertensive disease before pregnancy, either by documentation of previous high blood pressure levels, or by diagnosis of the process before the 20th week of pregnancy. Chronic hypertension, as well as some maternal diseases, may provoke alterations in foetal growth, perhaps as a consequence of reduced uteroplacental fluid. These vascular diseases, also including gestational hypertension, are clearly associated with reduced foetal growth [4]. Studies in the literature show that hypertension with increased resistance in the uterine artery was more frequently associated with IUGR than low-resistance hypertension [47]. It is currently accepted that there is a pathological increase in the thromboxane/prostacyclin index due to deficient trophoblastic production of prostacyclin, and probably of nitric oxide, with a concomitant increase in certain vasoconstrictor substances such as the endothelins. This imbalance, first at the level of the intervillous space and then in the systemic circulation, provokes increased vascular resistance and sensitivity to hypertension, with a reduced volume of plasma. Ultimately, there is an activation of coagulation, with increased platelet aggregation, thrombopenia, and general and local vasoconstriction, which leads to reduced systemic perfusion and, finally, to a decrease in the uteroplacental fluid which results in increased IUGR [3].

3.2.2. Renal diseases

Chronic nephropathies, the same as other maternal systemic diseases, have a vascular pathology that reduces uteroplacental perfusion [4]. Among the renal processes most closely associated with IUGR are chronic pyelonephritis, glomerulosclerosis, chronic glomerular disease and lupus glomerulonephritis. In all these cases, the retardation of foetal growth is also related with the important loss of protein associated with these processes [3]. Renal diseases are relatively rare in women of childbearing age, but when they appear during pregnancy they are associated with complications during gestation and birth. Studies like that of Fink et al. [48] detected a 0.03% incidence of these pathologies among pregnant women, with an increased risk of preterm births (OR=6.1) and of SGA (OR=5.3). It is well known that kidney transplant is the treatment of choice for chronic renal failure in patients under 55 years of age. Botet et al. [49], in a study showing that one of every 50 women who received a kidney transplant subsequently became pregnant, carried out a follow-up of these women and found that 52.9% of their infants were premature, and that the incidence of LBW among them was 47.1%.

3.2.3. Glucose metabolism disorders

An important factor that influences adequate foetal growth is the triangle formed by glucose, insulin and placental lactogen or chorionic somatotropin. Maternal postprandial hyperinsulinism has often been shown due to excessive secretion, to low tissue resistance to this hormone, or to insufficient placental destruction of insulin (low levels of placental lactogen). This excess of maternal insulin accelerates anabolism and impedes the passage of carbohydrates to the foetus, giving rise to a situation opposite to that of the diabetic mother [50]. Treatment of a diabetic pregnant woman with insulin and diet decreases perinatal mortality and the incidence of macrosomy in the infant, but may also increase the frequency of growth retardation due to iatrogenic hyperinsulinism and excessive caloric reduction [4] and [50]. Maternal hypoglycemia, either due to errors in food intake or to relative hyperinsulinism, interferes with foetal growth by stimulating lipolysis and maternal ketonemia or by increasing the liberation of catecholamines which decrease placental perfusion. This situation could worsen if there is an accompanying deficit of foetal insulin, which not only can increase carbohydrate deposits but also intervenes in the cellular formation and fixation of amino acids [3]. All these disorders may interfere with adequate foetal growth.

3.2.4. Chronic cardiorespiratory disease and other disorders that involve hypoxemia

Medical complications in the mother that alter the passage of oxygen to the foetus may cause IUGR. Patton et al. [51] showed that all maternal cyanotic heart diseases were associated with this alternation, mainly due to the fact that the uterine circulation carries insufficiently oxygenated blood to the intervillous space [3]. IUGR has been described in patients with cardiac or pulmonary diseases that cause hypoxemia: congenital heart disease, aortic coarctation, and even asthma [52] and [53]. In all cases the growth retardation seems to be the result of chronic hypoxemia. In this regard, severe maternal anemia (with hemoglobin<8 g/dl) is also related with IUGR, with up to 30% of infants of mothers so affected weighing less than 2500 g. Altitude also influences birth weight: at an altitude of 3000 m, mean birth weight drops by some 250 g, in direct relation with the reduced oxygen availability [4].

