Open Access

Impact of malaria during pregnancy on pregnancy outcomes in a Ugandan prospectivecohort with intensive malaria screening and prompt treatment

  • Pierre De Beaudrap1, 2Email author,
  • Eleanor Turyakira3, 4,
  • Lisa J White5, 6,
  • Carolyn Nabasumba3,
  • Benon Tumwebaze3,
  • Atis Muehlenbachs7,
  • Philippe J Guérin1, 6, 8,
  • Yap Boum3,
  • Rose McGready5, 6, 9 and
  • Patrice Piola8, 10
Malaria Journal201312:139

DOI: 10.1186/1475-2875-12-139

Received: 11 January 2013

Accepted: 7 April 2013

Published: 24 April 2013

Abstract

Background

Malaria in pregnancy (MiP) is a major public health problem in endemic areasof sub-Saharan Africa and has important consequences on birth outcome.Because MiP is a complex phenomenon and malaria epidemiology is rapidlychanging, additional evidence is still required to understand how best tocontrol malaria. This study followed a prospective cohort of pregnant womenwho had access to intensive malaria screening and prompt treatment toidentify factors associated with increased risk of MiP and to analyse howvarious characteristics of MiP affect delivery outcomes.

Methods

Between October 2006 and May 2009, 1,218 pregnant women were enrolled in aprospective cohort. After an initial assessment, they were screened weeklyfor malaria. At delivery, blood smears were obtained from the mother,placenta, cord and newborn. Multivariate analyses were performed to analysethe association between mothers’ characteristics and malaria risk, aswell as between MiP and birth outcome, length and weight at birth. Thisstudy is a secondary analysis of a trial registered with ClinicalTrials.gov,number NCT00495508.

Results

Overall, 288/1,069 (27%) mothers had 345 peripheral malaria infections. Therisk of peripheral malaria was higher in mothers who were younger, infectedwith HIV, had less education, lived in rural areas or reported no bed netuse, whereas the risk of placental infection was associated with morefrequent malaria infections and with infection during late pregnancy. Therisk of pre-term delivery and of miscarriage was increased in mothersinfected with HIV, living in rural areas and with MiP occurring within twoweeks of delivery.

In adjusted analysis, birth weight but not length was reduced in babies ofmothers exposed to MiP (−60g, 95%CI: -120 to 0 for at least oneinfection and -150 g, 95%CI: -280 to −20 for >1 infections).

Conclusions

In this study, the timing, parasitaemia level and number ofperipherally-detected malaria infections, but not the presence of fever,were associated with adverse birth outcomes. Hence, prompt malaria detectionand treatment should be offered to pregnant women regardless of symptoms orother preventive measures used during pregnancy, and with increased focus onmothers living in remote areas.

Keywords

Malaria in pregnancy Birth outcomes Sub-Saharan Africa Cohort

Background

Despite numerous studies conducted over the last decades, malaria in pregnancy (MiP)remains an important public health problem that has proved difficult to tackle. Manystudies from areas with different malaria transmission patterns have investigatedthe consequences of MiP on both maternal health and birth outcomes. While theconsequences of MiP on maternal health are dominated by anaemia, data onmalaria-related maternal mortality are sparse [1]. For the foetus, the most commonly reported adverse effect of MiP is anincreased risk of low birth weight (LBW) [25], which, in turn, is a significant risk factor for both impaireddevelopment [68] and infant mortality [9, 10]. However, most of these studies used only a single measurement point(from cross-sectional surveys or at delivery) to identify MiP and, therefore, do notcapture the multiple factors that play a role over an extended period of time.

While reliable assessment of MiP is critical to elucidating its impact on birthoutcomes and infant health, it is problematic because many factors (some of whichare difficult to fully capture) are relevant to a complete understanding. MiP may beeither continuous or intermittent, depending on a woman’s exposure to vectors,level of immunity and possible co-infections (e.g. other malaria species, HIV orhelminths), and on the efficacy of treatment and prevention interventions availableto her. Tools to measure parasite presence are limited by their sensitivity and byhow often women attend antenatal care services; hence MiP is often only partiallyobserved. To more fully evaluate the impact of MiP on both maternal and infantoutcomes, investigations must consider multiple aspects of malaria infection, suchas timing, frequency, intensity and severity of the infections, as well as thetreatment provided.

