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The Mechanisms of Low Birth Weight in Infants of Mothers With Homozygous Sickle Cell Disease

^a Department of Obstetrics, Gynaecology, and Child Health, University of the West Indies, Mona
^b Chronic Disease Research Centre, Tropical Medicine Research Institute, University of the West Indies, Barbados, West Indies
^c Sickle Cell Trust, Kingston, Jamaica

	ABSTRACT

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OBJECTIVE. A low mean birth weight is a constant finding in pregnancies of women with homozygous sickle cell disease. The factors responsible are largely unknown and have now been investigated in an 11-year retrospective analysis.

METHODS. Records for 126 pregnancies of mothers with homozygous sickle cell disease and 126 pregnancies of control women with an AA phenotype, matched according to age and date of delivery, were examined. Events during pregnancy and outcomes of pregnancy were recorded.

RESULTS. Pregnancy outcomes for mothers with homozygous sickle cell disease confirmed the lower birth weight, gestational age, and placental weight. A low birth weight in infants of mothers with homozygous sickle cell disease was strongly related to gestational age and placental weight and weakly related to reticulocyte counts and a history of preeclampsia in univariate analyses, but only gestational age and placental weight remained significant in multivariate analyses. No relationships were seen with maternal age, parity, anthropometric features, other hematologic features (hemoglobin levels, fetal hemoglobin levels, mean cell volume, and -thalassemia), pregnancy-induced hypertension, or prepartum hospital admissions (expressed as number or total days). Compared with Jamaican standards, birth weight was affected more than head circumference or length in infants of mothers with homozygous sickle cell disease, indicating asymmetric growth retardation, which occurred for 27% of boys and 38% of girls (compared with 4% and 9%, respectively, among infants of control mothers).

CONCLUSIONS. A chronic condition such as homozygous sickle cell disease might have been expected to cause symmetric growth retardation throughout pregnancy. The finding of asymmetric retardation might indicate adverse factors emerging late in pregnancy and might have relevance for the poor pregnancy outcomes in such mothers.

Key Words: homozygous sickle cell disease • birth weight • intrauterine growth • risk factors

Abbreviations: SS—homozygous sickle cell • HbF—hemoglobin F • IUGR—intrauterine growth retardation

Rates of fetal loss are increased in mothers with homozygous sickle cell (SS) disease, and low birth weight characterizes surviving pregnancies.^1–3 Gestational age, a major determinant of birth weight, is also lower in mothers with SS disease.^2,4 After controlling for maternal age, maternal genotype, and gestational age, the Cooperative Study of Sickle Cell Disease in the United States² found that birth weight was influenced by preeclampsia, acute anemic episodes, and maternal hemoglobin F (HbF) levels. However, the inclusion of different genotypes of sickle cell disease (which may have markedly different pregnancy outcomes) and the imprecise definition of acute anemic episodes were weaknesses of that study. Furthermore, data on placental weight, a factor of potential significance, were not presented in the Cooperative Study of Sickle Cell Disease. The Jamaican Cohort Study⁴ found that birth weight was influenced by maternal genotype (SS versus AA), gestational age, maternal prepregnancy weight, and the number of prepartum clinical events, but that study was limited by having only 43 live births among 33 mothers with SS disease and lacked data on other potential determinants. Those observations have now been extended in a retrospective study of 126 singleton deliveries to mothers with SS disease and 126 deliveries to control subjects over 11 years at the University Hospital of the West Indies (Kingston, Jamaica). The analysis provides a larger number of births, more baseline data (including steady-state hematologic data, weight gain, and blood pressure changes during pregnancy), placental weight, and newborn anthropometric data. A remarkable finding was that the growth retardation in infants born to mothers with SS disease was asymmetrical, which suggests a factor operating in later pregnancy.

	METHODS

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Patients and Control Subjects
The study included 126 singleton pregnancies of mothers with SS disease and a comparison group of 126 pregnancies of women with an AA phenotype, matched as closely as possible according to maternal age and date of delivery, that occurred at the University Hospital of the West Indies during an 11-year period (January 1, 1992, to December 31, 2002). Matching according to infant date of birth was performed after each delivery to a SS mother, and the mean interval between patient and control deliveries was 25.6 days, with 60 deliveries (48%) being matched within 30 days. Matching according to maternal age showed a mean difference of 0.58 years. The genotype diagnosis was based on standard criteria,⁵ and mean red blood cell volume and hemoglobin A₂ levels consistent with SS disease excluded the diagnosis of sickle cell β-thalassemia. The comparison group had an AA phenotype, as confirmed by hemoglobin A and hemoglobin A₂ in hemoglobin electrophoresis, but hemoglobin A₂ was not quantitated routinely and mothers with the β-thalassemia trait would not have been detected. This trait occurs in 1.5% of Jamaicans and might have accounted for 1 to 3 subjects.