3.2.5. Genitourinary anomalies

Uterine malformations may cause foetal loss and prematurity, as in the case of Müllerian anomalies or extrinsic masses such as myomas. The most important among them are uterine duplications, which have been associated with higher rates of miscarriage (four times more) and up to 10 times greater risk of prematurity (birth before 34 weeks of gestation). In addition, infants of mothers with this condition have lower mean birth weight percentiles [54]. In some cases a progressive increase in birth weight has been observed in subsequent pregnancies, perhaps in relation with the improved uterine vascularization produced with the first pregnancy.

3.2.6. Autoimmune diseases and inherited or acquired thrombophilia

Both systemic lupus erythematosus and antiphospholipid syndromes have been related with poor foetal growth [4]. The common factor in all these cases is, again, the underlying vascular pathology that reduces uteroplacental perfusion. Lupus is the most frequent autoimmune disease in the pregnant woman. It increases the frequency of low birth weight and preterm birth by 30–50%, especially when the disease involves the kidneys and hypertension. Lupus anticoagulant is a plasma immunoglobulin that can be found in 5–15% of women who suffer systemic lupus erythematosus. In one multi-center study [55] carried out to estimate the obstetric risks of antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), it was found that the presence of lupus anticoagulant and a previous history of at least three miscarriages could predict foetal loss, while the presence of anticardiolipin antibody could increase the risk of LBW.

Thrombophilias, which can be defined as conditions predisposing one for thrombosis, are associated with adverse obstetrical outcomes. Antithrombin, protein C and protein S deficiencies, factor V-Leiden mutations and plasminogen activator inhibitor, are well known as factors increasing the likelihood of thrombosis. Other factors such as lipoprotein A and hyperhomocystenemia have been related with a history of thromboembolism during pregnancy and placental hypoperfusion [56]. These situations induced thrombosis, which can diminish placental perfusion and cause decreased foetal blood volume. This can lead to decreased foetal renal glomerular filtration rate and affect foetal normal development [57].

3.2.7. Obstetrical history

Primiparity seems to be associated with a larger number of growth-retarded infants, preterm births and LBW infants [58], [59], and [60]. It is well known that second and third children weigh more than the first [22]. To explain this fact, it should be recalled that the first pregnancy is for all purposes a true maturation of the uterine structures, especially the vascular structures, making them more sensitive to gestational stimuli. In subsequent pregnancies, these improved local conditions permit greater placental development and, consequently, improved foetal nutrition [3]. It should also be noted that, beginning with the fourth pregnancy, this increased birth weight is inverted, so that the risk of LBW again increases with the fourth and subsequent children [61]. Another factor to be considered with regard to obstetrical history is the existence of previous miscarriages. A previous miscarriage may indicate a high-risk of adverse effects in subsequent pregnancies. In one study carried out in women with a history of previous miscarriages, it was observed that a previous miscarriage doubled the risk of a preterm birth and of LBW [62]. After adjusting for gestational age, the risk was only maintained for preterm birth [63]. A study of women with three or more previous miscarriages showed a higher risk of prematurity (RR=1.5), placenta previa (RR=1.8) and malformations (RR=1.8) [64]. The subject of induced abortions merits special mention. A considerable number of women who abort wish to have children in the future, therefore it is important to establish the possible undesirable effects of abortion on subsequent pregnancies, both from the cervical trauma derived from mechanical dilation, and from the possible cervical and uterine adhesions due to the curettage. In this regard, a study carried out by Mandelson et al. [65] did not find evidence of harmful effects on birth weight after one, two or even more induced abortions. Finally, a history of low birth weight in previous pregnancies is the strongest predictor of risk in the current pregnancy [66], [67], and [68], and this risk is maintained when birth weight is analyzed after controlling for different demographic and obstetric variables [69].

3.3. Risks of the current pregnancy

3.3.1. Gestational hypertension

Hypertension induced by pregnancy is defined as the development of blood pressure values higher than 140/90 mm/Hg after the 20th week of pregnancy, in at least two independent measurements, in the absence of proteinuria (<300 mg/dl in 24 h) or previous changes in blood pressure values. Hypertension associated with symptoms of proteinuria, edema, or both would indicate the presence of pre-eclampsia [70]. As previously seen, hypertension in pregnancy is associated with reduced uteroplacental flow, which leads to an increased risk of preterm birth [71] and of LBW [72] and [73]. Proteinuria, in particular, is associated with a significant increase in the number of SGA infants. On the other hand, birth weight is lower in pre-eclampsia than in pregnancy-induced hypertension, especially among white women [74]. For all the preceding reasons, studies emphasize the importance of rapid intervention to control hypertension in pregnancy, thus avoiding subsequent complications such as foetal growth retardation [70].

