Anthropometric Parameters of HIV-Infected and HIV-Uninfected Mothers and their Premature Infants

Anthropometric Parameters of HIV-Infected and HIV-Uninfected Mothers and their Premature Infants Abstract This study aimed to assess the maternal anthropometric parameters of human immunodeficiency virus (HIV)-infected and HIV-uninfected mothers as well as to assess the neonatal anthropometric parameters of premature infants in relation to maternal anthropometric parameters (weight, height and mid-upper-arm circumference), HIV status and anti-retroviral therapy (ART) regimen. Study participants included HIV-infected and HIV-uninfected mothers who gave birth to premature infants. All HIV-infected mothers received ART. The incidence of intra-uterine growth restriction (IUGR) among premature infants was high. Maternal anthropometric parameters, HIV status and ART exposure showed no association with IUGR in this study. Sufficient maternal ART exposure may positively influence head circumference at birth, which might determine the neurodevelopmental outcome of these infants. anthropometry, maternal anthropometry, HIV, premature infants, preterm, infectious diseases INTRODUCTION A premature infant is defined as an infant born at <37 weeks’ gestation [1]. Fifteen million premature births occur worldwide of which 60% of these deliveries occur in low- and middle-income countries [2]. Premature delivery is considered a significant global perinatal health problem with a rising incidence in Southern Africa [3]. In a meta-analysis by Beck and colleagues, the worldwide prevalence of premature birth was 9.6%, and 85% of these preterm births were from the African and Asian continents [3]. Evidence from developing countries suggests that human immunodeficiency virus (HIV)-infected mothers have an increased risk of giving birth to premature infants, and the occurrence is directly associated with the clinical stage of the disease [4–6]. Research shows that HIV-infected women were more likely to give birth to low birth weight (LBW) and intra-uterine growth restricted premature infants [2, 5, 6]. The role of anti-retroviral therapy (ART) in intra-uterine growth restriction (IUGR) is uncertain. Studies conducted in the developed world showed no association between in utero exposure to ART and IUGR [5, 7–9]; however, results obtained from the developing world are conflicting [9–12]. Maternal anthropometric parameters during pregnancy are key factors in determining foetal growth and anthropometrical parameters at birth. In South Africa, poor household food security and the effects of HIV/AIDS Wasting Syndrome, or the combination thereof, may contribute to maternal undernutrition [13]. In the undernourished mother, the supply of maternal foetal nutrients are compromised, thereby restricting foetal growth. Foetal growth is more affected by chronic maternal undernutrition than nutrient restriction during the pregnancy period [14]. In addition to undernutrition, the incidence of overweight and obesity is rising dramatically in South Africa [11]. In a small subset of people, maternal overnutrition may increase the risk of delivering a premature IUGR infant, though the exact mechanisms are poorly understood [15]. An observational study found that obese women had a higher rate of IUGR deliveries as well as an increased frequency of admissions to the neonatal intensive care unit [16]. Maternal overnutrition impedes placental growth and ultimately leads to growth faltering, which significantly increases neonatal morbidity and mortality [17]. Highly active antiretroviral therapy use is often associated with overnutrition and metabolic and endocrine abnormalities [18, 19]. South Africa is a country where the incidence of HIV infection and premature births is high and therefore the need existed to [4] to assess the maternal anthropometric parameters of HIV-infected and HIV-uninfected mothers as well as to assess the neonatal anthropometric parameters of premature infants in relation to maternal anthropometric parameters [weight, height and mid-upper-arm circumference (MUAC)], HIV status and ART regimen. METHODOLOGY A cross-sectional study with an analytical component was conducted in the postnatal wards of Kalafong Hospital, Gauteng, South Africa from August 2014 to April 2015. Consecutive sampling was used to recruit participants. The study population included postnatal lactating HIV-infected mothers receiving ART and HIV-uninfected mothers who gave birth to premature infants. All mothers received accommodation in the ward as per standard protocol. The sample size was estimated by a statistician based on data of live births from the institution. The sample size was calculated by a one-way ANOVA calculation to obtain an effect size root mean square error = 0.55. Consecutive consenting postnatal mother–premature infant pairs were included in the study. The study population consisted of HIV-infected and HIV-uninfected mothers who gave birth to premature infants. All HIV-infected mothers received ART. An HIV positive status was established by a routine confirmed positive rapid HIV test during the prenatal period, and an HIV negative status was confirmed with a routine enzyme-linked immunosorbent assay (ELISA) test in the postnatal period. Gestational age was estimated by using the Ballard score, as early sonars are rarely performed. Standard means of medical treatment was continued during the study period. A researcher-administered questionnaire, tested for face and content validity during a pilot project, was used to obtain demographic and clinical information from the mother. Information regarding HIV status, ART regimen and CD4 count was collected. Maternal anthropometric information was obtained on Day 7 postnatally. This included weight, height and the MUAC. Maternal undernutrition was classified as a body mass index (BMI) < 20.3 [20] and/or MUAC < 214 mm [21] and maternal overnutrition was defined as a BMI > 25 kg/m2 [20]. Birth infantile anthropometric information was obtained from the patient folder. This included birth weight, length and head circumference (HC). A trained dietitian repeated the length and HC measurements on Day 7 postnatally according to standardized procedures [20]. IUGR was defined as a weight, length or HC <10th percentile [1]. Symmetrical IUGR (s-IUGR) is defined as a weight, length and HC <10th percentile and a ponderal index (PI) ≥2.0 and asymmetrical IUGR (a-IUGR) as weight <10th percentile with the sparing of length and HC and a PI <2.0 [22, 23]. Medical information was noted from the hospital file. Data captured on Microsoft Excel 2013® was exported to Statistica version 12 [StatSoft Inc. (2015) STATISTICA (data analysis software system), www.statsoft.com] for data analysis. Statistical analysis was done with the assistance of Tygerberg Biostatistics Unit, Stellenbosch University. Descriptive statistics were used to report the demographics of participants. When groups were compared, ANOVA and t-tests were used. Statistical significance was defined as p < 0.05. The study was granted ethics approval from the human research ethics committee of Stellenbosch University (S13/09/165) and the research ethics committee of the Faculty of Health Sciences at the University of Pretoria (191/2014). The study was conducted in accordance with Good Clinical Practice Guidelines. RESULTS A total of 90 mother–infant pairs were screened for inclusion in the investigation. Sixteen pairs were excluded of which 12 mothers were discharged before data collection procedures were completed, one mother was not on ART at the time of data collection, two mothers were excluded owing to an ELISA test not performed and one mother declined consent. The final sample consisted out of 74 mother–infant pairs. Thirty-eight (51%) mothers were HIV-infected and 36 (49%) were HIV-uninfected. All HIV-infected mothers received a fixed dose combination ART, which consists of tenofovir, emtricitabine and efavirenz [24]. The mean ART treatment period was 8.9 months (SD ± 15.4; 1 day to 7 years). In this group, the mean CD4 was 367 cells/mm3 (SD ± 165; CI = 51–720) cells/mm3. There were no significant differences in the demographic characteristics of mothers or infants. The mean gestational age of HIV-exposed infants was 31.8 weeks (SD ± 3.2) and of HIV-unexposed was 32.4 weeks (SD ± 2.86). The mean birthweight was 1468 g (SD ± 458.8 g), length 40.7 cm (SD ± 5.0 cm) and HC 28.7 cm (SD ± 3.1 cm). The demographic characteristics are depicted in Table 1. Table 1 Demographic characteristics of the sample Demographics    Mothers   HIV-infected  HIV-uninfected  p-value*  n=38 (51%)  n=36 (49%)  Ethnicity    p=0.3  African  38 (100%)  35 (97%)    Caucasian  0 (0%)  1 (3%)  Age in years mean (SD)  29 (5.57)  27 (5.11)  p=0.18  Education level (%)    p=0.76  No formal education  7 (19%)  7 (18%)    >Grade 10  12 (33%)  8 (21%)  ≥Grade 12  11 (31%)  14 (3%7)  Tertiary level  8 (22%)  7 (18%)  Demographics    Mothers   HIV-infected  HIV-uninfected  p-value*  n=38 (51%)  n=36 (49%)  Ethnicity    p=0.3  African  38 (100%)  35 (97%)    Caucasian  0 (0%)  1 (3%)  Age in years mean (SD)  29 (5.57)  27 (5.11)  p=0.18  Education level (%)    p=0.76  No formal education  7 (19%)  7 (18%)    >Grade 10  12 (33%)  8 (21%)  ≥Grade 12  11 (31%)  14 (3%7)  Tertiary level  8 (22%)  7 (18%)  Significance defined as *p = 0.05. Table 1 Demographic characteristics of the sample Demographics    Mothers   HIV-infected  HIV-uninfected  p-value*  n=38 (51%)  n=36 (49%)  Ethnicity    p=0.3  African  38 (100%)  35 (97%)    Caucasian  0 (0%)  1 (3%)  Age in years mean (SD)  29 (5.57)  27 (5.11)  p=0.18  Education level (%)    p=0.76  No formal education  7 (19%)  7 (18%)    >Grade 10  12 (33%)  8 (21%)  ≥Grade 12  11 (31%)  14 (3%7)  Tertiary level  8 (22%)  7 (18%)  Demographics    Mothers   HIV-infected  HIV-uninfected  p-value*  n=38 (51%)  n=36 (49%)  Ethnicity    p=0.3  African  38 (100%)  35 (97%)    Caucasian  0 (0%)  1 (3%)  Age in years mean (SD)  29 (5.57)  27 (5.11)  p=0.18  Education level (%)    p=0.76  No formal education  7 (19%)  7 (18%)    >Grade 10  12 (33%)  8 (21%)  ≥Grade 12  11 (31%)  14 (3%7)  Tertiary level  8 (22%)  7 (18%)  Significance defined as *p = 0.05. The mean maternal BMI was 26.7 kg/m2 (SD ± 4.88 kg/m2, CI = 25.7–27.9) and the mean MUAC was 289 mm (SD ± 3.93 mm; CI = 28.0–29.8). Under- and overnutrition prevalence was low with two (3%) mothers classified as underweight and 14 (19%) as obese. Twenty-seven (36%) mothers’ anthropometric parameters fell within normal ranges and 31 (42%) mothers’ anthropometric parameters were classified as overweight. The mean BMI and MUAC did not differ between HIV-infected and -uninfected mothers (p = 0.89 and p = 0.71, respectively). Furthermore, ART exposure duration had no significant effect on maternal anthropometrical parameters (Figure 1). Fig. 1. View largeDownload slide Maternal anthropometric data, HIV status and ART exposure period. Maternal BMI (A) and MUAC (B). HIV: human immunodeficiency virus, ART: antiretroviral Therapy, IUGR: intrauterine growth restriction, s-IUGR: symmetrical-IUGR, a-IUGR: asymmetrical IUGR. *p = 0.05. Fig. 1. View largeDownload slide Maternal anthropometric data, HIV status and ART exposure period. Maternal BMI (A) and MUAC (B). HIV: human immunodeficiency virus, ART: antiretroviral Therapy, IUGR: intrauterine growth restriction, s-IUGR: symmetrical-IUGR, a-IUGR: asymmetrical IUGR. *p = 0.05. Fig. 2. View largeDownload slide Anthropometric parameters <10 percentile of HIV-exposed premature infants according to maternal ART period. ART: antiretroviral therapy, HC: head circumference, **p < 0.01. Fig. 2. View largeDownload slide Anthropometric parameters <10 percentile of HIV-exposed premature infants according to maternal ART period. ART: antiretroviral therapy, HC: head circumference, **p < 0.01. IUGR was present in 40 (54%) of the premature infants. Of these, 13 (33%) were s-IUGR (PI ≥ 2.0) and 27 (67%) were a-IUGR (PI < 2.0), indicating wasting at birth. Similar incidence of IUGR was found in infants born to HIV-infected and HIV-uninfected mothers. Furthermore, no significant differences (p = 1.00) existed between infants with s-IUGR and a-IUGR according to maternal HIV status. Maternal anthropometric classifications (p = 0.79) and maternal HIV-infection and -ART regimen (p = 0.82) had no effect on the prevalence of IUGR (Table 2). No differences existed for birthweight (p = 0.18) and length (p = 0.15) or HC (p = 0.27) between infants born to HIV-infected and HIV-uninfected mothers. HIV exposure did not influence birthweight (p = 0.18), length (p = 0.15) or HC (p = 0.27). Maternal ART exposure time had no effect on infantile weights and lengths (p = 0.764 and p = 0.647, respectively); however, infants of mothers who received ART for >20 weeks showed significantly less restrictions related to their HC measurements (p = 0.003). HIV exposed infants whose anthropometrics fell <10th percentile are depicted in Figure 2. Maternal ART exposure had no effect on birthweight categories (Figure 3). Similarly, maternal CD4 cell counts had no effect on the incidence of IUGR. Table 2 Neonatal anthropometric parameters according to maternal HIV status, treatment regimen and anthropometric parameters Maternal characteristics  IUGR (n=40)  Non-IUGR (n=34)  p-value*  n (%)  n (%)  HIV status    p=0.72  HIV-infected on ART  20 (50)  18 (53)     ART <4 weeks  5 (25)  2 (11)   ART 4–20 weeks  7 (35)  6 (33)   ART >20 weeks  8 (40)  10 (56)  HIV-uninfected  20 (50)  16 (47)  Maternal nutritional status    p=0.79  Undernourished  1 (1)  1 (1)    Normal  16 (22)  11 (15)  Overweight  16 (22)  15 (20)  Obese  7 (9)  7 (9)  Maternal characteristics  IUGR (n=40)  Non-IUGR (n=34)  p-value*  n (%)  n (%)  HIV status    p=0.72  HIV-infected on ART  20 (50)  18 (53)     ART <4 weeks  5 (25)  2 (11)   ART 4–20 weeks  7 (35)  6 (33)   ART >20 weeks  8 (40)  10 (56)  HIV-uninfected  20 (50)  16 (47)  Maternal nutritional status    p=0.79  Undernourished  1 (1)  1 (1)    Normal  16 (22)  11 (15)  Overweight  16 (22)  15 (20)  Obese  7 (9)  7 (9)  ART: antiretroviral therapy, HIV: human immunodeficiency virus, IUGR: intra-uterine growth restriction; *p = 0.05. Table 2 Neonatal anthropometric parameters according to maternal HIV status, treatment regimen and anthropometric parameters Maternal characteristics  IUGR (n=40)  Non-IUGR (n=34)  p-value*  n (%)  n (%)  HIV status    p=0.72  HIV-infected on ART  20 (50)  18 (53)     ART <4 weeks  5 (25)  2 (11)   ART 4–20 weeks  7 (35)  6 (33)   ART >20 weeks  8 (40)  10 (56)  HIV-uninfected  20 (50)  16 (47)  Maternal nutritional status    p=0.79  Undernourished  1 (1)  1 (1)    Normal  16 (22)  11 (15)  Overweight  16 (22)  15 (20)  Obese  7 (9)  7 (9)  Maternal characteristics  IUGR (n=40)  Non-IUGR (n=34)  p-value*  n (%)  n (%)  HIV status    p=0.72  HIV-infected on ART  20 (50)  18 (53)     ART <4 weeks  5 (25)  2 (11)   ART 4–20 weeks  7 (35)  6 (33)   ART >20 weeks  8 (40)  10 (56)  HIV-uninfected  20 (50)  16 (47)  Maternal nutritional status    p=0.79  Undernourished  1 (1)  1 (1)    Normal  16 (22)  11 (15)  Overweight  16 (22)  15 (20)  Obese  7 (9)  7 (9)  ART: antiretroviral therapy, HIV: human immunodeficiency virus, IUGR: intra-uterine growth restriction; *p = 0.05. Fig 3. View largeDownload slide Birthweight according to maternal ART exposure time and HIV-uninfected mothers. ART: antiretroviral Therapy, LBW: low birth weight, VLBW: very low birth weight, ELBW: extremely low birth weight, p = 0.63. Fig 3. View largeDownload slide Birthweight according to maternal ART exposure time and HIV-uninfected mothers. ART: antiretroviral Therapy, LBW: low birth weight, VLBW: very low birth weight, ELBW: extremely low birth weight, p = 0.63. DISCUSSION Early recognition of HIV infection is a key strategy in decreasing mother to child transmission. It is evident that the current Prevention of Mother to Child Transmission of HIV programme is effective when comparing the mean ART treatment period and mean gestation period. Our results did not show an association between maternal HIV-infection and adverse pregnancy outcomes, such as premature birth and IUGR. This is conflicting to numerous studies from Sub-Saharan Africa that reported significant results [4–6]. The short- and long-term effects of ART on in utero development are unknown, particularly in developing countries. While some studies found that maternal antiretroviral drugs compromised neonatal anthropometric classification [5, 7–9], others, including ours, did not [9–12]. Anthropometrics (birthweight, length and HC) and birthweight categories were not influenced by maternal HIV-status or ART use. While ART may increase the risk for LBW [5, 7–9], the importance of maternal ART provision is imperative to prevent Maternal to Child Transmission of HIV. However, other strategies to prevent LBW should be optimized, as LBW infants are at higher risk of mortality compared with a term appropriate-for-gestation infant [25]. Mothers had a mean BMI of 26.7 kg/m2, which suggests a risk for overweight among childbearing women. The prevalence of IUGR was high (53%) in this group. The combination of mothers at risk of overweight and infants being born with IUGR have important implications for HIV-infected and HIV-uninfected women of reproductive age, as it indicates possible metabolic disturbances for them and their offspring. The role of ART may further disturb clinical anthropometric and metabolic parameters. ART is associated with metabolic aberrations, including central obesity, dyslipidaemia and insulin resistance [18]. Although maternal anthropometrics were not influenced by ART exposure time, the possibility of pre-pregnancy or future morphological and/or metabolic effects should not be excluded. Epidemiological studies and animal models associate LBW with risk of adult obesity and metabolic syndrome. Maternal overnutrition, whether from obesity, high energy and fat diets or excessive weight gain in pregnancy, has delivered varied results concerning birth weight. However, in the adult offspring, obesity and metabolic abnormalities are highly prevalent, indicating evidence of metabolic programming [26–29]. The intrauterine exposure to endocrine disrupting chemicals (or obesogens), present in overweight mothers, alter the developmental programming of adipogenesis of the foetus through gene expression. The developing foetus responds by producing structural and functional changes in tissues and organ systems, known as foetal programming, which result in increased plasticity of adipocytes [30]. A third (32%) of infants with IUGR presented with low HC measurements. Subanalyses demonstrated a higher incidence of HC restriction among women with ART exposure <20 weeks and insufficient ART exposure. This holds important implications, as an impaired HC at birth is a strong indicator of impaired neurodevelopmental outcomes in childhood [31]. Studies that explored prenatal exposure to ART did not find differences in infant neurodevelopmental outcomes [32, 33]. The results indicate the possibility that increased ART exposure might protect infants against impaired brain development, as seen in studies on longer ART duration and association with reduction of some neurologic impairment in children [34]. CONCLUSION The incidence of IUGR among premature infants was high. Maternal anthropometric parameters, HIV status and ART exposure showed no association with IUGR, nor the type of IUGR in this study. Sufficient maternal ART exposure may positively influence HC at birth, which might determine the neurodevelopmental outcome of these infants. ACKNOWLEDGEMENTS Gratitude is extended to the Department of Paediatrics at Kalafong Hospital as well as the team that assisted with data collection for the support and assistance in the research project. The Tygerberg Biostatistics Unit of Stellenbosch University is acknowledged for assistance with the statistical analyses. FUNDING This work was supported by the Harry Crossley Foundation. REFERENCES 1 Goldenberg RL, Culhane JF, Iams JD, et al.   Epidemiology and causes of preterm birth. Lancet  2008; 371: 75– 84. Google Scholar CrossRef Search ADS PubMed  2 Vogel JP, Lee AC, Souza JP. Maternal morbidity and preterm birth in 22 low- and middle income countries: a secondary analysis of the WHO global survey dataset. BMC Pregnancy Childbirth  2014; 14: 56– 70. Google Scholar CrossRef Search ADS PubMed  3 Beck S, Wojdyla D, Say L, et al.   Worldwide incidence of premature birth: a systematic review of maternal mortality and morbidity. Bull World Health Org  2010; 88: 31– 8. Google Scholar CrossRef Search ADS PubMed  4 Rollins N, Coovadia H, Bland RM, et al.   Pregnancy outcomes in HIV-infected and –uninfected women in rural and urban South Africa. 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Anthropometric Parameters of HIV-Infected and HIV-Uninfected Mothers and their Premature Infants