The records of all pregnancies were examined for the mother's date of birth, dates of last menstrual period and expected delivery, date of first prenatal clinic attendance, and maternal height, weight, and BMI at first prenatal clinic attendance (missing heights and weights for SS subjects were supplemented with prepregnancy values from up to 1 year before pregnancy, because weight in early pregnancy does not differ from prepregnancy weight⁶). Height was measured with a stadiometer and weight was measured with a level balance, with heavy clothing removed. Events during pregnancy included prepartum SS-related hospital admissions (number, cause, and duration), changes in weight, blood pressure, and urinalysis results during the prenatal period, and diagnoses of preeclampsia or pregnancy-induced hypertension. The outcomes of pregnancy were recorded as live birth or stillbirth, gestational age, mode of delivery, and birth weight, head circumference, and crown-heel length of the infant. The study was approved by the University of the West Indies/University Hospital of the West Indies ethics committee.

Hematologic Methods
Routine hematologic indices were measured in venous blood on calibrated electronic counters, reticulocytes were counted manually after supravital staining with brilliant cresyl blue, and HbF was measured through alkali denaturation.⁷ Hemoglobin levels during pregnancy were measured at the time of prenatal clinic attendance. Hematologic indices used in the regression analysis of birth weights were the means of multiple steady-state measurements at >5 years of age. These values excluded those associated with acute clinical problems or pregnancy or obtained within 3 months after transfusion. Assessment of the presence of -thalassemia was based on analysis of globin gene number⁸ in DNA extracted from peripheral blood through routine measures.

Clinical Definitions
Fetal loss after 24 weeks was classed as stillbirth, and neonatal deaths were defined as occurring within 28 days after live delivery. Gestational age and maternal age were calculated from the last menstrual period. In almost all cases, gestational age was confirmed with ultrasonography and corrected if there was a clear discrepancy in results. The incomplete ultrasound data did not allow assessment of intrauterine growth retardation (IUGR), but small for gestational age implied a birth weight below the 10th percentile for gestational age,⁹ as derived from local standards.¹⁰ Growth was classified as symmetrical if all indices were below the 10th percentile and asymmetrical if only weight was affected.

Acute chest syndrome was defined as pulmonary symptoms associated with evidence of a new pulmonary infiltrate on chest radiographs. Painful crisis referred to typical SS-related bone pain of sufficient severity to require narcotic analgesia. Gestational hypertension (pregnancy-induced hypertension) was defined as pressure of 140 mm Hg (systolic) or 90 mm Hg (diastolic) after 20 weeks of gestation, in the absence of proteinuria, in subjects without chronic hypertension and for whom blood pressure returned to normal by 1 month after delivery.¹¹ Preeclampsia was indicated by the same blood pressure criteria but with proteinuria. Proteinuria was defined with dipsticks as a trace or more for SS patients (trace was included as significant because of the lower urinary concentration in SS disease) and 1 for AA subjects; lesser amounts were considered as absence of proteinuria. Urinary tract infection applied to urinary symptoms with positive urine culture results. Hospital admission was restricted to problems unrelated to the onset of labor (predelivery admissions).

Statistical Analyses
BMI was calculated from weight and height at the first prenatal visit. Logistic regression was used to assess potential associates of low birth weight and was modeled by using a manual stepwise procedure with adjustment for gestational age. For mothers with SS disease, potential associates of birth weight that were examined included maternal baseline characteristics (age, parity, weight, height, BMI, blood pressure, steady-state hemoglobin level, mean red blood cell volume, reticulocyte count, and HbF level), changes in weight and blood pressure during pregnancy, evidence of pregnancy-induced hypertension or preeclampsia during pregnancy, hospital admissions during pregnancy (expressed as number of admissions and total duration of inpatient days), gestational age at delivery, gender of child, and placental weight. For control mothers, potential associates of birth weight were similar except for the exclusion of hematologic data and hospital admissions during pregnancy. Because 10% of deliveries to mothers with SS disease terminated in stillbirths, which tend to be associated with prematurity and low birth weight, analyses were confined to live deliveries.

	RESULTS

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Baseline Characteristics of Patient Groups
There were similar maternal age distributions, marginally higher parity among control subjects, and lower weight, greater height, lower BMI values, lower systolic and diastolic blood pressures, and lower hemoglobin levels among mothers with SS disease (Table 1). Unexpectedly, a smaller proportion of mothers with SS disease (63% vs 91%) attended the prenatal clinic before 15 weeks.

