Beta-Thalassemia Minor During Pregnancy

Sheiner, Eyal MD*; Levy, Amalia PhD; Yerushalmi, Ronit MD; Katz, Miriam MD*
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From the Departments of *Obstetrics and Gynecology, Epidemiology and Health Services Evaluation, and Hematology, Faculty of Health Sciences, Soroka University Medical Center, Ben Gurion University of the Negev, Be'er-Sheva, Israel. Address reprint requests to: Eyal Sheiner, MD, Department of Obstetrics and Gynecology, Soroka University Medical Center, Box 151, Be'er-Sheva, Israel; e-mail: sheiner@bgumail.bgu.ac.il. Received January 14, 2004. Received in revised form February 29, 2004. Accepted March 11, 2004 .

Abstract
OBJECTIVE: To investigate pregnancy outcome of patients with -thalassemia minor. METHODS: A population-based study comparing all pregnancies of women with and without thalassemia minor was conducted. Deliveries occurred during the years 1988 2002 at Soroka University Medical Center. A multivariate logistic regression model, with backward elimination, was constructed to find independent risk factors associated with maternal -thalassemia minor. RESULTS: During the study period there were 159,195 deliveries, of which 261 (0.2%) occurred in patients with -thalassemia minor. The following conditions were significantly associated with thalassemia minor: oligohydramnios (odds ratio [OR] 2.1; 95% confidence interval [CI] 1.2%, 3.7%), intrauterine growth restriction (IUGR; OR 2.4; 95% CI 1.4%, 4.2%), Jewish ethnicity (OR 1.5; 95% CI 1.2%, 1.9%), and previous cesarean delivery (OR 1.4; 95% CI 1.1%, 2.0%). No significant differences were noted between the groups regarding perinatal outcomes such as birth weight, low Apgar scores, congenital malformations, or perinatal mortality. Patients with -thalassemia minor were more likely to have cesarean deliveries than were the nonthalassemic parturients (16.9% and 12.2%, respectively; P = .021). However, while controlling for possible confounders such as IUGR, oligohydramnios, and previous cesarean delivery, with another multivariate analysis with cesarean delivery as the outcome variable, thalassemia minor was not found as an independent risk factor for cesarean delivery (OR 1.3; 95% CI 0.9%, 1.9%). CONCLUSION: The course of pregnancy of patients with thalassemia minor, including perinatal outcomes, is favorable. Because higher rates of IUGR were found, we recommend ultrasound surveillance of fetal weight for early detection of IUGR. LEVEL OF EVIDENCE: II-2 Thalassemias are hemoglobinopathies characterized by impaired production of the normal globin peptide chains. Their prevalence and severity are population dependent. High prevalence exists among Mediterranean inhabitants, and thus many publications on this problem originated in Mediterranean countries.14 The -thalassemias are the consequence of impaired and reduced production of globin chains, in most cases caused by point mutation, and are extremely heterogeneous at the molecular as well as the phenotypic point. Thalassemia major (Cooley's anemia) is characterized by marked ineffective erythropoiesis and severe hemolysis. These patients tend to experience delayed sexual development and reduced fertility, mainly because of anovulation subsequent to hemosiderin deposition.5Pregnancy in thalassemia major patients was extremely rare until the introduction of hypertransfusions and iron chelation therapy in the late 1970s.1,6 Later, Jensen et al7 reported favorable perinatal outcome of 16 pregnancies in patients with -

thalassemia major, although they found a high cesarean delivery rate.7 Indeed, high rate of cesarean deliveries was reported by all other studies.14,69 Although -thalassemia major represents the homozygous state, -thalassemia minor represents the heterozygous state. Thalassemia minor results in a variable degree of the disease but, depending on the rate of -chain production, usually presents as asymptomatic anemia of mild degree (the hemoglobin is 12 g/dL lower than normal persons of the same age and sex). There is no specific therapy for thalassemia minor during pregnancy, but if the anemia becomes more severe, transfusions are sometimes necessary. Little is reported regarding perinatal outcome of patients with -thalassemia minor. A few studies including small numbers of patients suggested a favorable outcome.2,7,10 Fertility in general among these patients is not impaired, and no menstrual abnormalities exist.2 Likewise, the incidence of premature and low birth weight infants was found to be comparable to the general population.10 However, few reported adverse outcome caused by hypercoagulability,11 and the need for more data, particularly for the heterogeneous group of thalassemia minor patients, was recognized. 1 The present study was designed to investigate pregnancy outcome of patients with -thalassemia minor. During a 15-year period, we were able to examine a relatively large number of women with -thalassemia minor who delivered in the southern part of Israel.
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MATERIALS AND METHODS