3.3.2. Gestational diabetes

Glucose is the main source of energy for the foetus and the substance most used by the foetal brain. Glucose crosses the placenta and is captured by the foetus in proportion to the levels of maternal glucose and the mother–foetus concentration gradient, so that glucose levels in the newborn are 70–80% of those in the mother’s blood. It is well known that glucose availability plays a fundamental role in foetal growth. Foetuses with growth retardation have reduced concentrations of glucose in the intra-uterine blood and in cord blood. Conversely, it is also well known that increased levels of glucose and insulin in the mother’s blood are related with increased foetal size [75], so that when the mother is diabetic (glucose levels>130 mg/dl), the risk of having a macrosomic foetus is doubled. A study by Scholl et al. comparing pregnant women with low levels of postprandial glucose (99 mg/dl) with those who had higher levels showed that infant birth weight increased by a mean of 50 g among women with glucose levels of 99–30 mg/dl, and by 250 g for those who had levels >130 mg [75]. On the other hand, it has been shown that fluctuations in glucose levels, either hyperglycemias or hypoglycemias, observed at random on the glucose curve, are accompanied by a greater risk of IUGR. Diabetic mothers also have an increased risk of preterm birth and other complications [76] and [77]. In pregnancies complicated by non-insulin dependent diabetes mellitus, there is an elevated concentration of growth hormone (GH) binding protein. This increase has been observed especially in the last 4 weeks of pregnancy in women with LBW infants [78]. Finally, Plante [79] confirmed that female infants with low birth weight have a greater risk of developing diabetes later during pregnancy, and this would in turn imply a greater probability of having LBW children.

3.3.3. Weight gain

To provide the foetus with an adequate amount and diversity of substances, a normal woman should gain an average of 12–16 kg during pregnancy. Maternal weight gain during the first and second trimesters in pregnancy is mostly due to maternal components (blood, extra cellular liquid, tissues and fat reserves) and to the placenta, while weight gain during the third trimester is due to foetal tissue. Thus, weight gain is a factor that predicts foetal size [80]. In 1990, the US Institute of Medicine [81] published a series of guidelines based on the mother’s body mass index (BMI) before pregnancy. These recommendations showed that women with a low BMI (<19.8) should gain between 12.7 and 18.2 kg; those with a medium BMI (19.8–26) should gain between 11.4 and 15.9 kg; those with a high BMI (26.1–29) should gain between 6.8 and 11.4 kg. The authors of these recommendations recognize that there are no definitive data on optimal weight gain, and that discrepancies may exist with other publications [82] which consider these levels of weight gain to be excessive, except in the case of women with medium or low BMI, for whom the recommendations are recognized as appropriate [83]. It has already been pointed out that black women have a higher risk of SGA babies than do white women. In this regard, Caufield et al. [84] observed that, with regard to BMI, whereas there was no difference by race in women with low BMI, the higher risk for black women was maintained in women with medium and high BMI. Maternal attitudes towards weight gain are strongly influenced by the pre-pregnancy weight. Slender women usually have more positive attitudes, with greater weight gains, but with smaller children in the end, whereas obese women gain less weight, yet usually have children weighing more [85]. Eating disorders, such as anorexia and bulimia, merit separate mention. In general, the risk of LBW increases when these disorders exist prior to pregnancy [86]. Other studies, however, have not found greater pregnancy complications among women with eating disorders, either with regard to length of pregnancy or birth weight, although these mothers had more cesarean sections and postpartum depression [87].