Pregnancy Outcomes for Fetuses
Mothers with SS disease had greater fetal loss, that is, 13 stillbirths (10%) and 2 neonatal deaths, compared with 2 stillbirths and no neonatal deaths among control subjects (P = .001). Delivery methods did not differ between maternal genotypes (SS disease: vaginal deliveries, n = 89; lower-segment cesarean sections, n = 37, 29%; control: vaginal deliveries, n = 94; lower-segment cesarean sections, n = 33, 25%). Infants of mothers with SS disease had lower gestational age, birth weight, crown-heel length, and placental weight (Table 3) and Apgar scores at 1 minute, although by 5 minutes the difference in scores was no longer significant. For infants of mothers with SS disease, the deficit in birth weight was greater than the deficits in head circumference and crown-heel length, indicating asymmetric growth retardation. Compared with the 10th percentile of normal standards from the Jamaican Perinatal Study,¹⁰ infants of mothers with SS disease had low birth weights more frequently than did control subjects but head circumference and crown-heel length did not differ between maternal genotypes (Table 4). These observations indicate asymmetric growth retardation in infants of mothers with SS disease.

	DISCUSSION

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The low birth weight of infants born to mothers with SS disease is one of the most consistent findings. Birth weights were <2500 g in 28% of cases in Jamaica,¹ in 38% of cases in the Cooperative Study of Sickle Cell Disease in the United States,² in 31% of pregnancies managed without prophylactic transfusion in the United States,³ and in 20 (42%) of 48 cases in the Jamaican Cohort Study.⁴ Factors associated with lower birth weight for mothers with SS disease are varied and inconsistent but have included lower gestational age,^2,4 lower maternal age,² lower maternal weight,⁴ history of preeclampsia,² history of acute anemic episodes,² maternal HbF levels,² and the number of SS-related complications during pregnancy.⁴ The only consistent factor is lower gestational age, which could be influenced by a high frequency of early surgical delivery or premature induction, both of which are common interventions in management of pregnancy among mothers with SS disease. In the current study, the cesarean section rates were similar for patients and control subjects, and early induction of delivery did not contribute significantly to the lower gestational age.

In normal populations, maternal hemoglobin levels influence birth weight, although the relationship is complex. Some studies suggest a U-shaped relationship, with birth weights being higher in women whose lowest hemoglobin levels were in the 9.5 to 10.6 g/dL¹² or 9.0 to 10.9 g/dL¹³ range and low birth weights being more common with higher and lower hemoglobin levels; others reported only a lowered birth weight with a maternal hematocrit level of <24% in Nepal¹⁴ or a hemoglobin level of <6.0 g/dL in Ghana.¹⁵ In addition to a deleterious effect on birth weight, high hematocrit levels have been implicated in IUGR¹⁶ and preterm delivery.^17,18 However, interpretation of those studies may be confounded by the duration and severity of anemia, obstetric factors contributing to the anemia or to gestational age, and the role of nutritional supplementation during prenatal care. Furthermore, hemoglobin levels change during pregnancy, declining up to 20 weeks of gestation, remaining constant from 20 to 30 weeks, and increasing thereafter, and the timing of the hemoglobin sample may also be relevant. Steady-state hemoglobin levels between 6.0 and 9.0g/dL characterize most patients with SS disease, but hemoglobin S within red blood cells manifests a lower oxygen affinity, tending to increase oxygen delivery. Patients with the lowest oxygen affinity tend to have the lowest hematocrit levels, and low hemoglobin levels within the steady-state range do not necessarily imply low oxygen carriage. Therefore, it was not surprising that hemoglobin levels for mothers with SS disease did not influence birth weight, despite strong associations in the normal population. There is a dearth of data on the serial hematologic features of SS patients during pregnancy, and it would be of interest to monitor sequential changes before discounting any role of hemoglobin levels in pregnancy outcomes.

Other potentially important hematologic features of SS patients that inhibit sickling are increased levels of HbF and the presence of -thalassemia. Inhibition of sickling by high HbF levels might be beneficial, but HbF has high oxygen affinity and high maternal levels might conflict with oxygen transport to the fetus; there are conflicting data on the effects of high HbF levels on birth weights, which have been reported as low,¹⁹ normal,¹ or high.² The Cooperative Study of Sickle Cell Disease calculated that HbF levels above a median level of 5.2% were associated with birth weights 116 g higher than those with lower HbF levels, but no relationship was noted in the current study. -Thalassemia inhibits sickling by decreasing the mean cell hemoglobin concentration, but there was no beneficial effect on birth weight in the Cooperative Study of Sickle Cell Disease² or the current report. The lack of clear associations between birth weight and factors inhibiting sickling cast doubt on a role for sickling per se in the low birth weight of infants of mothers with SS disease.

