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Zidovudine treatment in HIV-infected pregnant women is associated with fetal cardiac remodelling

García-Otero, Laura; López, Marta; Gómez, Olga; Goncé, Ana; Bennasar, Mar; Martínez, Josep Maria; Valenzuela-Alcaraz, Brenda; Rodriguez-López, Mérida; Sitges, Marta; Loncà, Montserrat; Bijnens, Bart; Crispi, Fàtima; Gratacós, Eduard

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doi: 10.1097/QAD.0000000000001066
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Abstract

Introduction

Perinatal transmission of HIV is almost negligible if the current preventive strategies are applied [mainly the use of combined antiretroviral treatment (cART) during pregnancy] [1,2]. HIV-exposed to maternal cART but uninfected (HEU) children are generally considered healthy, although several studies have reported long-term differences in neurodevelopmental, immunological, and cardiac parameters as compared with controls [3,4]. In relation with the latter, consistent evidence has demonstrated subclinical changes in the cardiac structure and function of HEU patients from birth up to adolescence [5–7].

The underlying mechanism of cardiac changes in the offspring of HIV-infected mothers remains to be elucidated, but toxicity from antiretroviral drugs during fetal life is suggested as a pathogenic pathway [7,8]. Evidence from previous studies is inconclusive. A large study including 173 fetuses reported significant changes in fetal cardiac structure and function, but only one-third of the mothers received prenatal monotherapy with zidovudine (ZDV) [9]. A more recent study with 29 HIV-infected pregnancies on cART reported only mild changes in fetal cardiac function [10]. Aside from prenatal cART, HIV-infected pregnancies are more commonly exposed to perinatal complications including fetal growth restriction [11], prematurity [12], and preeclampsia [13], which could directly affect fetal cardiac structure and function [14–17], but the impact of these factors has not been assessed.

In this study, we comprehensively evaluate fetal cardiac structure and function in a cohort of 42-uninfected fetuses from HIV mothers under cART, which were compared with 84 controls. Our aim was to describe the pattern of fetal structural and/or functional cardiac changes during fetal life and to evaluate the independent and combined association with antiretroviral treatment (ART), maternal and perinatal factors.

Methods

Study populations

The study design was a prospective cohort including noninfected fetuses from HIV-infected pregnant women on cART followed up in the Maternal–Fetal Medicine Department at BCNatal in Barcelona (Spain) from May 2010 to December 2014. The control group included consecutive non-HIV-infected pregnancies from the same Department accepting to participate in the study. Controls were frequency paired (2 : 1) with HIV-infected pregnancies by gestational age at scan (±1 week). Twin pregnancies, diagnosis of fetal malformations (including congenital heart disease) or chromosomal anomalies, delivery before 24 weeks of gestational age as well as perinatal transmission of HIV were considered exclusion criteria. Both groups underwent the same study protocol including collection of baseline and perinatal characteristics and third trimester fetal echocardiography. The study protocol was approved by the local ethical committee and all pregnant women participating signed a written consent form.

Study protocol

Baseline characteristics and perinatal outcome

Maternal epidemiological and obstetric parameters were collected by interview and review of medical records, including maternal age, BMI, ethnicity, socioeconomic status (illiterate or only primary educational level were considered low socioeconomic status), smoking status and illicit substance abuse (heroin, cocaine, or cannabis) during pregnancy and maternal hepatitis C infection. Maternal comorbidity was defined as the presence of chronic hypertension, pregestational diabetes, or autoimmune disorder.

Upon delivery, pregnancy and perinatal outcomes were recorded including the presence of gestational diabetes, preeclampsia, preterm delivery (<37 weeks of gestation), gestational age at delivery, mode of delivery, birthweight, small for gestational age, Apgar score, umbilical artery pH, neonatal admission to ICU and perinatal morbidity and mortality. Small-for-gestational age was defined as birthweight below 10th centile according to local standards [18]. Gestational age was calculated according to first trimester crown-rump length [19]. Preeclampsia was defined by new onset of hypertension of more than 140 mmHg SBP or more than 90 DBP together with more than 300 mg proteins in 24 h urine [20]. Major neonatal morbidity was defined by the presence of bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular haemorrhage, periventricular leukomalacia, retinopathy, persistent ductus arteriosus, or sepsis. Perinatal mortality was defined by either intrauterine fetal death after 22 weeks of pregnancy or neonatal death within the first 28 days of life [21].