3.3.4. Maternal nutrition

It has long been known that maternal malnutrition is an important cause of IUGR, although its effect is moderate. According to the recommendations of the National Research Council of the American Academy of Sciences, the mother needs an additional intake of nutrients to achieve optimal foetal growth. This additional intake is 300 kcal per day more than the normal needs of a non-pregnant woman, that is, a minimum intake of 2500 kcal per day [80]. Most of our knowledge about maternal malnutrition and its relation with IUGR comes from several basic studies carried out during World War II in the Netherlands and Leningrad [4]. The groups most affected were women who were in extremely poor nutritional condition when they became pregnant (birth weight 400–600 g less than average), and those who suffered caloric deprivation in the third trimester (birth weight 250 g less than average). These decreases in birth weight were not seen in the infants of women who suffered malnutrition in the first or second trimester. In this regard, while it is an open question whether or not pregnant women with sufficient nutritional reserves need supplements in the first trimester, this complement is clearly recommended during the second and third trimester. The amount of protein should be reinforced (60 g per day), although excessive intake should be avoided because it increases the risk of premature birth. Vitamin intake should also be increased by 10–50%, and the amount of calcium and iron by 50–100% [80]. With regard to caloric needs, it has been seen that some countries achieve normal foetal growth with caloric intakes of less than the recommended amounts. Thus, in some populations, caloric requirements decrease due to the mother’s physiological adaptation, including decreased baseline metabolism, body temperature and fat reserves. Nevertheless, foetal growth is not assured with intakes of less than 1800 kcal per day. Some articles specifically review the role of the n-3 and n-6 fatty acids, supplements of which are influential in decreasing the incidence of premature birth and LBW [88].

3.3.5. Birth intervals

Short intervals between births constitute one of the main risk factors for prematurity and low birth weight, although information in this regard is contradictory. Ochoa found a strong association between short birth intervals and other covariates of obstetrical interest, such as a history of prematurity and LBW, and adolescent maternity [89]. Short birth intervals, varying from 3 to 6 months in developing countries and from 1 to 2 years in the developed countries, may lead to an increased tendency toward low birth weight and prematurity in subsequent pregnancies [90]. Other authors mention an increased risk of LBW when the birth interval is shorter than 1 year [90], [91], and [92] and when there is a history of miscarriage [69].

3.3.6. Multiple pregnancies

Multiple pregnancies may produce IUGR. Data published by Arbuckle et al. showed that up to 25% of twins had IUGR [93]. Although the growth rate of twins is similar to that of single foetuses during the first two trimesters of pregnancy, mean growth is 220–240 g per week by week 34 for single foetuses, and 160–170 g per week by week 30 in twins. The risk is even higher in pregnancies with a larger number of foetuses: in triplets, the mean weight of each infant by week 38 is equivalent to the 10th percentile of weight of a single foetus [4]. The main reason for this is the decreased availability of substances for each foetus. Race and maternal age also influence the adverse results of these pregnancies, with poorer outcomes observed in black women and younger women (≤22 years of age) [94].

3.3.7. Placental causes

Alterations in the placenta and the umbilical cord, such as chronic abruptio placentae, placental infarcts, placental hemangiomas and vascular anomalies are associated with IUGR. In all these cases, there is a decrease in blood transfer, which is especially important in the infarcted areas, changes in the villosities and if there is abnormal cord insertion. Premature displacement of a normally inserted placenta (abruptio placentae) may occur before expulsion or even before the beginning of labor. Its incidence varies between 0.42 and 1.16% of pregnancies. A study in Jordan [95] showed an association between abruptio placentae and multiparity (≥5), pre-eclampsia, hypertension and IUGR. Another placental anomaly, placenta previa, is also associated with rupture of the placental decidua, which may lead to impaired foetal oxygenation and a compensatory increase of hemoglobin in the blood [96]. The most important symptom of placenta previa is periodic hemorrhage in the last months of gestation. Other authors [97] comment that the association between LBW and placenta previa is mainly due to the higher frequency of prematurity and, to a lesser extent, to IUGR.

3.3.8. Bleeding

Vaginal bleeding is an important predictor of adverse effects in pregnancy. About 50% of women who bleed in the last half of pregnancy have placenta previa or abruptio placentae. When the bleeding occurs at the beginning of pregnancy, however, the cause is often unknown. Some studies associate bleeding in the first weeks with increased preterm births (RR=4.3) [72] and [98] and LBW (RR=2.1) [96]. If early bleeding is combined with increased α-fetoprotein, the probability of preterm birth is up to six times greater [99].

3.3.9. Increased α-fetoprotein

α-Fetoprotein is a glycoprotein synthesized by the foetus, which normally is produced only during foetal life and can be measured in the maternal blood [100]. Unexplained elevations in α-fetoprotein during the second and third trimester are associated with 20–38% of adverse obstetrical outcomes such as pre-eclampsia, LBW, preterm birth, IUGR, abruptio placentae and foetal death [101].

