The Journal of Maternal-Fetal and Neonatal Medicine, August 2005; 18(2): 101105

The effect of malarial infection on maternal-fetal outcome in Ecuador

E. ESPINOZA1, L. HIDALGO1, & P. CHEDRAUI1,2

1

High Risk Pregnancy Unit of the Enrique C. Sotomayor Obstetrics and Gynecology Hospital, Guayaquil, and 2Institute of Biomedicine, Facultad de Ciencias Me dicas, Universidad Cato lica de Santiago de Guayaquil, Ecuador

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Abstract Objective. To describe maternal and fetal outcome among pregnancies complicated with malarial infection. Methods. Charts of pregnancies complicated with malarial infection were reviewed. Parasital etiology and maternal/fetal data was analyzed. Results. During the year 2001, at the Enrique C. Sotomayor Obstetrics and Gynecology Hospital, Guayaquil-Ecuador, 80 pregnancies complicated with malarial infection were admitted for treatment. This rendered an incidence of 2.1 per 1,000 live births (80/37,579). Mean maternal age was 25.2 + 6.7 years and the 1929 age group was the most frequently affected (50%). On admittance, fever, chills, jaundice and anemia was present in 97.5%, 78.8%, 38.8% and 60% respectively. Falciparum was the most frequently presenting species (56.3%). Patients admitted at 5 20 weeks gestation (n = 17) had a 76.5% and 82.4% abortion and adverse fetal outcome rate respectively. Among those admitted at 2036 weeks (n = 55) the rates for preterm birth, intrauterine fetal death, low birthweight (LBW) and small-for-gestational age (SGA) were 34.5%, 11%, 40.8% and 48.9% respectively. Among patients admitted 4 36 weeks, 87.5% (7/8) ended in a live term delivery. Adolescents presented a higher rate of anemia and SGA neonates. The overall (n = 80) abortion, preterm delivery and intrauterine fetal demise rates were 16.3%, 25% and 8.8% respectively. Chloroquine effectively treated 98.8% of cases and there was one maternal death due to falciparum infection. Conclusions. In this Ecuadorian population, malarial infection complicating gestation was associated to adverse maternalfetal outcome, which was more evident among teenagers and pregnancies presenting malaria at an earlier gestational age.

Keywords: Anemia, gestational complications, malaria, plasmodium, pregnancy

Introduction Malaria is an anopheles mosquito-transmitted protozoan infection. In the world, several species have been identied, the most common: falciparum, vivax, malariae and ovale. Red blood cell destruction occurs during erythrocytic cycle of the parasital infection producing fever, chills, malaise, jaundice and severe anemia [1,2]. Adverse outcomes have been reported when malarial infection complicates pregnancy; in the mother: severe anemia, hypoglycemia, cerebral malaria, pulmonary edema and death; and in the fetus: preterm birth, low birthweight, abortions, fetal growth restriction and demise [36]. Factors predicting severity of malarial infection during gestation and therefore increasing the risk for adverse outcomes and perinatal transmission have been elucidated: maternal age, parity and immunological status (immunized vs. non immunized), geographical area (meso or holoendemic), protozoan species, degree of parasitemia and placental infection [711].

In Ecuador, the number of cases of malaria has increased continuously over the last years with more than 100,000 cases in the year 2000, 50% being diagnosed as falciparum malaria [12]. The majority of studies regarding pregnancy and malarial infection have been performed in holoendemic areas (i.e., Africa), whereas reports of this association in mesoendemic areas, such as the Americas including Ecuador, are to the best of our knowledge scarce or non-existent. Although multiple drug resistance has been reported, chloroquine is still a safe and effective agent used for the treatment and prevention of gestational malarial infection [1315]. The objective of the present research was to describe in an Ecuadorian population maternal-fetal outcome among pregnancies complicated with malarial infection. Materials and methods After Institutional Review Board approval we carried out this retrospective study at the Enrique C.