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Abstract

Abstract This study aimed to assess the maternal anthropometric parameters of human immunodeficiency virus (HIV)-infected and HIV-uninfected mothers as well as to assess the neonatal anthropometric parameters of premature infants in relation to maternal anthropometric parameters (weight, height and mid-upper-arm circumference), HIV status and anti-retroviral therapy (ART) regimen. Study participants included HIV-infected and HIV-uninfected mothers who gave birth to premature infants. All HIV-infected mothers received ART. The incidence of intra-uterine growth restriction (IUGR) among premature infants was high. Maternal anthropometric parameters, HIV status and ART exposure showed no association with IUGR in this study. Sufficient maternal ART exposure may positively influence head circumference at birth, which might determine the neurodevelopmental outcome of these infants. anthropometry, maternal anthropometry, HIV, premature infants, preterm, infectious diseases INTRODUCTION A premature infant is defined as an infant born at <37 weeks’ gestation [1]. Fifteen million premature births occur worldwide of which 60% of these deliveries occur in low- and middle-income countries [2]. Premature delivery is considered a significant global perinatal health problem with a rising incidence in Southern Africa [3]. In a meta-analysis by Beck and colleagues, the worldwide prevalence of premature birth was 9.6%, and 85% of these preterm births were from the African and Asian continents [3]. Evidence from developing countries suggests that human immunodeficiency virus (HIV)-infected mothers have an increased risk of giving birth to premature infants, and the occurrence is directly associated with the clinical stage of the disease [4–6]. Research shows that HIV-infected women were more likely to give birth to low birth weight (LBW) and intra-uterine growth restricted premature infants [2, 5, 6]. The role of anti-retroviral therapy (ART) in intra-uterine growth restriction (IUGR) is uncertain. Studies conducted in the developed world showed no association between in utero exposure to ART and IUGR [5, 7–9]; however, results obtained from the developing world are conflicting [9–12]. Maternal anthropometric parameters during pregnancy are key factors in determining foetal growth and anthropometrical parameters at birth. In South Africa, poor household food security and the effects of HIV/AIDS Wasting Syndrome, or the combination thereof, may contribute to maternal undernutrition [13]. In the undernourished mother, the supply of maternal foetal nutrients are compromised, thereby restricting foetal growth. Foetal growth is more affected by chronic maternal undernutrition than nutrient restriction during the pregnancy period [14]. In addition to undernutrition, the incidence of overweight and obesity is rising dramatically in South Africa [11]. In a small subset of people, maternal overnutrition may increase the risk of delivering a premature IUGR infant, though the exact mechanisms are poorly understood [15]. An observational study found that obese women had a higher rate of IUGR deliveries as well as an increased frequency of admissions to the neonatal intensive care unit [16]. Maternal overnutrition impedes placental growth and ultimately leads to growth faltering, which significantly increases neonatal morbidity and mortality [17]. Highly active antiretroviral therapy use is often associated with overnutrition and metabolic and endocrine abnormalities [18, 19]. South Africa is a country where the incidence of HIV infection and premature births is high and therefore the need existed to [4] to assess the maternal anthropometric parameters of HIV-infected and HIV-uninfected mothers as well as to assess the neonatal anthropometric parameters of premature infants in relation to maternal anthropometric parameters [weight, height and mid-upper-arm circumference (MUAC)], HIV status and ART regimen. METHODOLOGY A cross-sectional study with an analytical component was conducted in the postnatal wards of Kalafong Hospital, Gauteng, South Africa from August 2014 to April 2015. Consecutive sampling was used to recruit participants. The study population included postnatal lactating HIV-infected mothers receiving ART and HIV-uninfected mothers who gave birth to premature infants. All mothers received accommodation in the ward as per standard protocol. The sample size was estimated by a statistician based on data of live births from the institution. The sample size was calculated by a one-way ANOVA calculation to obtain an effect size root mean square error = 0.55. Consecutive consenting postnatal mother–premature infant pairs were included in the study. The study population consisted of HIV-infected and HIV-uninfected mothers who gave birth to premature infants. All HIV-infected mothers received ART. An HIV positive status was established by a routine confirmed positive rapid HIV test during the prenatal period, and an HIV negative status was confirmed with a routine enzyme-linked immunosorbent assay (ELISA) test in the postnatal period. Gestational age was estimated by using the