3.3.10. Anemia

In a normal pregnancy, maternal concentrations of hemoglobin decrease in the first 20 weeks, remain constant up to week 30, and then increase slightly. Some authors have observed that hemoglobin of less than 9 g/dl during pregnancy is associated with an increased risk of LBW and prematurity [102]. Steer pointed out that the lowest incidence of LBW was seen at hemoglobin values between 9.5 and 10.5 g/dl and that, conversely, elevated hemoglobin values of over 12 g/dl increased the incidence of both LBW and prematurity; this risk was shown to be independent of coexisting risk factors [103]. In this regard, a meta-analysis by Allen emphasized that the relation between hemoglobin concentration and birth weight can be described in a U-shaped curve [104].

3.3.11. Infections

Numerous microorganisms can cross the placenta and cause infection in the foetus. If the infection occurs at a critical moment in foetal development, some organisms can affect the foetal cells and cause IUGR. The earlier intra-uterine infection occurs, the more serious the consequences; when they occur in the first trimester they can alter foetal development and are also related with IUGR [4]. Many agents are associated with foetal growth disorders, including toxoplasma, rubella, cytomegalovirus and herpes simplex. In addition, different studies conclude that there is an association between LBW and such maternal infections as Chlamydia, b-hemolytic Streptococcus, Ureoplasma urealyticum, Mycoplasma, Trichomonas, Staphylococcus aureus and other vaginal infections, as well as untreated gonorrhea and syphilis [105] and [106]. It is also maintained that if these infections were treated adequately, the incidence of LBW could decrease [107]. Other, more frequent processes in pregnancy are periodontal infections, which have only recently been related with LBW. A study by Dasanayake [108] concludes that periodontal disease during pregnancy is a potential risk factor for LBW. Similar studies support this conclusion [109], observing in addition that up to 18.2% of LBW could be attributed to the existence of periodontal infection. Davenport et al. [12] affirm that two physiological mediators present during labor, E2 prostaglandin and tumor necrosis factor (TNF), are elevated during periodontal infections, all of which emphasizes the importance of controlling these types of infection. Women with HIV infection have twice the risk of having a LBW infant as compared to non-infected women of the same socio-economic level, even after adjusting for gestational age [110] and [111]. However, pregnancy outcomes in these women appear to be more heavily influenced by the existence of risk behavior such as smoking, alcohol and other factors [112].

3.3.12. Foetal congenital anomalies

Several chromosomal influences on neonatal weight are known. Foetuses with trisomy 21 are smaller at birth, with a mean weight at term of 2900 g, that is, a standard deviation smaller than average [4]. Syndromes causing multiple malformations, such as Roberts’ syndrome, often lead to IUGR. Single congenital malformations such as anencephaly are also usually associated with IUGR. Foetal heart diseases, especially those associated with septal defects, may be associated with IUGR. For all of these reasons, it is important to consider cytogenetic analysis in infants with dysmorphic features and low birth weight [113].

3.4. Health care

3.4.1. Prenatal care

It is a generally accepted opinion that small improvements in health care can lead to important benefits, for example, those derived from better and earlier diagnosis of risk factors for LBW. The controversy with respect to the effectiveness of these types of care stems form the difficulty of defining what constitutes adequate prenatal care. A widely used index is that of Kesnner, based on the following data: date of the first visit, total number of visits and length of pregnancy [114]. Many studies have established a link between these factors and LBW [67], [115], and [116], a relation that is stronger if the first visit is delayed or if the number of visits is smaller than normal (<80%). Another study noted that up to 25% of high-risk women had received inadequate care, while the corresponding proportion of low-risk women was under 10% [117]. Also of interest are the factors that can influence the difficulty of accessing health care, such as ethnic or racial factors [46], place of residence or rates of unemployment. Prenatal care begins later in rural areas [118], although this fact is not independently associated with increased LBW. The protective effect of prenatal care has been shown, however, in neighborhoods with lower rates of unemployment [119]. On the other hand, excessive testing during pregnancy can create anxiety and may lead to an increase of unfavourable outcomes such as LBW [120].

In summary, it can be concluded that adequate prenatal care prevents LBW, regardless of the existence of possible confounding variables [121], [122], [123], [124], and [125].