Correspondence: Peter Chedraui, MD, Institute of Biomedicine, Facultad de Ciencias Me dicas, Universidad Cato lica de Santiago de Guayaquil, PO Box 0901-4671, Guayaquil, Ecuador. Tel/Fax: + (5934) 220 6958. E-mail: peterchedraui@yahoo.com ISSN 1476-7058 print/ISSN 1476-4954 online 2005 Taylor & Francis DOI: 10.1080/147670500231989

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E. Espinoza et al. respectively. A p value of 5 0.05 was considered signicant. Results During the year 2001, 80 obstetrical patients were admitted and treated for malarial infection. This rendered an incidence of 2.1 per 1,000 live births (80/37,579). General maternal demographics, symptoms and laboratory results on admittance are depicted on Table I. Mean maternal age was 25.2 + 6.7 years. All patients were of low socioeconomic condition and 45% came from rural endemic areas. Among the most important symptoms on admittance were fever, chills and jaundice (97.5%, 78.8% and 38.8% respectively). The most frequently affected age group was the 1929 (50%). In 60% (n = 48) of cases, anemia was present (hemoglobin 5 11 g/dL) of which 30 required transfusion and 12 were admitted to ICU (Data not shown). Patients were admitted as only presenting with symptoms of malarial infection in 51.3% of cases, the remaining were additionally admitted with an obstetrical associated complication of which the three most important were: premature rupture of membranes, threatened preterm labor and abortion: 13.8%, 13.7% and 7.5% respectively (Table II). A general overview of all 80 cases regarding maternal fetal outcome is depicted on Table III. Patients were divided into three groups according to gestational age on admittance: 5 20 weeks, 2036 weeks and 4 36 weeks gestation. Only two species of malaria were encountered in this series, vivax and falciparum, the latter the most frequent (56.3% 45/ 80).

Sotomayor Obstetrics and Gynecology Hospital, Guayaquil, Ecuador. We reviewed the charts of obstetrical patients admitted during the year 2001, of any gestational age, with suspected clinical diagnosis of malarial infection (high grade fever, chills, anemia, jaundice, hypoglycemia), conrmed with a fast Giemsa thick blood smear. We excluded patients with malarial infection admitted in the puerperal phase and those referred from other institutions in whom malarial treatment had been already initiated. Maternal analyzed data included: demographics, symptoms on admission, initial laboratory results, percentage of patients presenting only with symptoms of malarial infection and those presenting malarial symptoms and an associated obstetrical complication. If the patient did not live within city limits either of Guayaquil or any other main city, she was considered as coming from a rural area. Low socio-economic status was dened as total family monthly income of 5 US $336 [16]. Plasmodium species, drug used for treatment and maternal outcome and death rate were recorded. Adverse maternal outcome was dened if a given patient presented at least one of the following: anemia (hemoglobin 5 11 g/dL) requiring transfusion, admittance to adult intensive care unit (ICU), maternal death or any other medical complication associated to malarial infection as severe hypoglycemia, cerebral malaria etc. Fetal data included: gestational age on admission and delivery and the rates for abortion, preterm/term delivery, intrauterine fetal demise, low birthweight (LBW), small-for-gestational-age (SGA) and adverse fetal outcome. We dened adverse fetal outcome if at least one of the following complications were present: abortion, intrauterine fetal or neonatal death, preterm delivery, LBW, SGA, neonatal respiratory distress syndrome, birth Apgar 5 7 at 5 min, sepsis, neonatal asphyxia (birth Apgar of 3 at 5 min and a cord pH of 5 7.0 presenting with newborn respiratory complication), admittance to neonatal intensive care unit and if neonate was born with congenital malaria. We dened preterm birth when gestational age was 5 37 completed weeks and SGA when birth weight was 5 10th percentile [17]. Infant LBW was dened as a birth weight of 5 2,500 g. Gestational age calculation was performed using last menstrual period, rst trimester sonography and/or neonatal examination according to Ballard scoring. Statistical analysis was performed with the use of EPI-INFO 6.04 data base and statistical program (Centers for Disease Control, Atlanta, GA, USA; WHO, Basel, Switzerland). All data is expressed as mean + standard deviation (SD) and percentages. Non paired Students t test and chi-square test were used to compare continuous and categorical data

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Table I. Demographics, symptoms and initial laboratory test. General Maternal age (year) Multiparity Coming from a rural area Symptoms on admittance Fever Chills Jaundice Malaise Vomiting Splenomegaly Hepatomegaly Initial laboratory results Anemia (hemoglobin 5 11 g/dL) Glycemia (mg/dL) Total bilirubin (mg %)
a

n = 80 25.2 + 6.7a 80.0% 45.0% 97.5% 78.8% 38.8% 27.5% 20.0% 5.0% 2.5% 60.0% 100 + 20 1.8 + 0.4