HIV-infection parameters

Immunovirological parameters for HIV-infected women were also recorded, including mode of HIV transmission, presence of previous opportunistic infections, diagnosis of HIV during pregnancy, months of HIV infection at delivery, CD4+ T-cell count (by flow-cytometry), and plasmatic viral load by HIV-RNA copy quantification (Amplicor HIV Monitor; Roche Diagnostic Systems, Branchburg, New Jersey, USA) at first trimester and at delivery. We also documented the haemoglobin in the third-trimester blood test to detect maternal anaemia. All HIV-infected pregnant women were treated with cART. The specific cART regimen during pregnancy was decided by the practitioner following local and international guidelines [22,23]. Type and duration of ART before and during pregnancy were recorded.

Fetal standard ultrasound and echocardiography

All pregnancies underwent ultrasonographic examination at 26–32 weeks of gestation using a Siemens Sonoline Antares (Siemens Medical Systems, Malvern, Pennsylvania, USA) with 6–4 MHz linear curved-array and 2–10 MHz phased-array probes, including estimated fetal weight, feto-placental Doppler, and fetal echocardiography. Ultrasounds were performed by maternal–fetal medicine specialists skilled in fetal echocardiography who were blinded to the particular ART but not to the HIV status. Fetal weight was estimated measuring the abdominal circumference, head circumference, biparietal diameter, and femur length, following the Hadlock formula [24]. Feto-placental Doppler assessment included the measurement of pulsatility index of uterine arteries, umbilical artery, and middle cerebral artery as well as the peak velocity of systolic blood flow in the middle cerebral artery according to the previously published methodology [25–28].

A comprehensive two-dimensional, M-mode, and Doppler echocardiographic examination was performed initially to assess structural heart integrity and to evaluate cardiac morphometry and function. The cardiothoracic ratio was calculated as the ratio of the area of the heart to that of the thorax on two-dimensional images from an apical or basal four-chamber view [29]. The presence of pericardial effusion was evaluated at the midventricular level from a transverse four-chamber view and was considered present when it exceeded 2 mm. Ventricular base-to-apex lengths and basal diameters were measured on two-dimensional images from an apical or basal four-chamber view at end-diastole [30]. Left and right ventricular sphericity indices were calculated as base-to-apex length/basal diameter. Myocardial wall thicknesses (septum and left and right free wall) were measured on two-dimensional images from a transverse four-chamber view. Relative wall thickness was calculated as septal wall thickness plus posterior wall thickness divided by left ventricular end-diastolic diameter [31]. Left and right atrial areas were measured at maximum distension from a four-chamber view. Left and right ventricular ejection fraction (%) were obtained from M-mode transverse four-chamber views using the Teichholz‘s formula. Mitral/tricuspid annular displacement (MAPSE/TAPSE) was assessed by M-mode from an apical or basal four-chamber view [32]. Tissue Doppler Imaging was applied in the spectral Doppler mode to record systolic (S′) and early diastolic (E′) peak velocities at mitral (septal) and tricuspid annuli from an apical or basal four-chamber view and measured in real time [33]. Atrioventricular flows were obtained from a basal or apical four-chamber view, placing the pulsed Doppler sample volume at the tip of atrioventricular valve leaflets. Right and left E/A ratios were calculated by dividing early ventricular filling (E-wave) by late ventricular filling (A-wave). Left isovolumic and ejection times were measured from a single Doppler spectrum including mitral inflow and aortic outflow as previously described [34,35]. Left isovolumic contraction time was measured from the closure of the mitral valve to the opening of the aortic valve. Left ejection time was measured from the opening to the closure of the aortic valve. Left isovolumic relaxation time was measured from the closure of the aortic valve to the opening of the mitral valve [36].