Recent studies focused on one or a few features of malaria, such as timing and/orfrequency [1115], or the effect of a single infection early in pregnancy (when weeklyscreening was routinely provided throughout pregnancy [13]), and have produced inconsistent results. Several investigations foundthat LBW risk was associated specifically with malaria infections occurring in earlypregnancy [11, 14, 15]. In contrast, a study conducted in Benin reported a higher risk of LBWassociated with malaria infection after six months of pregnancy [12], and data from Thailand did not show a significantly lower birth weightin newborns of mothers with a single treated malaria episode in the first trimestercompared to newborns of mothers without malaria infection [13]. Likewise, conflicting results have also been reported on the associationbetween the number of malaria infections and the risk of LBW [11, 1416].

MiP is thought to affect birth outcomes through two mechanisms, intrauterine growthrestriction (IUGR) and preterm delivery, which might - at least partially - explainthese discordant findings. It has been estimated that MiP in settings with stablemalaria transmission in Africa is potentially responsible for up to 70% of IUGR and36% of preterm delivery [4]. The former has been consistently associated with placental infection [1724], while the latter appears to correlate with systemic manifestations ofmalaria infection in the mother [2527]. However, accurate determination of gestational age is required todistinguish IUGR from preterm delivery—a determination that is difficult tomake in resource-constrained settings, where tools such as ultrasound are rarelyavailable. As a result, evidence of the relative importance of IUGR versus pretermdelivery due to MiP remains limited [28].

In recent years control of MiP has relied partly on intermittent preventive treatment(IPT), with WHO currently recommending at least two doses withsulphadoxine-pyrimethamine (SP) [29]. However, growing resistance of malaria parasites to SP in many regions [30, 31], combined with the changing epidemiology of malaria, indicate that otherprevention approaches must be strengthened. To help fill the evidence gap regardingthe impact of MiP on delivery outcomes in accurately dated pregnancies, this studyreports on the findings from a prospective cohort of pregnant women with access toweekly antenatal malaria screening and prompt treatment.

Methods

Population and setting

The study was conducted in Mbarara district, southwestern Uganda. Thispredominantly rural area lies at an altitude of about 1,500 m above sea leveland has moderate levels of malaria transmission [32]. Between October 2006 and May 2009, 1,218 pregnant women with anestimated gestational age ≥13 weeks were enrolled in a prospectiveobservational cohort. The first 1197 women in this cohort screened for malariawith a positive rapid diagnostic test (RDT) confirmed by a positive blood smearwere invited to participate in an additional study comparing the efficacy andtolerance of artemether–lumefantrine with oral quinine for the treatmentof uncomplicated falciparum malaria published elsewhere [33].

Clinical and monitoring procedures

At baseline, a comprehensive assessment of the pregnant women’ssocio-demographic characteristics and health status was performed, including amedical and obstetrical history, clinical and obstetric examination, ultrasoundevaluation, blood smear and hemoglobin measurement. Estimated gestational age bywas determined by ultrasound in all women enrolled in the study between week16–20 of pregnancy (72% of the cohort). For the remaining mothers, i.e.,those recruited after the 20th week of gestation, we turned to apublished model that predicts gestational age from symphysis-fundal height (SFH)measurements and calibrated it using the data from the 16–20 week group [34], and then used these results to predict gestational age at deliveryin the subset of mothers without ultrasound (Additional file 1).

After this initial assessment, the mothers returned to the clinic weekly for aclinical examination and malaria RDT. In case of positive RDT, malarialinfection was confirmed with a blood smear. Treatment of uncomplicatedfalciparum malaria included a random allocation of artemether-lumefantrine forthree days or quinine for seven days. Infections with only Plasmodiumvivax were treated with chloroquine. All women in the cohort receivedstandard supervised IPT with two doses of SP given at intervals of one month ormore during the second and third trimesters, as well as iron and folatesupplementation, antihelmintic treatment and insecticide-treated bed nets (ITN).All treatments were provided free-of-charge.

At delivery, blood smears were obtained from the mother, placenta, cord andnewborn to test for the presence of Plasmodium and malaria pigment.Placental histology was available only for a subset of the cohort (n=260).Placental malaria cases were classified according to the presence of parasitizederythrocytes, intervillous inflammation and haemozoin deposition [18, 35]. Newborns were given an initial standardized physical examination bya medical officer, weighed to the nearest 10g using a SECA mechanical typescale, and measured for length to the nearest centimeter using a portablestadiometer (Shorr productions, US). Infants delivered outside of a healthfacility were examined within 24 hours of birth by a study medical officer.