Mean + Standard Deviation (SD)

Malarial infection and maternal-fetal outcome In the 5 20 week group, there was a 76.5% abortion rate (13/17). Of the remaining (4/17), three delivered at term and one preterm which was also SGA. The transfusion and admittance to ICU rate was similar in all groups. Although not reaching statistical signicance, the adverse fetal outcome rate was higher in the 5 20 week group, patients among which falciparum infection was more prevalent. Accordingly, the falciparum infection rate among patients with adverse maternal outcome was higher in the 5 20 week group (data not shown). Among patients admitted at 2036 weeks gestation there was an 11% intrauterine fetal demise rate (6/55). In this group, the rate for preterm delivery, LBW and SGA was 34.5%, 40.8% and 48.9% respectively. Among patients admitted for treatment at 4 36 weeks (n = 8), seven ended in a live term delivery and one was admitted as an intrauterine fetal demise. One maternal death due to falciparum infection was encountered in this group. When patients of 4 18 years (n = 18) were compared to the group 4 18 years (n = 62), teenagers presented a higher rate of anemia and SGA neonates: 83.3% vs. 53.2% and 50% vs. 27.4%, p 5 0.05 respectively (data not shown). The overall (n = 80) abortion, preterm delivery and intrauterine fetal demise rates were 16.3%, 25% and 8.8%, respectively (Table III). The incidence of congenital malaria in this series was 1.3% (1/80). Although this neonate infected with vivax species was born preterm (33 weeks), LBW and with severe anemia he was successfully treated. In this series there were no neonatal deaths and one case was born with omphalocele. Discussion In Ecuador more than 100,000 cases of malaria were reported during the year 2000, of which 50% were due to falciparum species. While socio-economic background and geographical area are established factors associated to the increasing rise of malarial

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Table II. Presenting clinical picture. Presenting clinical picture Presenting only with symptoms of malarial infection Malarial infection and associated obstetrical complication Premature rupture of membranes Threatened preterm labor Abortion Labor Threatened abortion Intrauterine fetal death n = 80 51.3% 48.7% 13.8% 13.7% 7.5% 6.2% 3.8% 3.7%

infection in developing countries, factors predicting severity of malarial infection during gestation, leading to increased risk for adverse maternal fetal outcomes, have not been completely elucidated and may include: maternal age, parity and immunological status, geographical area, protozoan species, degree of parasitemia and placental infection [711]. To illustrate the latter, in one study performed in Gambia, holoendemic for malaria, the prevalence of parasitemia in pregnant women during a 15 year period was 31.8% (169/532 cases) in comparison to non-pregnant women 25.9% (586/2,265). This difference was higher among nulliparas and those living in rural areas in comparison to multiparous women and those living in urban areas, respectively [18]. Bouyou-Akotet and co-workers [19] determined that among 311 women from Gabon, 57% had microscopic parasitemia, 64% were primigravid and 64% were teenagers. We did not nd any relationship between parity and outcome, perhaps due to the fact that sample size was too small. However in our series maternal age was related to adverse maternal-fetal outcome, as teenagers presented a higher rate of anemia and SGA neonates when compared to non-teenagers (83.3% vs. 53.2% and 50% vs. 27.4%, p 5 0.05 respectively). Concerning immunity, non-pregnant subjects living in holoendemic areas usually have high levels of immunity to malaria [20] among which infection is frequently asymptomatic and severe disease is uncommon. Despite this, non-immunized nulliparous pregnant women, living in holoendemic areas, are at higher risk for adverse maternal-perinatal outcomes when compared to multiparous controls. While some authors support placental parasital sequestration as the cause of this phenomena [20,21] others sustain pregnancy-induced immune suppression, reected by cortisol increase, as the pathogenic mechanism for these differences [22]. As this was a retrospective study, unfortunately placental examinations were not performed routinely in all cases and further research in this area is warranted. In the present series due to the fact that only one case had a history of malarial infection no signicant correlation was found between maternal immunity to malaria and adverse maternal-fetal outcome. Moreover, Ecuador and other Latin American countries are considered to be mesoendemic, therefore immunological status and its correlation to outcome may be difcult to analyze. In Ecuador, several rural areas have demonstrated to be highly endemic the year round whereas urban cases of malarial infection are usually due to outbreaks during the rainy season (January to May) in low socio-economic residential areas. This study conrms this issue, as all patients were of low socioeconomic status and 45% of them came from rural