Statistical analysis

Data are presented as mean (standard deviation), median (interquartile range), or number (percentage) as appropriate. Normal distribution of variables was checked using Kolmogorov–Smirnov test. Values of annular peak velocity measured by TDI were chosen to calculate sample size as a representative parameter of cardiac dysfunction previously described in fetuses [33,37]. On this basis, sample size was calculated to allow observation of a difference of 0.55 cm/s in systolic peak velocity (S′) at mitral (septal) valve compared with controls. For a power of 80% and an α risk of 0.05, a minimum of 40 patients per study group (HIV-infected pregnancies) and 80 per control group (HIV-uninfected pregnancies) were required. We included 42 and 84 fetuses, respectively.

Differences on baseline and perinatal characteristics between the study groups were assessed using χ-square, t-test, or Mann–Whitney as appropriate. Differences on cardiovascular parameters were assessed by using multivariate regression analysis adjusting by the potential baseline and perinatal confounders detected in the univariate analysis. To assess the potential factors associated with fetal cardiac changes, the exposed group was subdivided taking into account the most relevant cardiac findings selected from a principal component analysis (details in Supplementary material), and comparisons among these two groups were assessed by χ-square, t-test, or Mann–Whitney as appropriate. SPSS Statistics 19 (IBM, Armonk, New York, USA) was used for the statistical analysis. All reported P-values are two-sided. The level of significance was set at 0.05 for all the statistical tests.

Results

Baseline and perinatal characteristics

A total of 42 HIV-infected pregnant women and 84 non-HIV-infected pregnant women were included (the acceptance rates to participate in the study were 100 and 92%, respectively). Baseline and perinatal characteristics of the study groups are shown in Table 1. Baseline characteristics were similar among groups, with the exception of higher prevalence of black ethnicity, toxics exposure (smoking and illicit substance use during pregnancy) and hepatitis C among the HIV-infected women as compared with noninfected women.

Table 1
Table 1:
Baseline characteristics and perinatal outcome of the study populations.

As expected, HIV pregnancies presented a worse perinatal outcome including higher prevalence of preterm delivery, small-for-gestational age, caesarean section, and admission to neonatal ICU. No perinatal transmission of HIV occurred.

HIV-infection parameters

HIV infection characteristics of the HIV-infected pregnancies are described in Table 2. Most HIV infections were diagnosed and were receiving cART before pregnancy (88.1 and 76.2%, respectively), and all of them received cART during pregnancy. The main cART regimens – decided according to the practitioner practice – included two nucleoside reverse transcriptase inhibitor (NRTI) and one nonnucleoside reverse transcriptase inhibitors or one boosted protease inhibitor. Regarding NRTI, the most common combinations during pregnancy were ZDV + lamivudine (47.6%), emtricitabine + tenofovir (35.7%), and abacavir + lamivudine (21.4%). The mean CD4+ cell count throughout pregnancy was more than 500 cells/μl, and 73.8% of patients at first trimester, and 95.2% at third trimester had undetectable viral load.

Table 2
Table 2:
HIV infection parameters among the HIV-infected pregnancies.

Fetal standard ultrasound and echocardiography

Gestational age at scan, estimated fetal weight, and feto-placental Doppler were similar between the study groups (Table 3). Fetuses from HIV mothers showed larger hearts (increased cardiothoracic ratio) with thicker myocardial walls and more spherical and smaller LV cavities and atria compared with controls. In addition, 35% of fetuses from HIV-infected pregnancies presented pericardial effusion. All cases of pericardial effusion were mild (2–5 mm). Fetuses from HIV mothers also showed signs of systolic and diastolic dysfunction with decreased mitral S′ and increased left isovolumic contraction and relaxation time compared with controls. Most fetal cardiac changes remained significant after adjustment by maternal black ethnicity, smoking and other toxics during pregnancy, preterm delivery, and small-for-gestational age. Fetal echocardiographic results were similar among male and female offsprings (data not shown).

Table 3
Table 3:
Fetal standard ultrasound and echocardiography among the study groups.