Laboratory procedures

Paracheck® RDTs were performed using a finger-prick blood sample andinterpreted according to the manufacturer’s instructions. Thick and thinblood smears were prepared and stained with Giemsa. Parasitaemia was calculatedby counting parasites against 200 white blood cells (or 500, if nine parasitesor fewer were counted against 200 white blood cells). Placental smears weretaken by incising a fresh placenta on the maternal surface halfway between thecord and the periphery, and were then examined for the presence of parasites andpigment [35].

HIV testing and treatment was proposed to all participants and performedaccording to national guidelines [36], which include cotrimoxazole prophylaxis for people infected withHIV. Haemoglobin was measured from a fingerprick sample by the HaemocueB-Haemoglobin analyzer (Ängelholm, Sweden).

Definitions

Low birth weight was defined as <2,500 g measured within 24 hours of birth;preterm as newborn gestational age <37 weeks at delivery; stillbirth as thedelivery of a non-living foetus ≥28 weeks gestation; and miscarriage asthe delivery of a non-viable foetus either at <28 weeks gestation or weighing<500 g.

Statistical analysis

Malaria infection in pregnancy model

Various parameters of malaria exposure during pregnancy were described andanalysed for their temporal change and for their association with maternalcharacteristics or study interventions that may have affected MiPcharacteristics. Peripheral malaria was defined as the occurrence of a positiveperipheral blood smear. After a treated malaria episode, a subsequent episodewas considered a recurrence only after a minimum of 14 days, with at least onenegative blood smear during this period [10]. Placental malaria was defined as the detection by microscopy of anyparasite in a placental or cord blood smear.

The risk of peripheral malaria infection was analysed with a mixed-effectsPoisson model [37, 38]. Since the occurrence of malaria before enrolment in the study couldnot be observed (left censoring), the at-risk time period was defined as theinterval from study enrolment to delivery. Lead time bias was (partially)accounted for by including the gestational age at enrolment as a covariate. Eachindividual follow-up (from enrollment to delivery) was split into intervalselapsing from one visit to another, and the log duration of these intervals wasincluded as an offset. Baseline risk was modeled using a spline function. Thelevel of parasitaemia (log transformed) was analysed using a linear model. Whenmore than one malaria episode was observed in a pregnancy, the maximalparasitaemia level recorded per episode was used as a dependent variable. Thepresence of fever and the occurrence of placental malaria infection wereanalysed with logistic models. In each model, maternal age, gravidity, HIVstatus, education level, residency area (rural versus urban), and gestationalage at inclusion were considered as potential risk factors.

The number of IPT doses was introduced as a time-dependent covariate in the modelfor peripheral malaria risk. However, IPT was interrupted after the treatment ofa malaria infection, making the number of IPT doses an endogenous variable [39]. Since data were censored at the first malaria episode, only therelationship between the number of IPT doses received up to the beginning of atime interval and the risk of the first malaria episode during this timeinterval was assessed (using a log-linear model).

Birth outcomes

The adverse outcomes evaluated in this study were stillbirth, preterm delivery,low birth weight and IUGR. IUGR was defined as a birth weight below the 10thpercentile of the birth weight-for-gestational age. Type I (symmetric) IUGR andtype II (asymmetric) IUGR were distinguished according to whether the Rohrerindex was above the 10th percentile of Rohrer index for gestational age or not.United States population-based references were used as standard [40, 41]. The association of each outcome with the various parameters ofmalaria exposure and with maternal characteristics were analysed separately forthe full cohort, the subset of mother--newborn pairs with no or only oneperipheral malaria infection, and the subset of mother--newborn pairs withultrasound assessment of gestational age at baseline. Maternal age, educationlevel (no education, primary level or ≥secondary level), residence area(rural versus urban), HIV status, number of clinic follow-up visits before birthoutcome (<4 versus ≥4), and the newborn’s gender and gestationalage at birth were included in all models. Stillbirth was analysed as a binaryvariable using a logistic model. Preterm delivery was analysed with gestationalage at birth included as a continuous or binary variable (gestational age <37weeks) using respectively a linear and logistic model. Weight and length atbirth were both considered as continuous variables and analysed with a linearmodel adjusted for gestational age at birth. Parasitaemia was categorized asnone, low (log parasitaemia ≤6 log parasites/μL) or high (>6 logparasites/μL). Late malaria infection was defined as a peripheral malariainfection occurring in the last two weeks before delivery. To better understandthe effect of malaria infection timing independently of the enrolment timing,the association between birth weight and gestational age at infection (<15,15-<20, 20-<24, ≥24 weeks) was analysed with a linear modelrestricted to the subset of mothers with no or only one malaria infection andwith a gestational age <15 weeks at enrolment.

