Hypertension is an independent modifiable risk factor for the development of cardiovascular diseases (CVDs) (1). Although hypertension is prevalent in adults and increasingly becoming prevalent in children (1), there has been documented reports of hypertension in neonates (2). The Neonatal Intensive Care Unit (NICU) report showed that hypertension may occur in up to 3% of neonates (3) while a large multi-centre study by the Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) reported a 1.8% incidence rate of neonatal hypertension (4). Although the origin and major predisposing factors for high blood pressure (BP) in neonates is unknown, studies have shown that acute kidney injury (4), maternal hypertension and pre-eclampsia (PE) may be responsible (5). PE is a hypertensive disorder defined as the presence of hypertension (BP ≥ 140/90 mm Hg) on two occasions at least 4 h apart with proteinuria or severe hypertension (BP ≥ 160/110 mm Hg) with or without proteinuria occurring after 20 weeks of gestation in a previously normotensive woman (6). PE is thought to be a contributor to neonatal hypertension and has been associated with small for gestational age babies with increased risk for CVDs (7).

As suggested by the concept of the Developmental Origins of Health and Disease, the maternal gestational environment may have a significant impact on foetal health with offspring been programmed for hypertension, obesity, diabetes, and CVDs in adulthood (8). Foeto-placental vascular endothelial dysfunction may cause epigenetic alteration in the intrauterine environment of the foetus and may be the origin of chronic diseases later in life (9). Moreover, PE has been reported to be associated with foeto-placental vascular endothelial dysfunction (10, 11). More so, there is evidence that children born to pre-eclamptic mothers have higher intima media thickness, adverse cardiac remodelling and higher blood pressure (12, 13) suggesting that offspring of pre-eclamptic mothers are prone to CVDs. However, all these studies were done in non-African populations and therefore may not necessarily apply to people of African ancestry.

In South Africa, PE affects about 5% of pregnant women and 12% of primigravidae (14, 15). Although the cause(s) of PE remain unclear, it is thought to stem from placental malfunction during pregnancy (16) resulting in foetal hypo-perfusion associated with oxidative stress and low-grade inflammation (17–19). Studies have shown an imbalance of antioxidants and reactive oxygen species (ROS)-generating enzymes in pre-eclamptic placentas with endothelial dysfunction (20, 21). Furthermore, placental hypoxia which is common in PE has been shown to be associated with maternal endothelial dysfunction (22). These findings suggest PE to be associated with endothelial dysfunction, a precursor of CVDs. This has been evident in pre-eclamptic subjects compared to normotensive controls (23, 24). It is therefore possible that exposure of the unborn child to this pro-CVD environment may program the offspring for greater susceptibility to hypertension and CVDs (25, 26). Although Meeme et al. showed endothelial dysfunction to be associated with PE in rural South African women (27), it is still unknown whether children born to these pre-eclamptic mothers are at greater risk of CVDs. Hence, this protocol is for a study aiming to assess CVD risk profile of neonates and infants exposed to PE in-utero and correlate them with markers of maternal cardiovascular risk, oxidative stress and endothelial function. The study will:

This study aims to investigate the relationship between PE and cardiovascular risk in children born to pre-eclamptic mothers in a rural South African population of African descents. It has been suggested that the foeto-placental vascular endothelial dysfunction may cause epigenetic alteration in the intrauterine environment of the foetus (39). Therefore, the maternal gestational environment may be programmed to have a significant impact on foetal and offspring health later in life (9). In fact, some studies have undertaken to investigate whether children born to pre-eclamptic mothers may predispose them to cardiovascular risk factors. Miller et al. demonstrated as early as 1983 that full-term neonates born to pre-eclamptic mothers have transient hypertension during the first hours of life (40). A meta-analysis study with over 45,000 individuals reported a 1.35 mmHg and 2.39 mmHg higher DBP and SBP in children and young adults born to pre-eclamptic pregnancies (41). The timing of the onset of PE has been reported to be a determinant of hypertension in offspring later on in life as offspring born to mothers with early PE onset were found to have increased central and peripheral SBP (6 mmHg) (42). Also, offspring of pre-eclamptic pregnancies showed a distinct vascular phenotype which could possibly mediate increased risk of hypertension in future (13). More so, impaired flow mediated endothelial responses as well as increased carotid intima-media thickness which suggest endothelial dysfunction was observed in preterm-born young adults exposed to a hypertensive pregnancy (12). A Spanish study on in-utero growth restricted children showed that children born to pre-eclamptic parents had higher BP, cardiac remodeling, and evidence of endothelial dysfunction at 6 months of age. Follow-up studies on school age children showed that they had higher SBP and DBP, smaller hearts, increased heart rate and features of cardiac diastolic dysfunction (43). A Norway study of 15,778 participants of which 343 were born to pre-eclamptic mothers showed increased BP, body mass index, wider waist circumference, higher non–HDL-cholesterol and triglycerides suggesting increased risk of CVDs (44). All these studies have shown that children born to pre-eclamptic mothers are prone to obesity, hypertension, diabetes and CVDs in their adult life (45, 46). However, all these findings were established in western populations with little or no reports from children of African origin. To our knowledge there is yet to be such a study in an African population. Conversely, it remains unclear whether the high prevalence of cardiovascular risk factors (obesity, hypertension etc) observed in South African children of African ancestry (47, 48) may have originated from pre-eclamptic mothers. The assessment of cardiovascular risk in pre-eclamptic pregnant women and the follow-up of their offspring after birth for possible cardiovascular risk may address this concern.