Association of fetal echocardiography with baseline and perinatal characteristics

Principal component analysis identified myocardial septal wall thickness as the most representative cardiac morphometric parameter among HIV pregnancies (see Supplementary material). Then, the HIV group was subdivided into fetal cardiac hypertrophic (septal wall thickness ≥ 4.5 mm that corresponds to the 95th centile reported in normal fetuses [38] and the 75th centile of our cases) and nonhypertrophic (< 4.5 mm) phenotype to evaluate its association with baseline and perinatal factors. Characteristics of these fetal cardiac phenotypic groups are described in Table 4. The use of ZDV during pregnancy, mainly from the first trimester was significantly associated with the hypertrophic fetal heart (Fig. 1). No other maternal baseline characteristic, pregnancy and perinatal outcome, or HIV infection parameter neither the use of other cART regimens were related to the fetal cardiac hypertrophic phenotype.

Table 4
Table 4:
Baseline and perinatal characteristics in HIV-infected pregnancies subclassified by the presence of fetal cardiac hypertrophy.
Fig. 1
Fig. 1:
Relationship between fetal cardiac remodelling and maternal use of zidovudine (ZDV).Upper panel: fetal echocardiographic images illustrating the concentric hypertrophic phenotype in HIV-infected pregnancies (b) compared with non-HIV-infected pregnancies (a). Lower panel (c): box and whiskers graph of fetal cardiac septal wall thickness among non HIV-infected and HIV-infected subdivided according to the use of ZDV during the first trimester. A significant trend of thicker septal wall among the categories was observed. HIV-infected women treated with ZDV from the first trimester presented significantly thicker septal myocardial walls compared with HIV-infected women treated without ZDV during the first trimester or non-HIV-infected women. *P value calculated by ANOVA test among the three categories. Boxes in the graphic represent 25th, 50th (band inside the box), and 75th centile values. Whiskers express dispersion (1.5 × interquartilic range).

Discussion

Fetuses from HIV-infected pregnant women presented signs of cardiac concentric hypertrophy in utero, which was significantly associated to maternal treatment with ZDV. This is the first study in the cART era to assess the association of ART with fetal cardiac remodelling.

Fetuses exposed to maternal HIV and cART presented larger hearts, smaller and more spherical left cavities, and increased wall thickness which is consistent with a pattern of concentric hypertrophy. In addition, 35% of the cases presented mild pericardial effusion and most of them showed signs of subclinical systolic and diastolic dysfunction. These results are partially in agreement with previously reported data in HIV-exposed fetuses. Hornberger et al.[9] reported reduced LV cavities and increased wall thickness but with preserved cardiac function in HIV-exposed fetuses. However, this study was conducted in the pre-cART era, including infected and noninfected fetuses with only one-third of mothers receiving ZDV. A more recent study evaluated cardiac function in 29 fetuses from HIV-infected pregnant women under cART showing prolonged diastolic time with preserved shortening fraction and E/A ratios [10]. They also evaluated cardiac morphometry by means of mitral, tricuspid, aortic and pulmonary valves diameters, and no changes were observed, which is in line with our findings. In the present study, we further evaluated ventricular sphericity and wall thickness, cardiothoracic ratio and highly sensitive myocardial imaging techniques such as tissue Doppler which allowed us to ascertain with higher accuracy a pattern of cardiac concentric hypertrophy with systolic and diastolic dysfunction in non-HIV-infected fetuses under cART.

From a pathophysiological point of view, the cause of cardiac remodelling in HIV exposed noninfected fetuses is unclear. Although fetal cardiac remodelling has been previously described in other obstetrical conditions such as small-for-gestational age fetuses, prematurity, or preeclampsia [14–17] in the present study, we could not demonstrate any association between fetal cardiac changes and maternal or perinatal factors in our population. The only significant association was found with the use of ZDV above all and from the first trimester. This finding may suggest direct fetal cardiac toxicity. The role of ZDV in cardiac function among HEU children has been previously evaluated with conflicting results. The P2C2 HIV study stated that prophylaxis with ZDV monotherapy is not related to increased risk of cardiac abnormalities in these children [39]. Conversely, a secondary analysis of 50 children from the Protease Inhibitor Monotherapy Evaluation study demonstrated mild but significant cardiac changes in 1-year-old girls exposed to cART containing ZDV from 26 weeks of pregnancy. Finally, Lipshultz et al.[7] recently described different associations between specific antiretroviral exposures and different echocardiographic findings among 3–5-year-old HEU children from the Pediatric HIV/AIDS Cohort Study, and exposure to ZDV was found to be related to ventricular wall thickness. These controversial results could be explained by the use of ZDV monotherapy or the late initiation of ZDV in the third trimester, together with the fact that cardiac assessment was conducted postnatally with a considerable time lapse between the exposure and the echocardiography. In contrast with previous studies, our study was set up in a single-centre modern cohort, mostly treated with cART from the first trimester, and the impact of ART in cardiac function has been assessed directly in the fetus, concurrently with the maternal exposure to the presumptive toxic drugs.