All analyses were performed using the open source statistical software R [42].

Ethical approval

Written informed consent for study participation was obtained from allparticipants to the study. The study was approved by the institutional reviewboards of Mbarara University of Science and Technology, Uganda National Councilfor Science and Technology, and France’s “Comité de Protectiondes Personnes - Ile-de-France XI”. This study was registered withClinicalTrials.gov, number NCT00495508.

Results

Study population characteristics

Of the 1,218 women enrolled in the cohort, 149 (12%) were excluded from thisanalysis because they were lost to follow-up before their pregnancy reached anoutcome (Figure 1). These excluded women were youngerand had shorter follow-up (p=0.0001). One maternal death unrelated to malariawas observed (from sepsis five days after a caesarean section for obstructedlabour in a term pregnancy).
https://static-content.springer.com/image/art%3A10.1186%2F1475-2875-12-139/MediaObjects/12936_2013_Article_2748_Fig1_HTML.jpg
Figure 1

Flow chart.

Characteristics of the 1,069 women included in this cohort are summarized inTable 1. Women with malaria were enrolledsomewhat later in their pregnancy than those with no infection detected(Table 1). Most of the mothers delivered in ahealth facility (84% at the regional hospital and 3% in a private clinic), withthe remainder delivering at home. Median gestational age at enrolment was 19weeks (Inter Quartile Range, IQR: 16–22) and median follow-up time was 21weeks (IQR: 16–24). Almost 50% of the mothers reported the use of bed netsbefore the first visit. The mean number of visits, equivalent to the mean numberof screening tests, was high (18, IQR: 10–23) (Table 1).
Table 1

Characteristics of the study population

 

No MiP

MiP

Mother characteristics at inclusion (n = 1069)

n=714

n=355

Median age, year (IQR)

24 (21 – 27)

22 (19 – 25)

Median gestational age, week (IQR)

18 (15 – 20)

21 (17 – 28)

Residence, n (%)

  

   Urban

429 (60)

118 (33)

   Rural

285 (40)

236 (67)

Place of delivery, n (%)

  

   Health facility

633 (88%)

291 (82%)

   Home/transport

76 (11%)

62 (17%)

Education level, n (%)

  

   No education

68 (10)

47 (13)

   Primary

285 (40)

210 (59)

   ≥ Secondary

361 (50)

98 (28)

HIV status, n (%)

  

   Negative

533 (74)

255 (71)

   Positive

114 (16)

34 (10)

   Unknown

67 (10)

66 (19)

Primigravid, n (%)

241 (34)

160 (45)

Delivery outcomes

  

   Abortion

23 (3)

5 (1)

   Stillbirth

13 (2)

9 (2)

Mean number of visits (IQR)

20 (17 – 23)

16 (10 – 22)

Newborn characteristics – liveborn singletons (n=967)

Gestational age at birth, weeks (IQR)

40 (39 – 41)

40 (39 – 41)

Preterm delivery, n (%)

42 (7)

29 (9)

Median weight, kg (IQR)

3.11 (2.87 – 3.44)

3.095 (2.80 – 3.33)

Median length, cm (IQR)

50 (47 – 51)

49 (48 – 51)

Female, n (%)

344 (54)

183 (56)

Mothers without ultrasound assessment of gestational age were more likely to livein remote rural areas (OR: 1.68, 95%CI: 1.21 - 2.31) and to be at a moreadvanced stage of the pregnancy at enrolment (mean gestational at enrolment was23.5 weeks in mothers without ultrasound, versus 18.5 weeks in those withultrasound, p<0.001). Of the 1,018 live births, 40 were excluded from theanalysis on birth weight and length (Figure 1).