The findings from this study will provide information on the cardiovascular risk profile of offspring of pre-eclamptic mothers of African ancestry living on the African continent. It will also provide an opportunity to understand the relationship between the maternal environment and foetus, and how this may influence the risk for CVDs. A knowledge of the risk profile of the offspring of pre-eclamptic mothers may be used to develop plans/programs for CVD prevention in the offspring of women with PE. Also, findings from this study may help to develop policy around maternal and child health to ensure CVD risk prevention in both pregnant women with PE and children born to them. For the purpose of primary prevention of CVDs in children and later in life, it is important to identify predisposing risk factors in pregnant women so that intervention strategies for preventing intrauterine programming as a result of PE may be developed. This may give insight on lifestyle modifications that may be useful for the mother and child both during pregnancy and after birth. To our knowledge, this will be the first longitudinal study to assess the risk factors for CVD in-utero and at two time points after birth in a population of pre-eclamptic women of African ancestry. This will be the first study to assess vascular function and its markers in children exposed to the PE environment in-utero in an African community and done in children of African ancestry.

Despite the strengths of this study, we will also want to acknowledge some limitations of the study. This study will be conducted in Mthatha in the Eastern Cape Province of South Africa, a region highly dominated by African Ancestry population. Other ethnic populations within South Africa will not be considered. However, the ethnicity of the children born of these mothers may not be restricted because of the background of their fathers. The prevalence of PE in South Africa is very low, and therefore, recruitment of patients will be challenging. To curb this challenge, we will work with medical personnel at the recruiting hospital to alert us on eligible patients during antenatal visits. The study intends to follow-up offspring after birth for a period of 6 weeks which may not be sufficient to assess the progression of cardiovascular risk in children. However, this limitation in the short follow-up period was with respect to the available funding for the project. Ultrasound-based flow-mediated dilatation (FMD) measurements of the brachial artery which is known to be the goal standard for the assessment of endothelial function (49, 50) will not be used for this study as this equipment requires participants to be stable during assessment, but such stable state may not be achieved during pregnancy especially when pregnant women are in their 3rd trimester experiencing labour (uterus contractions). As such, endothelial function assessments will be limited to biomarkers of endothelial function. As reported by the developmental origin of health and diseases (DOHaD) certain drugs have been reported to affect the in-uterine environment and/or the foeto-placental endothelium which may predispose offspring to cardiovascular risk factors (51). This study will not be able to control the effects of drugs that can affect the in-utero environment and foeto-placental endothelium. To address this concern pregnant women will report all drugs that they had taken during pregnancy and their duration. Our statistician will be able to identify such drugs with long duration that could affect the study outcome and will be considered as confounding variable during statistical analysis.

In all, this study will seek to address the possible relationship between PE and cardiovascular risk in children born to pre-eclamptic mothers in South Africans of African ancestry. This study will be of importance to the South African population as there is evidence of rising prevalence of cardiovascular risk factors such as obesity, hypertension, diabetes and metabolic syndrome observed in South African children without a clear understanding of the underlining cause. The findings of this study may contribute to the development of policies that can help in the prevention of CVD risk in pre-eclamptic mother and their children. It may also help to develop intervention strategies for the prevention of intrauterine programming resulting from PE in pregnancy.

This study involving human participants was reviewed and approved by Walter Sisulu University Human Research, Ethics and Biosafety Committee with approval number: 070/2021. The patients/participants will provide their written informed consent to participate in this study.

BN-C and GE conceptualised the research project and wrote the manuscript. BN-C, GE, CB, NG, KK-H, and AK design the study and developed the questionnaire. BN-C, GE, CB, AK, and NG wrote the original grant proposal. CB, KK-H, AK, and NG reviewed and edited the manuscript. All authors approved the final manuscript.

This study was supported by the South African Medical Research Council (SAMRC) with funds received from South African Department of Science and Innovation awarded to BN-C.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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