From a clinical point of view, Spanish and international guidelines [22,23] consider ZDV as one of the preferred NRTI when starting or continuing cART during pregnancy because of its long experience of use, while ZDV is no longer considered a first choice treatment in adult because of its toxic profile [40]. It is unquestionable that the benefits of cART in controlling perinatal transmission outweigh the risks. Nevertheless, were our results to be confirmed, they support the possibility of considering safer alternative cART regimens during pregnancy, mainly during the first trimester to guarantee the prevention of perinatal transmission with the fewest adverse effects.

The clinical relevance of cardiac remodelling in the offspring of HIV women remains to be elucidated. Concerning childhood, previous studies suggested cardiac dysfunction and reduced ventricular cavities with controversial results on myocardial thickness in HEU children [6,7]. Some authors have proposed that the observed cardiac changes in HEU children are probably not clinically relevant [7,10]. However, for several conditions such as obesity and hypertension [41,42], cardiac remodelling in childhood is considered a precursor of clinical heart failure [43] associated with incident cardiovascular disease and mortality later in life [44–46]. Therefore, we believe that the evidence of cardiac remodelling in HIV-noninfected exposed fetuses and children warrants the need for long-term follow-up studies to assess the long-term clinical impact of these changes.

Some strengths and limitations have to be acknowledged in this study. In the present work we have succeeded in conducting a comprehensive fetal cardiac evaluation in a well described cohort. This fact has made it possible to identify the factors associated with fetal cardiac changes. This is the first study in the cART era to assess the impact of ART on cardiac function during fetal life. The fact of being closer to the insult by studying the fetuses in cART exposed HIV-infected mothers has enabled us to find stronger associations with ZDV exposure during pregnancy. On the other hand, we acknowledge the small sample size may have underestimated other factors potentially associated with fetal cardiac changes in exposed fetuses and might limit the interpretation of the multiple comparisons performed in this study. We also acknowledge that our study might be underpowered to detect differences among the subgroups and the results should be confirmed in larger studies. Secondly, although we tried to adjust our results according to confounders, we acknowledge the existence of residual potential confounders and recognize that the influence of maternal factors associated to the HIV infection (such as black ethnicity or comorbidities) could not be completely ruled out. Owing to the fact that all HIV-infected pregnant women were treated with cART makes it difficult to discriminate between potential cardiac effects of maternal HIV infection and fetal exposure to antiretroviral agents. Future studies are warranted to try to elucidate the still unexplained issues and describe the intrinsic mechanisms related to cardiac remodelling in fetuses and children from HIV-infected mothers.

In conclusion, our data demonstrate the presence of fetal cardiac remodelling in HIV pregnancies leading to an impaired systolic and diastolic function already in utero. These changes were significantly associated with maternal treatment with ZDV. The existent evidence of cardiac remodelling in non-HIV-infected fetuses under cART warrants future studies to evaluate potential long-term cardiovascular consequences and risks later in life.

Acknowledgements

The study was supported by grants from Instituto de Salud Carlos III y Ministerio de Economia y Competitividad (PI12/00851, PI14/00226) cofinanciado por el Fondo Europeo de Desarrollo Regional de la Unión Europea ‘Una manera de hacer Europa’, Spain; Obra Social la Caixa; Cerebra Foundation for the Brain Injured Children, Carmarthen Wales, UK. L.G.-O was supported by a grant (Premi Emili Letang 2014) from Hospital Clinic, Barcelona, Spain.

Disclosures: None of the authors has any financial, consultant, institutional and other relationship that might lead to bias or a conflict of interest for the present manuscript. The present manuscript has not been submitted elsewhere.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

antiretroviral therapy; fetal heart; HIV; pregnancy; zidovudine

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