Malaria exposure during pregnancy

Peripheral malaria infection

A total of 304 (28%) women had one or more malaria infections detected byperipheral blood smear (all species included) during follow-up visits,resulting in a total of 361 peripheral malaria infections (range: 1–4malaria infections). Of the 242 (67%) infections recorded at inclusion, allinvolved Plasmodium falciparum, with six mixed infections. The 111subsequent malaria infections included three mixed infections and 16infections with non-falciparum species. Of the 55 positive RDT results withnegative blood smear, 31 (52%) were observed at inclusion but no detectablemicroscopic parasitaemia were identified, while 24 (48%) were observed laterduring the follow-up period but with no previously documented infection.Peripheral malaria infection was associated with fever in only 16% of cases(n=62/361). The geometric mean (range) of parasitaemia was 1669 (24 –302 500) parasites/μL. There were 23 women who had malaria and were notin the trial. Of them, 13 (57%) received quinine, 6 (26%)artemether-lumefantrine and the information was missing for 4 patients(17%).

In multivariate analysis, the risk of peripheral malaria was increased inmothers who were infected with HIV, were younger, primigravidae, had a lowereducation level, lived in rural areas and did not report bed net use atenrolment (Table 2, left column). In contrast,gestational age at inclusion was negatively associated with the risk ofmalaria infection. Compared to women who did not receive any IPTp, those whoreceived one or two doses had an almost five or ten-fold reduction,respectively, in malaria infection risk (adjusted relative risk, RRa: 0.20,95%CI: 0.14 - 0.30 and 0.10, 95%CI: 0.06 - 0.18). Women who experienced≥2 malaria episodes were more likely to come from a rural area (2.23,95%CI: 1.01 - 4.89) and to have enrolled in the study later during theirpregnancy (OR: 0.95, 95%CI: 0.91 - 1.00) than those who had only oneepisode. Maximum parasitaemia was higher in women who were infected withHIV, included late during gestation or experienced recurrent malariainfections (Table 2, central column). Women withrecurrent infection showed no significant difference in parasitaemia levelbetween the first and subsequent infections (p=0.7).
Table 2

Risk factors for peripheral malaria during pregnancy,parasitaemia and placental malaria (multivariate analysis)

 

Peripheral malaria (rate ratio)

Parasitaemia (log)

Placental malaria (Odds ratio)

Maternal agea

0.97 (0.94 - 0.98)

−0.01 (−0.04 to 0.01)

0.90 (0.80 - 1.02)

Education level

   

   Primary level

0.76 (0.56 - 1.04)

−0.10 (−0.40 to 0.20)

1.01 (0.17 - 5.81)

   ≥ secondary level

0.50 (0.35 - 0.72)

−0.22 (−0.57 to 0.12)

2.05 (0.33 - 12.64)

Rural residence

1.97 (1.54 - 2.52)

0.04 (−0.18 to 0.27)

6.00 (1.29 - 28.02)

Primigravidae

1.31 (1.02 - 1.69)

0.08 (−0.17 0.33)

1.00 (0.33 – 3.00)

Use of bednet

0.71 (0.56 - 0.90)

−0.08 (−0.30 to 0.14)

0.91 (0.30 - 2.77)

Gestational age at inclusionb

1.05 (1.03 - 1.07)

0.02 (0.00 to 0.04)

1.14 (1.05 - 1.24)

HIV status

0.92 (0.62 - 1.38)

0.42 (0.04 to 0.79)

2.68 (0.61 - 11.74)

# IPT doses

   

   1

0.25 (0.17 – 0.35)

‐‐

‐‐

   2

0.10 (0.06 – 0.18)

‐‐

0.92 (0.22 – 3.76)

# malaria episodes

   

   1

‐‐‐

‐‐‐

3.30 (0.69 -15.88)

   ≥2

‐‐‐

0.47 (0.19 to 0.74)

15.80 (2.77 - 90.27)

a.By 10 years; b. by week; IPT:intermittent preventive treatment.