Ballard score, as early sonars are rarely performed. Standard means of medical treatment was continued during the study period. A researcher-administered questionnaire, tested for face and content validity during a pilot project, was used to obtain demographic and clinical information from the mother. Information regarding HIV status, ART regimen and CD4 count was collected. Maternal anthropometric information was obtained on Day 7 postnatally. This included weight, height and the MUAC. Maternal undernutrition was classified as a body mass index (BMI) < 20.3 [20] and/or MUAC < 214 mm [21] and maternal overnutrition was defined as a BMI > 25 kg/m2 [20]. Birth infantile anthropometric information was obtained from the patient folder. This included birth weight, length and head circumference (HC). A trained dietitian repeated the length and HC measurements on Day 7 postnatally according to standardized procedures [20]. IUGR was defined as a weight, length or HC <10th percentile [1]. Symmetrical IUGR (s-IUGR) is defined as a weight, length and HC <10th percentile and a ponderal index (PI) ≥2.0 and asymmetrical IUGR (a-IUGR) as weight <10th percentile with the sparing of length and HC and a PI <2.0 [22, 23]. Medical information was noted from the hospital file. Data captured on Microsoft Excel 2013® was exported to Statistica version 12 [StatSoft Inc. (2015) STATISTICA (data analysis software system), www.statsoft.com] for data analysis. Statistical analysis was done with the assistance of Tygerberg Biostatistics Unit, Stellenbosch University. Descriptive statistics were used to report the demographics of participants. When groups were compared, ANOVA and t-tests were used. Statistical significance was defined as p < 0.05. The study was granted ethics approval from the human research ethics committee of Stellenbosch University (S13/09/165) and the research ethics committee of the Faculty of Health Sciences at the University of Pretoria (191/2014). The study was conducted in accordance with Good Clinical Practice Guidelines. RESULTS A total of 90 mother–infant pairs were screened for inclusion in the investigation. Sixteen pairs were excluded of which 12 mothers were discharged before data collection procedures were completed, one mother was not on ART at the time of data collection, two mothers were excluded owing to an ELISA test not performed and one mother declined consent. The final sample consisted out of 74 mother–infant pairs. Thirty-eight (51%) mothers were HIV-infected and 36 (49%) were HIV-uninfected. All HIV-infected mothers received a fixed dose combination ART, which consists of tenofovir, emtricitabine and efavirenz [24]. The mean ART treatment period was 8.9 months (SD ± 15.4; 1 day to 7 years). In this group, the mean CD4 was 367 cells/mm3 (SD ± 165; CI = 51–720) cells/mm3. There were no significant differences in the demographic characteristics of mothers or infants. The mean gestational age of HIV-exposed infants was 31.8 weeks (SD ± 3.2) and of HIV-unexposed was 32.4 weeks (SD ± 2.86). The mean birthweight was 1468 g (SD ± 458.8 g), length 40.7 cm (SD ± 5.0 cm) and HC 28.7 cm (SD ± 3.1 cm). The demographic characteristics are depicted in Table 1. Table 1 Demographic characteristics of the sample Demographics    Mothers   HIV-infected  HIV-uninfected  p-value*  n=38 (51%)  n=36 (49%)  Ethnicity    p=0.3  African  38 (100%)  35 (97%)    Caucasian  0 (0%)  1 (3%)  Age in years mean (SD)  29 (5.57)  27 (5.11)  p=0.18  Education level (%)    p=0.76  No formal education  7 (19%)  7 (18%)    >Grade 10  12 (33%)  8 (21%)  ≥Grade 12  11 (31%)  14 (3%7)  Tertiary level  8 (22%)  7 (18%)  Demographics    Mothers   HIV-infected  HIV-uninfected  p-value*  n=38 (51%)  n=36 (49%)  Ethnicity    p=0.3  African  38 (100%)  35 (97%)    Caucasian  0 (0%)  1 (3%)  Age in years mean (SD)  29 (5.57)  27 (5.11)  p=0.18  Education level (%)    p=0.76  No formal education  7 (19%)  7 (18%)    >Grade 10  12 (33%)  8 (21%)  ≥Grade 12  11 (31%)  14 (3%7)  Tertiary level  8 (22%)  7 (18%)  Significance defined as *p = 0.05. Table 1 Demographic characteristics of the sample Demographics    Mothers   HIV-infected  HIV-uninfected  p-value*  n=38 (51%)  n=36 (49%)  Ethnicity    p=0.3  African  38 (100%)  35 (97%)    Caucasian  0 (0%)  1 (3%)  Age in years mean (SD)  29 (5.57)  27 (5.11)  p=0.18  Education level (%)    p=0.76  No formal education  7 (19%)  7 (18%)    >Grade 10  12 (33%)  8 (21%)  ≥Grade 12  11 (31%)  14 (3%7)  Tertiary level  8 (22%)  7 (18%)  Demographics    Mothers   HIV-infected  HIV-uninfected  p-value*  n=38 (51%)  n=36 (49%)  Ethnicity    p=0.3  African  38 (100%)  35 (97%)    Caucasian  0 (0%)  1 (3%)  Age in years mean (SD)  29 (5.57)  27 (5.11)  p=0.18  Education level (%)    p=0.76  No formal education  7 (19%)  7 (18%)    >Grade 10  12 (33%)  8 (21%)  ≥Grade 12  11 (31%)  14 (3%7)  Tertiary level  8 (22%)  7 (18%)  Significance defined as *p = 0.05. The mean maternal BMI was 26.7 kg/m2 (SD ± 4.88 kg/m2, CI = 25.7–27.9) and the mean MUAC was 289 mm (SD ± 3.93 mm; CI = 28.0–29.8). Under- and overnutrition prevalence was low with two (3%) mothers classified as underweight and 14 (19%) as obese. Twenty-seven (36%) mothers’ anthropometric parameters fell within