Adverse clinical events during pregnancy might affect birth weights, which were lower in the Cooperative Study of Sickle Cell Disease² for mothers with a history of acute anemic episodes, but such events were poorly defined and were likely to be heterogeneous. The Jamaican Cohort Study⁴ found a significant contribution from SS-related events (painful crisis, acute chest syndrome, or urinary tract infection), with a single event lowering birth weight by 0.35 kg and 2 events lowering birth weight by 0.49 kg. A history of preeclampsia lowered birth weight by a mean of 0.17 kg in the Cooperative Study of Sickle Cell Disease,² and regression models including a history of preeclampsia, acute anemic events, and HbF levels accounted for 63% of the variance in birth weight. The Jamaican Cohort Study,⁴ using similar regression techniques, found that gestational age, maternal weight, and SS-related events during pregnancy accounted for 67% of the variance in birth weight. None of these relationships was apparent in the present study, which, with regression analysis based on 71 deliveries to mothers with SS disease, was able to confirm significant relationships only with gestational age and placental weight. The conflict between these data and those reported previously in the Jamaican Cohort Study⁴ is difficult to explain, because they involve similar populations, but the intensive prospective monitoring in the Jamaican Cohort Study might have yielded more-sensitive and more-accurate data on complications.

The placenta, an integral unit of fetal growth and hence birth weight,^19,20 weighed significantly less among SS women and commonly showed placental pathologic features usually attributed to placental infarction.²¹ Placental weight cannot be assumed to equate with placental function, but progressive placental infarction might be expected to reduce the overall placental mass and weight. The occurrence of placental pathologic features in mothers with SS disease is supported by the significantly increased prevalence of retained placenta. The mechanisms contributing to placental infarction need clarification with additional study.

The definition of growth retardation is for indices to fall in the <10th percentile for the normal population. Only limited data are available on newborn indices in the Jamaican population, and we depended on those derived from the Jamaican Perinatal Study performed in 1986.¹⁰ Contrary to the expectation that 10% of values would fall below this cutoff point, only 3% to 4% of the normal control subjects in the current study did so, consistent with significant secular changes having occurred in the past 20 years. Such secular changes could also explain the high mean and median percentiles among normal control subjects, compared with values predicted from 20-year-old data. However, this does not negate the clear genotype-related differences in newborn anthropometric features. Furthermore, it could be argued that the definition of asymmetry might be derived from minor differences in actual values, such as weight in the 9th percentile and length in the 10th percentile, but it is clear from Table 4 that median weights were in the 12th to 19th percentile, compared with median lengths in the 44th to 57th percentile. There is little doubt that infants born to mothers with SS disease have low ponderal indices, similar to their mothers.

IUGR has been classified as symmetric (all organs reduced proportionately in size) or asymmetric (brain less affected than other organs), on the basis of autopsy studies²² or clinical ultrasonographic findings.²³ The latter authors studied 31 small-for-gestational age infants and noted that 22 (71%) were asymmetric, with low birth weights but high head circumference/abdominal circumference ratios. Subsequent pediatric examination showed these infants to be wasted, with thin skinfolds, and it was proposed that the timing of the adverse factor was crucial,²⁴ with symmetric IUGR reflecting adversity in early pregnancy (maternal malnutrition, smoking, drug exposure, congenital abnormalities, or intrauterine infection) and asymmetry following "uteroplacental failure." However, this hypothesis could not be confirmed in several studies,^25–27 and the distribution of ultrasound indices followed a single Gaussian curve, with no evidence of 2 populations.²⁸ Comparisons of head circumference/abdominal circumference ratios with newborn anthropometric features²⁴ or ponderal indices²⁹ cast doubt on the value of head circumference/abdominal circumference ratios, which seemed less sensitive than weight/length ratios. Although the interpretation of symmetry or asymmetry in IUGR may be open to debate, the distinction may be important in predicting neonatal outcomes.^24,30 Despite the extensive literature on anemia and reduced birth weight, no published information could be found on symmetry, asymmetry, or ponderal indices of growth-retarded infants in anemia resulting from either iron deficiency or sickle cell disease. The current study is the first identifying this IUGR as asymmetric, contrary to the symmetric IUGR that might have been anticipated for mothers with a chronic disease.

A minor but potentially important finding was the later first attendance at the prenatal clinic of SS women, but this requires cautious interpretation. Patients with SS disease are usually monitored in the "high-risk" clinic at the University Hospital, which makes allowance for late attenders. Normal women who present late for prenatal care are often referred to services in other hospitals, and early attenders are more likely to be accepted for prenatal care. However, the importance of prenatal care must be stressed to SS patients, because early attendance allows close monitoring, which is likely to improve pregnancy outcomes.

	FOOTNOTES

 
Address correspondence to Minerva Thame, DM, PhD, Department of Obstetrics, Gynaecology, and Child Health, University of the West Indies, Mona, Kingston 7, Jamaica, West Indies. E-mail: piperhcp{at}cwjamaica.com

The authors have indicated they have no financial relationships relevant to this article to disclose.

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This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Thame, M. Articles by Serjeant, G. Search for Related Content PubMed PubMed Citation Articles by Thame, M. Articles by Serjeant, G. Related Collections Blood

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