Placental malaria infection

Of the 665 placental smears available, parasites were observed in 20 (3%) andpigment in 17 (2.5%) cases. The presence of pigment was associated withdetectable parasites in 12 (7%) of the cases. Most of the infected placentas(17/20) came from mothers who had peripheral malaria detected during theirenrolment in the study; in the remaining three women, no peripheralmicroscopic or positive RDT was detected during pregnancy or at delivery.Conversely, almost all of the placental biopsies from mothers withoutmalaria detected during pregnancy had no haemozoin deposition norparasitized erythrocytes by histology (72/79). All eight malaria infectionsin mothers with detectable parasites, but no pigment in the placental smearwere observed during the third trimester. In adjusted analysis, theoccurrence of a placental infection was associated with the number ofperipheral malaria episodes, but not with parity (Table 2, right column). Similar results were seen in the subset ofwomen with only one malaria infection (OR: 8.89, 95%CI: 1.07 - 74.21 forrural versus urban residency; 1.14, 95%CI: 1.03 - 1.27 for each additionalweek in gestational age, and 1.51, 95%CI: 1.03 - 2.22 for each log10increase in parasitaemia level).

The association between the time since last malaria infection and the risk ofplacental malaria was assessed in a multivariate model restricted to womenwho experienced at least one malaria infection. Risk of placental malariawas negatively associated with the interval between the last peripheralinfection and delivery (OR: 0.992, 95%CI: 0.985 - 0.998 per week) andpositively associated with parasitaemia level (OR: 1.06, 95%CI: 1.02 -1.10per log10 increase). No microscopic placental malaria was detected in womenwith a positive RDT, but negative blood smear.

Delivery outcomes

Miscarriage and stillbirth

A total of 28 (3%) miscarriages and 22 (2%) stillbirths were observed in thestudy cohort. In adjusted analysis, the risk of miscarriage or stillbirthwas significantly increased in mothers who were HIV-infected, living inurban areas or completed fewer follow-up visits (Table 3). Notably, in a model adjusted for HIV status and area ofresidence, malaria within two weeks of delivery was associated with atwofold greater risk of stillbirth (OR: 2.15, 95%CI: 1.04-4.46). It was notpossible to include both the number of follow-up visits and the occurrenceof malaria infection late during gestation as covariates in the same modelbecause of their association with one another.
Table 3

Risk factors for adverse birth outcomes (multivariateanalysis)

 

Stillbirth/ abortion

Preterm delivery (<37 wks)

Full dataset

Mother with US

Urban residency

2.60 (1.31 - 5.16)

1.38 (0.81 - 2.34)

1.49 (0.79 - 2.83)

HIV status

2.70 (1.19 - 6.11)

2.33 (1.17 - 4.64)

3.21 (1.43 - 7.22)

# follow-up visits

0.74 (0.70 - 0.79)

0.86 (0.83 - 0.90)

0.81 (0.76 - 0.87)

Pre-term delivery

Overall 65 (7%) live-born pre-term deliveries were observed, with 45 (6%)occurring in the sub-group of mothers with ultrasound estimation ofgestational age. In adjusted analysis of both the full cohort data and thesubset with ultrasound, the risk of pre-term delivery was increased in womeninfected with HIV and in those with fewer follow-up visits (Table 3). As with stillbirth, an association between the riskof pre-term delivery and the occurrence of a malaria infection within thelast two weeks of pregnancy was observed when the number of follow-up visitswas dropped from the model, in both the full cohort dataset and theultrasound subset (adjusted OR were 1.91, 95%CI: 1.05 – 3.50 and 2.84,95%CI: 1.26 – 6.38, respectively).

Effect of malaria on gestation

In adjusted analysis, shortened gestation (because of miscarriage, stillbirthor pre-term delivery) was associated with the occurrence of malariainfection within the last two weeks of pregnancy (Figure 2). A borderline association of shortened gestation with febrilemalaria infection associated was also found (p=0.06).
https://static-content.springer.com/image/art%3A10.1186%2F1475-2875-12-139/MediaObjects/12936_2013_Article_2748_Fig2_HTML.jpg
Figure 2

Summary of the association between risk of stillbirth or pretermdelivery and different parameters of malaria exposure duringpregnancy (odds ratio with 95% confidence intervals fromanalyses adjusted for maternal characteristics).