A population-based study comparing all pregnancies of women with and without -thalassemia minor was conducted. Deliveries occurred during the years 1988 2002 at the Soroka University Medical Center. This is the sole hospital in the Negev, the southern part of Israel, and it serves the entire obstetric population in this region. Thalassemia was diagnosed according to the referral documents. These women were identified by the referring physician because of an incidental finding of anemia, symptomatic anemia, or a history of thalassemia in the family. Women presenting for routine prenatal care were not offered genetic thalassemia screening. Data were collected from the computerized perinatal database that consists of information recorded directly after delivery by an obstetrician. Only 4 skilled medical secretaries examine the information routinely before entering it into the database. Coding was done after assessing the medical prenatal care records as well as the routine hospital documents. These procedures assure maximal completeness and accuracy of the database. The following clinical characteristics were evaluated: ethnicity (ie, Jewish or Bedouin Arabs), maternal age, parity, gestational age, maternal anemia during pregnancy (hemoglobin less than 10 g/dL), birth weight, and small for gestational age (birth weight below the 10th percentile, using local standards). The following obstetric risk factors were examined: previous cesarean delivery, recurrent abortions (2 or more consecutive pregnancies resulting in spontaneous abortion), fertility treatments, hypertensive disorders,12,13 gestational diabetes mellitus,14 and premature rupture of membranes. In addition, the following risk factors were investigated during routine third-trimester ultrasound screening: hydramnios (amniotic fluid index more than 24 cm), oligohydramnios (amniotic fluid index 5 cm or less), and intrauterine growth restriction (IUGR).15 The following labor characteristics and perinatal outcomes were assessed: placental abruption, placenta previa, meconium-stained amniotic fluid, cephalopelvic disproportion, vacuum extraction, cesarean delivery, Apgar score at 1 and 5 minutes less than 7, congenital malformations, perinatal mortality, postpartum hemorrhage, and maternal packed-cell transfusions. The local ethics institutional review board approved the study. Statistical analysis was performed with the SPSS package (SPSS Inc, Chicago, IL). Statistical significance was calculated by using the 2 or Fisher exact test for differences in qualitative variables and the ttest for differences in continuous variables. A multivariate logistic regression model, with backward elimination, was constructed to find independent risk factors associated with maternal -thalassemia minor. Odds ratios (ORs) and their 95% confidence intervals (CIs) were computed. A value of P < .05 was considered statistically significant. Receiver operating characteristic curve analysis was used to describe the relationship between the sensitivity (true positive rate) and the false-positive rate for hemoglobin level in the prediction of IUGR. The data points for the receiver operating characteristic curve were derived

exclusively from the thalassemia subjects. The area under the receiver operating characteristic curve was calculated by SPSS 11.0 statistical software package.
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RESULTS
During the study period there were 159,195 deliveries, of which 261 (0.2%) occurred in patients with thalassemia minor. Beta-thalassemia minor was significantly more common among Jewish than Bedouin parturients. No statistically significant differences were noted between the groups regarding maternal age, birth order, or birth weight (Table 1). Higher rates of maternal anemia were found among the thalassemic than the nonthalassemic women.

Table 1
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Obstetric risk factors are presented in Table 2. There were higher rates of previous cesarean delivery, oligohydramnios, and IUGR among parturients with -thalassemia minor than nonthalassemic patients.

Table 2
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Patients with -thalassemia minor were more likely to have cesarean deliveries than the nonthalassemic parturients (Table 3). No significant differences were noted between the groups regarding perinatal outcomes such as low Apgar scores, congenital malformations, or perinatal mortality. Higher rates of treatment with packed-cell transfusions were observed among patients with -thalassemia minor.

Table 3
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By using a multivariate analysis with backward elimination, the following conditions were significantly associated with -thalassemia minor (Table 4): IUGR, oligohydramnios, Jewish ethnicity, and previous cesarean delivery. However, by using a receiver operating characteristic curve investigating hemoglobin level in predicting IUGR among the thalassemic patients, the plot was close to the diagonal line (the area under the curve was 0.58; Figure 1).

Table 4

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Figure 1

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After controlling for possible confounders, such as IUGR, oligohydramnios, and previous cesarean delivery, by using another multivariate analysis with cesarean delivery as the outcome variable, thalassemia minor was not found as an independent risk factor for cesarean delivery (Table 5).