3.5. Environmental and behavior risks

3.5.1. Maternal work and psychosocial stress

A literature review [126] points out that, while most studies confirm the relation between maternal work and prematurity and LBW, many of them did not control for possible confounding variables such as socio-economic level or actual level of physical activity. These authors conclude that moderate exercise may be beneficial for pregnancy outcome, but that intense exercise undoubtedly increases the risk of LBW. Other studies have evaluated the role of stressful situations during pregnancy, showing that continuous stress may decrease the length of gestation and increase the number of premature births [127]. On the other hand, it was seen that women who managed to control their work pace and stress level had better pregnancy outcomes [128]. An increased risk of complications during pregnancy and in the infant was also detected among those women who perceived physical effort as important [129], in those who worked more than 45 h a week [130], and in those in who took more than 1 h to commute to work [131].

Finally, a special problem that may cause stress in pregnancy is abuse: physical, sexual and emotional abuse during pregnancy is related with LBW (OR=1.4) [132]. It should be kept in mind that the definition of abuse includes a wide range of interacting factors that contribute in different ways to the alteration of normal foetal growth.

3.5.2. Smoking

Of all the drugs consumed by the mother that can affect the foetus, tobacco is undoubtedly the most common. Smoking during pregnancy leads to birth weights of 200 g less than the mean birth weight of children of non-smokers, with a range of 150–250 g less [133], [134], [135], [136], and [137]. The association between smoking and other undesirable effects is also well known, such as the higher incidence of miscarriage and prematurity. Nevertheless, up to 25% of pregnant women continue to smoke [138]. There is not, however, universal agreement about the mechanism by which tobacco leads to decreased foetal weight. This is probably due to the fact that several of the following effects are involved:

  • Increase in carboxyhemoglobin, with the consequent reduction in oxygen transport capacity.
  • Deviation to the left of the hemoglobin dissociation curve, altering the passage of oxygen to the tissues.
  • Vasoconstrictive effect of some components of tobacco, especially nicotine.
  • Reduced plasma volume in women who smoke as compared to non-smokers, probably related with decreased placental perfusion.
  • Increased requirements in smokers for vitamin B12 and some amino acids needed to detoxify the cyanins in tobacco.

Several epidemiological studies corroborate the relation between smoking and low birth weight, an association that is maintained even after controlling for possible confounding factors [137]. Some authors estimate a mean weight loss of 0.5 kg in women who smoke a pack of cigarettes a day [139]. This confirms the dose–response relation that other studies have identified between smoking and LBW [138]. Thompson et al. suggest that up to 18% of IUGR is due to smoking [140]. Stopping smoking, however, if it occurs before the third trimester, leads to a significant reduction in the incidence of LBW [141]. Finally, and in relation to passive smokers, studies show an increased risk for LBW independent of other confounding factors [142], [143], [144], and [145].

3.5.3. Alcohol consumption

Foetal alcohol syndrome (FAS) is characterized by three main findings: abnormal facies, central nervous system (CNS) alterations and IUGR [4]. Occasional or very infrequent consumption of alcohol during pregnancy probably does not have undesirable effects on the foetus. The development of FAS depends on the dose and time of consumption, with a greater risk when exposure is during the first trimester [4] and [146]. Studies confirm that up to 10% of the children of moderate drinkers (10–60 g of pure ethanol per day) may present signs of FAS [147]. A multi-center study [146] of the relation between alcohol and LBW detected a synergistic effect with tobacco, when alcohol consumption was higher than 20 g/dl, the risk increased in both groups, smokers and non-smokers.

In conclusion, many authors affirm that there is often concurrent consumption of tobacco, alcohol and even other drugs, causing a significant amount of LBW [147], [148], [149], [150], [151], and [152].

3.5.4. Caffeine consumption

The methylxantines, especially caffeine and teofiline, are contained in many food products, frequently consumed beverages (coffee, tea, cola and chocolate drinks), and drugs (against allergies, diuretics, stimulants) [153]. The methylxantines consumed by the mother cross the placenta and can enter the foetal blood, where they act as CNS and heart muscle stimulants, and smooth muscle relaxants. Several studies have shown that caffeine consumption is decreased during pregnancy, perhaps in relation to a certain aversion induced by pregnancy [4] and [153]. The adverse effects of caffeine during pregnancy are well known, such as congenital malformations, IUGR, prematurity and miscarriage. The possibility of genetic effects due to caffeine consumption before conception has also been mentioned, although these results have not been sufficiently confirmed given that there are multiple confounding factors [153]. The association between caffeine consumption and low birth weight, however, remains a subject of some debate. While some authors maintain that this association exists for consumption of 300 mg per day [154], others do not find this relation, probably because there are discrepancies due to varying levels of individual tolerance to caffeine [155]. Wisborg et al. observed that the risk of preterm birth in women who consumed large doses of caffeine (>400 mg per day) and also smoked was three times higher than that of women who did not consume caffeine [156].

