While there has been an increase in interest on the role circulating pro and anti-angiogenic factors play in the pathophysiology of GH, less is known on how these biomarkers vary over the duration of pregnancy and after delivery. This is particularly true in Malaysia where the incidence of GH is relatively high [10
] but biomarker screening and follow up studies are limited. The present study accordingly performs three periodic assessments of both sFtl-1 and PlGF in GH women. It is further complemented with morphometric studies that allowed correlation of biomarker values and its role in placental structural development. Furthermore, this study emphasizes GH specifically; most published articles investigated the use of the biomarkers (PlGF and sFlt-1) for preeclampsia, a more serious condition superseding GH. Findings from this study also serve as a valuable reference point for an ethnically diverse population like Malaysia.
We observed lower PlGF but higher sFlt-1 levels in GH women in comparison to normotensive during antepartum and intrapartum, with correlation analysis confirming an inverse relationship. Salahudin et al
., (2007) reported similar findings in that sFlt-1 levels in GH women were significantly higher than normotensive women in a prevalence case control study done in the United States [11
]. Findings by Maynard et al
., (2003) and Levine et al
., (2005) both observed reduction in PlGF and an increase in sFlt-1 in preeclamptic women [5
]. While the latter studies proposed this for preeclampsia, this study proves these biomarkers are also significantly altered in GH. Furthermore, the inverse relationship between sFlt-1 and PlGF observed in our study is representative of findings from an ethnically diverse population. We acknowledge that results from this study present a contrasting finding compared to a previous cross sectional study. In the latter study, while no absolute values of the biomarkers were discussed, analysis for sFlt1:PlGF ratios demonstrated no significant differences between GH and normotensive mothers except at 33 through 36 weeks of pregnancy [13
]. This contrast could be due to variations in the study population (for example: age, parity, ethnicity, smoking status) or on the actual onset of GH versus the diagnosis of GH.
PlGF levels in GH and normotensive women during the postpartum period were similar and this can be attributed to the fact that PlGF is primarily expressed by the placenta which is no longer present at postpartum. Our study showed that sFlt-1 levels remain significantly higher in GH women compared to normotensive women during postpartum period. This finding raises important questions on the effect of persistently raised postpartum levels of sFlt-1, may have on the period of surveillance and continuation of anti-hypertensive drugs. Cohort studies that have used population-based pregnancy databases consistently identify a clinically significant association of GH and preeclampsia with later hypertensive disorders [14
]. This clearly defines a need for long term follow-up for the development of essential hypertension in GH women. A recent study by Berks et al., 2009, on preeclamptic women in the Netherlands indicates that it can take up to 2 years for hypertension and proteinuria to resolve [15
]. Findings from these studies suggest that it may be necessary to further evaluate the effect prolonged exposure to high levels of sFlt-1 may have and it's subsequent clinical utility in the management of GH cases.
The findings for villous capillarization and intervillous space were not significantly different among the two groups investigated (normotensive and GH). Our morphological findings were consistent with that of Mayhew et al
., (2004) who reported that in cases of preeclampsia not accompanied with intrauterine growth restriction, placental morphometry is similar to that of control (normotensive) group [16
]. It is hypothesized that, in GH cases there is increased anti-angiogenic property thus causing defective angiogenesis, in turn leading to decreased villous capillarization [5
]. However, increased villous capillarization can also occur in GH women as a form of a compensatory mechanism. Hypoxic experiments with placental tissue have previously demonstrated an increase in vascular endothelial growth factor expressions [17
]. These angiogenic factors may thus bind to receptors to exert their effect and promote angiogenesis by increasing capillarization explaining the lack of morphometric differences between normotensive and GH as seen in our study.
The inverse correlation PlGF levels show with TCsa - C and VC - C warrants further investigation. While is it expected that PlGF should increase capillarization, it needs to be ascertained whether this inverse relationship is a compensatory response, in that, when there is low capillarization, PlGF is released to promote capillarization thus explaining the scenario whereby the lower TCSA - C and VC - C is, the more PlGF is released. Future studies using animal models would be valuable in elucidating the existence of such a compensatory mechanism. There were several limitations that were present in this study. Shortfalls with regards to follow-up of patients from time of first contact was attributed to the fact that many women use the free government antenatal care services but prefer to deliver at alternative delivery centers which included returning to their parent's homes or to private medical centers when they were at term gestation. In the initial recruitment Body Mass Index (BMI) of patients were not obtained and thus we were unable to adjust for its confounding effects. Furthermore as this study examined two-dimensional evaluations of the placenta, future studies should include three-dimensional morphometric assessments with precise and in-depth structural and stereological features.