Table 5
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DISCUSSION

The present study includes a large number of patients with -thalassemia minor. Our study design differed extensively from most other studies investigating pregnancy outcome of patients with thalassemia. Whereas the latter were mostly descriptive, giving detailed characteristics of the thalassemic patients, we performed a population-based study, enabling us to describe independent risk factors associated with -thalassemia minor. The major finding of our population-based study is that thalassemia minor is not associated with adverse perinatal outcome. Perinatal mortality, congenital malformations, and Apgar scores are similar in patients with and without thalassemia minor. This is in accordance with previous studies, done with small numbers of patients.2,7,10 An exception is the rates of IUGR and oligohydramnios, which were found to be higher in the thalassemic patients than in the rest of our population. Chronic maternal anemia during gestation might lead to fetal hypoxia, predisposing the fetus to IUGR.16,1,7 Thus, it was suggested that hemoglobin concentration should be maintained above 10 g/dL during pregnancy.16 However, no significant association was found between hemoglobin levels and IUGR among thalassemic women in our study using a receiver operating characteristic curve, suggesting that a different mechanism is responsible for IUGR in thalassemia minor patients. The power of this study to detect an association between hemoglobin and IUGR with difference in means of 0.38 g/dL is 95.3%. Oligohydramnios is associated with IUGR15 and might be part of the relative hypoxemic state. It should be noted that although a nonsignificant trend toward higher rates of small for gestational age neonates among the thalassemic patients was found, it did not reach statistical significance (OR 1.4; 95% CI 0.9%, 2.2%; P = .09). All studies investigating pregnancy outcome of patients with -thalassemia found higher rates of cesarean delivery.14,69 Likewise, in our study we found higher rates of cesarean delivery, about 17%. Although statistically significant, the cesarean delivery rates are lower than those described previously.14,6 9 Moreover, after controlling for confounders such as oligohydramnios, IUGR, and previous cesarean delivery, -thalassemia minor was not found to be an independent risk factor for cesarean delivery (Table 5). Thus, it is the association with other risk factors, and not the thalassemia minor per se that led the obstetrician to perform a cesarean delivery. Cephalopelvic disproportion, caused by spleen enlargement, was suggested as a possible cause for cesarean delivery in thalassemic patients. 7,9,16Significant enlargement of the spleen, leading to dystocia during labor, was previously related to patients with thalassemia minor.1,16Interestingly, although no data regarding the size of the spleen exist in our database, no cases of relative cephalopelvic disproportion were recorded. High demand for ovulation induction and in vitro fertilization was found among patients with thalassemia.2,5,7,8 This was accounted for basically by -thalassemia major, where hemosiderin deposition in the hypothalamus and pituitary leads to anovulation.5 Indeed, in the -thalassemia minor state, low rates of fertility treatments (of 9.6%) were reported.2 Aessopos et al1 investigated well-treated patients with thalassemia (major and minor), and found the rates of infertility and spontaneous abortions to be comparable to those expected among healthy women. Low rates of fertility treatments (including ovulation induction and in vitro fertilization) were found in our study; these rates were equivalent to the rest of the population. Likewise, the rates of spontaneous abortions were comparable to patients without thalassemia minor. A large proportion of our population comprises Bedouin women. The Bedouins are a traditional society that attributes great importance to familial cohesiveness and to fertility. The Bedouins tend to underuse prenatal care services because of objective problems of access (physical distance, need to be accompanied when traveling, etc), cultural barriers (avoiding invasive procedures and abortions), and personal choices.1719 The relative low rates of -thalassemia minor found in our study may represent underdiagnosis of this condition in our Mediterranean population in general and among the Bedouins in particular. Indeed, no general screening was performed, and the lack of uniform testing for thalassemia represents a weakness of the study. It confounds the conclusions with the probability that cases of thalassemia minor were missed, and a significant number of unidentified carriers were in the control group. It also seems that because prenatal care varied for different ethnic populations, the frequency of prenatal screening for thalassemia would likely vary for the different populations in the study. In conclusion, the results of our population-based analysis are encouraging. The course of pregnancy of patients with -thalassemia minor, including perinatal outcomes, is favorable. However, higher rates of IUGR were found among thalassemic women. Although this conclusion requires confirmation by a second

observational study before intervention is recommended, careful surveillance should be performed. Such follow-up should include early third-trimester ultrasound assessment of fetal weight for early detection of IUGR. Further prospective studies among high-risk populations for -thalassemia should investigate the efficacy of such surveillance programs.
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