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E. Espinoza et al.
Table III. Maternal and fetal outcome according to gestational age. Group A 5 20 weeks (n = 17) Group B 2036 weeks (n = 55) Group C 4 36 weeks (n = 8) Total N = 80

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Maternal age (years) Gestational age on admittance (weeks) Falciparum rate Abortion rate Preterm delivery rate Term delivery rate Intrauterine fetal death Low birth weight Small-for-gestational-age Transfusion rate (%) Admittance to adult ICU Cesarean section rate Adverse fetal outcome Adverse maternal outcome

28.0 + 6.0 10.1 + 3.7 (range: 837) 70.6% 76.5% 5.9% 17.6% 25.0% 25.0% 35.3% 11.8% 0.0% 82.4% 47.1% (12/17) (13/17) (1/17) (3/17) (1/4) (1/4) (6/17) (2/17) (0/4) (14/17) (8/17)

24.8 + 6.6 22.4 + 7.6 * 25.2 + 6.7 32.9 + 3.4 (range: 2136) 38.0 + 0.7 (range: 3740) 28.6 + 10.3 (range: 539) 52.7% 34.5% 54.5% 11.0% 40.8% 48.9% 36.4% 14.5% 20.0% 63.6% 36.4% (29/55) (19/55) * (30/55) (6/55) (20/49) (24/49) (20/55) (8/55) (11/55) (35/55) (20/55) 50.0% 87.5% 12.5% 50.0% 25.0% 25.0% 62.5% 50.0% (4/8) 56.3% 16.3% 25.0% 50.0% 8.8% 35.0% 31.5% 37.5% 15.0% 19.4% 67.5% 40.0% (45/80) (13/80) (20/80) (40/80) (7/80) (21/60) (19/60) (30/80) (12/80) (13/67) (54/80) (32/80)

(7/8) ** (1/8)

(4/8) (2/8) (2/8) (5/8) (4/4)

* Signicant difference compared to Group A; ** Signicant difference compared to Group A and B.

endemic areas, which were mostly admitted during the dry season of Guayaquil (June to November) whereas urban patients were admitted more frequently during the rainy season. All patients were therefore uniformly distributed during the year 2001 (data not shown). We found an association between gestational age on admittance, plasmodium species involved and maternal-fetal outcome. Although fetal outcomes vary widely from one study to another, the association between gestational age at the time of malarial infection has not been clearly addressed. The results presented here support the fact that malarial infection occurring at an earlier gestational age is associated with adverse fetal outcome. Very few cases of congenital malaria have been reported in the world literature [23,24]. The incidence of congenital malaria in this series was 1.3% (1/80). Although this neonate infected with vivax species was born preterm (33 weeks), LBW and presented with severe anemia he was successfully treated. Falciparum species has been reported to correlate with severe maternal infections causing adverse outcome. We agree with this fact and although no cases of cerebral falciparum malaria were encountered in this series, falciparum infection was more prevalent (56.3%) and was associated with one maternal death. Although multiple drug resistance has been reported and other alternative therapeutic agents have been used during pregnancy, chloroquine is still a safe and effective agent used for the treatment and prevention of gestational malarial infection [13 15,25]. In our series, all patients were treated with oral chloroquine (1 g in divided doses during 3 days), provided without cost by the Ecuadorian

Ministry of Public Health. With this scheme, chloroquine effectively treated 98.8% of cases. To the best of our knowledge data regarding pregnancy and malarial infection in Latin American countries were malaria has been reported to be low to moderate is scarce or non existent. The results of this descriptive research may serve as a model for mesoendemic countries. The increasing trend of malarial infection in Ecuador warrants further research of this association to further explore the relationship between gestational malarial infection, known risk factors such as maternal parity and immunological status and adverse outcomes. In conclusion, malarial infection complicating gestation in this Ecuadorian population, was associated with adverse maternal-fetal outcome, which was more evident among teenagers and those pregnancies presenting malaria at an earlier gestational age. Acknowledgement We would like to thank Dr Eduardo Gomez, an Ecuadorian expert on malarial infection, for his comments.

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