Weight and length at birth

In total, there were 57 (7%) infants with low birth weight, 39 (6%) with type IIIUGR (asymmetric) and 89 (13%) type I IUGR (symmetric). In analysis adjusted forgender and for estimated gestational age at delivery, birth weight was reducedin primiparae, in mothers with low education level and in those who attended≤4 follow-up visits (Table 4). Greater birthweight was observed in mothers with higher average hemoglobin level duringpregnancy (+30g, 95%CI: 10–50), however this association disappeared inmultivariate analyses adjusted for MiP. Of the various parameters of malariaexposure during pregnancy, all but placental malaria and symptomatic malariawere associated with lower weight at birth (Figure 3). However, the presence of malaria pigment in the placental smear wasassociated with reduced birth weight in univariate analysis (−0.26, 95%CI:-0.49 to −0.032) though not in adjusted analysis (p=0.2). Type I IUGR wasnot associated with any aspect of malaria in pregnancy (Additional file 2). By contrast, type II IUGR was increased in motherswith more than one malaria episode and with symptomatic malaria (Additional file3). Median gestational age at last malariainfection was 21 weeks (19–22) in women with type I IUGR and 23 weeks(22–24) in women with type II IUGR (p=0.08).
Table 4

Factors associated with weight and length at birth (multivariateanalysis, n = 967)

 

Weight at birth

Length at birth

Newborn gendera

−0.01 (−0.07 to 0.04)

−0.03 (−0.44 to 0.38)

Maternal ageb

0.05 (−0.02 to 0.12)

0.32 (−0.19 to 0.83)

Education level

  

  Primary level

0.06 (−0.03 to 0.15)

−0.25 -0.92 0.42

  ≥ Secondary level

0.10 (0.00 to 0.20)

−0.05 -0.75 0.65

Rural residency

−0.01 (−0.07 to 0.05)

−0.54 -0.97 -0.11

Primigravidae

−0.12 (−0.19 to −0.05)

−0.38 -0.88 0.11

HIV status

0.02 (−0.06 to 0.11)

−0.20 -0.82 0.41

>4 follow-up visits

0.45 (−0.01 to 0.92)

−2.42 -6.55 1.71

Gestational age at birth (wks)

0.11 (0.09 to 0.12)

0.67 (0.56 to 0.77)

Any peripheral malaria

−0.07 (−0.13 to 0.00)

0.17 (−0.30 to 0.64)

a Female versus male; b. by 10 years.

https://static-content.springer.com/image/art%3A10.1186%2F1475-2875-12-139/MediaObjects/12936_2013_Article_2748_Fig3_HTML.jpg
Figure 3

Summary of the association between birth weight and differentparameters of malaria exposure during pregnancy (mean change with95% confidence intervals from analyses adjusted for maternalcharacteristics).

Analyses restricted to mothers with ultrasound-verified gestational age, or tothose with no or only one malaria infection, found qualitatively similarassociations, although sometimes with only borderline significance(Figure 3). Birth weight was not associated withthe timing of the first malaria infection in mothers with gestational age <15weeks at enrolment (p=0.8). This conclusion did not change when the cut-offsused for gestational age at enrolment was varied. No association was foundbetween malaria exposure during pregnancy and newborn length.

Discussion

The novel features of this cohort study are the frequent, intensive malariascreenings (median of 21 screens per pregnancy) and the provision of treatment basedon the presence of parasite in the blood rather than on symptoms—practiceswhich differ markedly from those common in endemic Africa. Another strength of thisstudy is the accurate determination of gestational age for the majority ofpregnancies.

Our results suggest that peripheral malaria infections during pregnancy, includingthose occurring late during gestation, contribute significantly to perinatalmorbidity. Malaria infection at the end of pregnancy and those with fever ratherthan other aspects of malaria exposure, were associated more specifically withmiscarriage or pre-term delivery. A similar association between malaria infectionswith fever and an increased risk of miscarriage has been reported in mothers with asingle malaria episode during the first trimester of pregnancy [13]. Likewise, increased infant mortality has been reported after symptomaticmalaria infections occurring at the end of the pregnancy [10, 43]. In low endemic areas, 80% of microscopically detected infections becomesymptomatic if left untreated [44]. Since women in this cohort were treated if they had a positive bloodsmear, irrespective of whether they showed symptoms, it seems likely that this earlydetection and treatment of asymptomatic infections prevented higher rates ofmiscarriage and pre-term delivery. Current WHO policy calls for “theadministration of at least two doses of SP during the second and third trimesters ofpregnancy” [45, 46]. More effective protection during late pregnancy is critical inlow-endemic settings such as Mbarara, and addition of an extra (third) SP dose forall pregnant women rather than (as per current WHO policy) only to HIV-infectedwomen, or monthly dosing, could provide more effective protection in allpregnancies.

