Sympathetic neural tone: large and in charge throughout pregnancy

Gestational hypertension, or pregnancy- induced hypertension, is the development of high blood pressure (≥140/90 mmHg) after the 20th week of gestation. Preeclampsia, a specific type of gestational hypertension, includes the development of new-onset proteinuria. Approximately 10% of pregnancies are associated with gestational hypertension or preeclampsia, and these conditions increase the risk of adverse maternal and prenatal complications. In fact, it is estimated that up to 16% of all maternal deaths in developed countries are attributed to gestational hypertension (Khan et al. 2006). Mechanisms underlying gestational hypertension and preeclampsia are most certainly multifactorial, but elevated sympathetic neural activity has been suggested to be a key contributor, perhaps even a trigger. Schobel et al. (1996) was the first to apply microneurographic techniques to directly record post-ganglionic sympathetic nerve activity in pregnant women. When compared to normotensive pregnant women, preeclamptic women demonstrated elevated muscle sympathetic nerve activity (MSNA) during the third trimester, suggesting that the typical increase in peripheral vascular resistance observed during preeclampsia is mediated, in part, by heightened sympathetic neural activation. Greenwood et al. (1998, 2001) later established that sympathetic overactivity also exists during the third trimester in subjects with gestational hypertension, and that the elevations in sympathetic activity are not different between gestational hypertension and preeclamptic subjects (Greenwood et al. 2003). Of the studies examining sympathetic neural activity during pregnancy (Schobel et al. 1996; Greenwood et al. 1998, 2001, 2003; Fischer et al. 2004), only one has recorded MSNA multiple times during the pregnancy (Fischer et al. 2004). Fischer et al. (2004) examined MSNA and limb blood flow in pregnant women with a history of preeclampsia twice during pregnancy (2nd and 3rd trimesters) and once post-partum. In contrast to their original findings (Schobel et al. 1996), MSNA and forearm vascular resistance were not different between preeclamptic and normotensive pregnant women (Fischer et al. 2004). Moreover, levels were not significantly different during the second and third trimesters in either group, suggesting that sympathoexcitation might not be a direct stimulus for preeclampsia. Importantly, all six subjects that experienced preeclampsia demonstrated sympathoexcitation during both the second and third trimesters when compared to post-partum (Fischer et al. 2004). Thus, the authors speculated that pregnancy-induced sympathetic overactivity is a precursor for preeclampsia, only leading to preeclampsia when vasodilating mechanisms fail. In the current issue of The Journal of Physiology, Jarvis and colleagues (2012) provide novel and important insight regarding sympathetic neural control during early pregnancy. The authors performed an elegant and technically difficult study in which they recruited individuals planning a pregnancy, and recorded MSNA both before pregnancy and during early pregnancy (i.e. 1st trimester). Early pregnancy was associated with a robust increase of MSNA after only ∼6 weeks of gestation. Interestingly, this increase of MSNA was not associated with changes in blood pressure or forearm vascular resistance, suggesting increases of MSNA are being offset by vasodilatory mechanisms. Thus, these findings (Jarvis et al. 2012) support and advance the hypothesis put forth by Fischer et al. (2004) that sympathetic overactivity is likely to be a precursor, not a third trimester trigger, to gestational hypertension and preeclampsia. It seems prudent that future work might examine MSNA throughout an entire pregnancy and, importantly, include simultaneous assessment of endothelial function. Ideally, future studies will not only assess MSNA and endothelial function throughout a normal pregnancy, but also throughout pregnancies that eventually result in gestational hypertension or preeclampsia. While this approach clearly encompasses an element of chance, it is simply a matter of studying enough subjects since statistically 1 in 10 women are likely to develop gestational hypertension. Moreover, the prevalence of gestational hypertension is a bit higher in primigravidae pregnancies and non-primiravidae pregnancies that previously included gestational hypertension, and thus future studies might preferentially recruit such subsets. Finally, it is worth highlighting that studies examining gestational MSNA have primarily focused on women with relatively normal pregestational body mass indices. The World Health Organization estimates that worldwide obesity levels have nearly doubled since 1980. Sadly, childhood obesity has risen even more aggressively; the Center for Disease Control and Prevention reports that childhood obesity has more than tripled in the past 30 years. Accordingly, the prevalence of obese pregnancies has risen in recent years, and we can unfortunately expect continued increases in the foreseeable future. It is well established that obesity is often associated with heightened MSNA in humans. Moreover, risk of preeclampsia appears to be much higher in women with pregestational obesity (Bodnar et al. 2005). Future studies might focus on examining MSNA and endothelial function through pregnancies in overweight and obese women, as well as in other at-risk populations. In summary, the findings of Jarvis et al. (2012) significantly advance our understanding of sympathetic neural control during pregnancy by demonstrating marked sympathoexcitation during early pregnancy. This was a missing piece of the puzzle, as previous work had only reported MSNA during mid and late pregnancy. Collectively, it appears that pregnancy is associated with sympathetic overactivity throughout the entire gestation. The field would benefit from a comprehensive, longitudinal study in which MSNA and endothelial function are measured pre-gestation, throughout all three trimesters, and post-partum. Such an approach, while technically challenging, would provide key mechanistic insight toward the development of new therapeutic strategies aimed at reducing the prevalence of gestational hypertension and preeclampsia.