3.5.5. Drug consumption

The consumption of illicit drugs has been associated with a lower birth weight, due not only to the increase in prematurity, but also to the increased risk of IUGR [157].

The consumption of cocaine, especially crack cocaine, may produce IUGR, mainly as a consequence of vasoconstriction of the uterine vessels, which impedes the passage of nutrients to the foetus [158]. In this regard, it is estimated that up to 25–30% of women who consume cocaine during pregnancy will give birth to a SGA infant [4], a fact of great importance considering that consumption of this drug, especially crack, is increasing in the developed countries. A recent study identified cocaine as the drug with the strongest association with preterm birth and LBW [159]. A meta-analysis that reviewed this subject concluded that the children of mothers who consumed cocaine have a higher risk of congenital malformations, LBW, prematurity and placental alterations such as abruptio placentae or premature rupture in comparison to the children of non-users. But when the risk was compared with that of mothers who consumed multiple drugs, the individual effects of cocaine were attenuated [160].The risk related with the consumption of other drugs should also be considered. The consumption of crystal meta-amphetamine is also associated with IUGR. Narcotics such as heroin may produce IUGR seven times more frequently than in the general population [4], although it is not clear if opiates are an independent risk factor for IUGR. The consumption of methadone, marijuana or hallucinogenic drugs, alone, does not appear to be associated with IUGR, although it should be noted that it is difficult to isolate the effect of the consumption of a specific drug on foetal growth; several different drugs are usually associated with one another, often in combination with smoking and poor nutrition [4] and [160]. Finally, some drug prescriptions for the treatment of specific maternal diseases have been associated with increased IUGR, such as the coumarins and phenytoin [4]. As a general recommendation, investigators maintain that adequate prenatal care of female drug dependents can reduce the risk and severity of IUGR [161], [162], and [163].

3.5.6. Exposure to toxic substances

A pioneering study in Sweden between 1976 and 1986 found an increased incidence of LBW and prematurity in a cohort of women workers in the chemical industry. It was also observed that when occupational improvements aimed at palliating the risks were introduced, the adverse effects on pregnancy slowly decreased [164]. Since that time, many substances have been associated with LBW, among them, exposure to organochlorine compounds [165], [166], and [167] and sulfur dioxide [168]. Another documented source of toxicity for the foetus is exposure to formaldehyde, and many authors have related this agent directly with LBW and other reproductive problems [169].

3.5.7. Environmental exposures

Agricultural contamination of groundwater may represent a health risk through the drinking water. Among these risks, an ecologic study highlighted exposure to drinking water contaminated with nitrates and its relation to IUGR and prematurity [170]. The results confirm a positive association with a clear dose–response association. Other studies analyze the recent hypothesis of a relation between environmental contamination and LBW. Infants born in highly contaminated areas have a lower mean weight than those born in non-contaminated areas. The association is maintained after adjusting for other confounding factors [171]. Finally, there is no doubt that exposure to ionizing radiation during pregnancy can give rise to serious IUGR, together with the appearance of CNS lesions. The vulnerability of the foetus depends both on the dose of radiation received and on the moment in pregnancy when it is produced. Early exposures, in the first trimester, may cause general growth retardation, sometimes associated with microcephaly and other CNS anomalies. The effects of radiation on foetal weight also depend on how the radiation acts on the placenta [3].

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Footnotes

a Department of Obstetrics and Gynecology, Hospital Universitario Santa Cristina and Medicine School of Autonomous University of Madrid, Spain

b Health Center “Canal de Panamá”, Área Sanitaria 4 of Madrid, Spain

c Department of Preventive Medicine and Public Health, Medicine School of the Complutense University of Madrid, Spain

* Corresponding author. Tel.: +34-91-394-1520; fax: +34-91-394-1895.