Adjusting for gestational age at birth, we found that peripheral malaria infectionduring pregnancy was associated with lower birth weight, and that this associationwas consistently seen in both the full dataset and the subset of mother withultrasound examination. Furthermore, more severe birth weight impairment wasobserved after multiple malaria infections and in malaria infections with highparasitaemia, even when IPT and bed net use was reported. These findings underscorethe importance of implementing efficacious prevention, prompt diagnosis and highlyeffective anti-malarial treatment during pregnancy [47].

In addition to primigravidity, a well-known risk factor for MiP [1, 4], it was found that low education level and rural residence wereindependently associated with malaria during pregnancy. These findings furthersupport the notion that it is essential to scale up malaria prevention efforts inmore isolated and deprived communities as recently highlighted in a meta-analysis ofdatasets from 25 African countries [48]. A low number of antenatal visits was also associated with reduced birthweight. The emphasis on at least four antenatal visits is required for improvedcontrol of malaria in pregnancy [45].

A limitation of this study was that documentation of malaria infection began onlyafter the first trimester of pregnancy, resulting in left censored data. Women withmultiple infections were more likely to have been enrolled later during theirgestation and, therefore, early infections might have been missed. This couldexplain the absence of association in this analysis between MiP early duringgestation and low birth weight, in contrast to results from other studies [11, 14, 15]. Alternatively, effective treatment of a single infection may allowrecovery from infection and catch-up growth in utero.

Placental malaria has been shown to be a key intermediate factor in the pathologicalpathway of malaria [2, 4, 18, 19]. However in our study, the proportion of placental infections (asdetermined from placental smears) was low, which most likely reflects ourstudy’s intensive detection and rapid treatment of malaria infections, aspreviously observed [20]. However, for placental malaria diagnosis the sensitivity of parasite(rather than pigment) on placenta smear is low, so the actual proportion ofplacental infection might also have been underestimated [49]. In a cohort study of women actively screened and tested in the Gambia,the presence of pigment was reported to better reflect past infection with malaria [50], a finding which may explain why an association between low birth weightand the presence of pigment but not with the presence of parasite in placental smearwas found in univariate analysis. Nevertheless, as the placenta cannot be examineduntil delivery, hence until after the adverse effect has already occurred, itsutility for clinical diagnosis and prevention remains limited.

On the other hand, peripheral parasitaemia, which was associated with impaireddelivery outcomes in this cohort, can be detected by frequent screening, so thatprompt treatment can be given and adverse effects of the infection reduced. Sincepreventive efforts (IPT with SP and insecticide-treated bed net) still leave a largeproportion of women with parasitaemia, taking the opportunity to screen women whenthey present to antenatal care is a strategy that should be considered. However,diagnostics for MiP remain problematic, since pregnant women often have low levelsof parasitaemia and require diagnostic tools with greater sensitivity thanmicroscopy (and good specificity)—for example, the Loop-mediated isothermalamplification (LAMP) [49, 51]. As malaria prevalence decreases, the risk-to-benefit ratio for providingIPT also reduces. Hence efforts to determine the optimal number of screenings forwomen in malaria endemic areas are also required.

In conclusion, this study shows that the timing, parasitaemia, symptoms and number ofperipherally detected malaria infections observed during pregnancy are associatedwith adverse outcomes. Prompt detection and treatment with an effectiveanti-malarial should be offered, irrespective of symptoms and use of otherpreventive measures in pregnancy. While frequent screening was associated withimproved birth outcome, reaching mothers living in remote areas to prevent lateattendance and low number of visits at antenatal care is essential, as they are morelikely to suffer from poor outcomes.

Declarations

Acknowledgements

This study was funded by Médecins Sans Frontières and the EuropeanCommission. We are very grateful to Patricia Kahn for editing this article andto François Nosten for comments on the early version of this article.

Authors’ Affiliations

(1)
Epicentre
(2)
UMI 233, Institut de Recherche pour le Développement, Université Montpellier I
(3)
Epicentre
(4)
Mbarara University of Science and Technology (MUST)
(5)
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University
(6)
Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford
(7)
University of Washington
(8)
WorldWide Antimalarial Resistance Network (WWARN)
(9)
Shoklo Malaria Research Unit (SMRU), Mahidol University
(10)
Institut Pasteur

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© De Beaudrap et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), whichpermits unrestricted use, distribution, and reproduction in any medium, provided theoriginal work is properly cited.

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