normal ranges and 31 (42%) mothers’ anthropometric parameters were classified as overweight. The mean BMI and MUAC did not differ between HIV-infected and -uninfected mothers (p = 0.89 and p = 0.71, respectively). Furthermore, ART exposure duration had no significant effect on maternal anthropometrical parameters (Figure 1). Fig. 1. View largeDownload slide Maternal anthropometric data, HIV status and ART exposure period. Maternal BMI (A) and MUAC (B). HIV: human immunodeficiency virus, ART: antiretroviral Therapy, IUGR: intrauterine growth restriction, s-IUGR: symmetrical-IUGR, a-IUGR: asymmetrical IUGR. *p = 0.05. Fig. 1. View largeDownload slide Maternal anthropometric data, HIV status and ART exposure period. Maternal BMI (A) and MUAC (B). HIV: human immunodeficiency virus, ART: antiretroviral Therapy, IUGR: intrauterine growth restriction, s-IUGR: symmetrical-IUGR, a-IUGR: asymmetrical IUGR. *p = 0.05. Fig. 2. View largeDownload slide Anthropometric parameters <10 percentile of HIV-exposed premature infants according to maternal ART period. ART: antiretroviral therapy, HC: head circumference, **p < 0.01. Fig. 2. View largeDownload slide Anthropometric parameters <10 percentile of HIV-exposed premature infants according to maternal ART period. ART: antiretroviral therapy, HC: head circumference, **p < 0.01. IUGR was present in 40 (54%) of the premature infants. Of these, 13 (33%) were s-IUGR (PI ≥ 2.0) and 27 (67%) were a-IUGR (PI < 2.0), indicating wasting at birth. Similar incidence of IUGR was found in infants born to HIV-infected and HIV-uninfected mothers. Furthermore, no significant differences (p = 1.00) existed between infants with s-IUGR and a-IUGR according to maternal HIV status. Maternal anthropometric classifications (p = 0.79) and maternal HIV-infection and -ART regimen (p = 0.82) had no effect on the prevalence of IUGR (Table 2). No differences existed for birthweight (p = 0.18) and length (p = 0.15) or HC (p = 0.27) between infants born to HIV-infected and HIV-uninfected mothers. HIV exposure did not influence birthweight (p = 0.18), length (p = 0.15) or HC (p = 0.27). Maternal ART exposure time had no effect on infantile weights and lengths (p = 0.764 and p = 0.647, respectively); however, infants of mothers who received ART for >20 weeks showed significantly less restrictions related to their HC measurements (p = 0.003). HIV exposed infants whose anthropometrics fell <10th percentile are depicted in Figure 2. Maternal ART exposure had no effect on birthweight categories (Figure 3). Similarly, maternal CD4 cell counts had no effect on the incidence of IUGR. Table 2 Neonatal anthropometric parameters according to maternal HIV status, treatment regimen and anthropometric parameters Maternal characteristics  IUGR (n=40)  Non-IUGR (n=34)  p-value*  n (%)  n (%)  HIV status    p=0.72  HIV-infected on ART  20 (50)  18 (53)     ART <4 weeks  5 (25)  2 (11)   ART 4–20 weeks  7 (35)  6 (33)   ART >20 weeks  8 (40)  10 (56)  HIV-uninfected  20 (50)  16 (47)  Maternal nutritional status    p=0.79  Undernourished  1 (1)  1 (1)    Normal  16 (22)  11 (15)  Overweight  16 (22)  15 (20)  Obese  7 (9)  7 (9)  Maternal characteristics  IUGR (n=40)  Non-IUGR (n=34)  p-value*  n (%)  n (%)  HIV status    p=0.72  HIV-infected on ART  20 (50)  18 (53)     ART <4 weeks  5 (25)  2 (11)   ART 4–20 weeks  7 (35)  6 (33)   ART >20 weeks  8 (40)  10 (56)  HIV-uninfected  20 (50)  16 (47)  Maternal nutritional status    p=0.79  Undernourished  1 (1)  1 (1)    Normal  16 (22)  11 (15)  Overweight  16 (22)  15 (20)  Obese  7 (9)  7 (9)  ART: antiretroviral therapy, HIV: human immunodeficiency virus, IUGR: intra-uterine growth restriction; *p = 0.05. Table 2 Neonatal anthropometric parameters according to maternal HIV status, treatment regimen and anthropometric parameters Maternal characteristics  IUGR (n=40)  Non-IUGR (n=34)  p-value*  n (%)  n (%)  HIV status    p=0.72  HIV-infected on ART  20 (50)  18 (53)     ART <4 weeks  5 (25)  2 (11)   ART 4–20 weeks  7 (35)  6 (33)   ART >20 weeks  8 (40)  10 (56)  HIV-uninfected  20 (50)  16 (47)  Maternal nutritional status    p=0.79  Undernourished  1 (1)  1 (1)    Normal  16 (22)  11 (15)  Overweight  16 (22)  15 (20)  Obese  7 (9)  7 (9)  Maternal characteristics  IUGR (n=40)  Non-IUGR (n=34)  p-value*  n (%)  n (%)  HIV status    p=0.72  HIV-infected on ART  20 (50)  18 (53)     ART <4 weeks  5 (25)  2 (11)   ART 4–20 weeks  7 (35)  6 (33)   ART >20 weeks  8 (40)  10 (56)  HIV-uninfected  20 (50)  16 (47)  Maternal nutritional status    p=0.79  Undernourished  1 (1)  1 (1)    Normal  16 (22)  11 (15)  Overweight  16 (22)  15 (20)  Obese  7 (9)  7 (9)  ART: antiretroviral therapy, HIV: human immunodeficiency virus, IUGR: intra-uterine growth restriction; *p = 0.05. Fig 3. View largeDownload slide Birthweight according to maternal ART exposure time and HIV-uninfected mothers. ART: antiretroviral Therapy, LBW: low birth weight, VLBW: very low birth weight, ELBW: extremely low birth weight, p = 0.63. Fig 3. View largeDownload slide Birthweight according to maternal ART exposure time and HIV-uninfected mothers. ART: antiretroviral Therapy, LBW: low birth weight, VLBW: very low birth weight, ELBW: extremely low birth weight, p = 0.63. DISCUSSION Early recognition of HIV infection is a key strategy in decreasing mother to child transmission. It is evident that the current Prevention of Mother to Child Transmission of HIV programme is effective when comparing the mean ART treatment period and mean gestation period. Our results did not show an association between maternal HIV-infection and adverse pregnancy outcomes, such as premature birth and IUGR. This is conflicting to numerous studies from Sub-Saharan Africa that reported significant results [4–6]. The short- and long-term effects of ART on in utero development are unknown, particularly in developing countries. While some studies found that maternal antiretroviral drugs compromised neonatal anthropometric classification [5, 7–9], others, including ours, did not [9–12]. Anthropometrics (birthweight, length and HC) and birthweight categories were not influenced by maternal HIV-status or ART use. While ART may increase the risk for LBW [5, 7–9], the importance of maternal ART provision is imperative to prevent Maternal to Child Transmission of HIV. However, other strategies to prevent LBW should be optimized, as LBW infants are at higher risk of mortality compared with a term appropriate-for-gestation infant [25]. Mothers had a mean BMI of 26.7 kg/m2, which suggests a risk for overweight among childbearing women. The prevalence of IUGR was high (53%) in this group. The combination of mothers at risk of overweight and infants being born with IUGR have important implications for HIV-infected and HIV-uninfected women of reproductive age, as it indicates possible metabolic disturbances for them and their offspring. The role of ART may further disturb clinical anthropometric and metabolic parameters. ART is associated with metabolic aberrations, including central obesity, dyslipidaemia and insulin resistance [18]. Although maternal anthropometrics were not influenced by ART exposure time, the possibility of pre-pregnancy or future morphological and/or metabolic effects should not be excluded. Epidemiological studies and animal models associate LBW with risk of adult obesity and metabolic syndrome. Maternal overnutrition, whether from obesity, high energy and fat diets or excessive weight gain in pregnancy, has delivered varied results concerning birth weight. However, in the adult offspring, obesity and metabolic abnormalities are highly prevalent, indicating evidence of metabolic programming [26–29]. The intrauterine exposure to endocrine disrupting chemicals (or obesogens), present in overweight mothers, alter the developmental programming of adipogenesis of the foetus through gene expression. The developing foetus responds by producing structural and functional changes in tissues and organ systems, known as foetal programming, which result in increased plasticity of adipocytes [30]. A third (32%) of infants with IUGR presented with low HC measurements. Subanalyses demonstrated a higher incidence of HC restriction among women with ART exposure <20 weeks and insufficient ART exposure. This holds important implications, as an impaired HC at birth is a strong indicator of impaired neurodevelopmental outcomes in childhood [31]. Studies that explored prenatal exposure to ART did not find differences in infant neurodevelopmental outcomes [32, 33]. The results indicate the possibility that increased ART exposure might protect infants against impaired brain development, as seen in studies on longer ART duration and association with reduction of some neurologic impairment in children [34]. CONCLUSION The incidence of IUGR among premature infants was high. Maternal anthropometric parameters, HIV status and ART exposure showed no association with IUGR, nor the type of IUGR in this study. Sufficient maternal ART exposure may positively influence HC at birth, which might determine the neurodevelopmental outcome of these infants. ACKNOWLEDGEMENTS Gratitude is extended to the Department of Paediatrics at Kalafong Hospital as well as the team that assisted with data collection for the support and assistance in the research project. The Tygerberg Biostatistics Unit of Stellenbosch University is acknowledged for assistance with the statistical analyses. FUNDING This work was supported by the Harry Crossley Foundation. REFERENCES 1 Goldenberg RL, Culhane JF, Iams JD, et al.   Epidemiology and causes of preterm birth. Lancet  2008; 371: 75– 84. Google Scholar CrossRef Search ADS PubMed  2 Vogel JP, Lee AC, Souza JP. Maternal morbidity and preterm birth in 22 low- and middle income countries: a secondary analysis of the WHO global survey dataset. BMC Pregnancy Childbirth  2014; 14: 56– 70. Google Scholar CrossRef Search ADS PubMed  3 Beck S, Wojdyla D, Say L, et al.   Worldwide incidence of premature birth: a systematic review of maternal mortality and morbidity. Bull World Health Org  2010; 88: 31– 8. Google Scholar CrossRef Search ADS PubMed  4 Rollins N, Coovadia H, Bland RM, et al.   Pregnancy outcomes in HIV-infected and –uninfected women in rural and urban South Africa. 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Journal of Tropical PediatricsOxford University Press

Published: Aug 3, 2017

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