Research Update on Immune Function 2010

Immune Func­tion — Preg­nancy and Exer­cise — c. 2010 Ann Cowlin

Dur­ing preg­nancy, the immune sys­tem must first become pro-inflammatory to per­mit fer­til­iza­tion and implan­ta­tion, then anti-inflammatory to pro­tect the mother and fetus, and then again pro-inflammatory to allow for a rejec­tion response to help expel the infant. These cytokine and chemokine shifts, described in depth in Mor’s Immunol­ogy of Preg­nancy [1], occur roughly at the start of each trimester in a healthy preg­nancy [2]. But, in a dys­func­tional or preeclamp­tic preg­nancy, there is not suf­fi­cient mod­u­la­tion at the crit­i­cal points to sus­tain the appro­pri­ate inflam­ma­tory response [1]. Genes [3–4] and infec­tion [1,5–7] can con­tribute to an inabil­ity of the mater­nal immune sys­tem to develop the appro­pri­ate level of inflam­ma­tory response for a robust tro­phoblast inva­sion. The result­ing poorly func­tion­ing pla­centa under­lies the inabil­ity of the immune sys­tem to counter micro­bial or meta­bolic stres­sors that can lead to hyper­ten­sion, pre­ma­tu­rity and low birth weight, or an inabil­ity to mount a rejec­tion response near term.

How­ever, women who exer­cise in the six months prior to preg­nancy and/or dur­ing preg­nancy show a greatly reduced risk for preeclamp­sia [8–11]. The most likely expla­na­tion involves the abil­ity of aer­o­bic exer­cise to mod­ify inflam­ma­tory responses by reduc­ing oxida­tive stress and pre­vent­ing or revers­ing endothe­lial dys­func­tion [8,12]. This sets the stage for nor­mal tro­phoblast inva­sion, which is essen­tial for fur­ther appro­pri­ate inflam­ma­tory sta­tus as the preg­nancy pro­gresses. If preeclamp­sia does develop, exer­cise may still pro­vide some pro­tec­tion against pre­ma­tu­rity and low birth weight by atten­u­at­ing the dys­func­tion [13].

There are not clear lines divid­ing the immuno­log­i­cal effects of meta­bolic syn­dromes, sep­sis, car­dio­vas­cu­lar dis­ease or chronic stress on maternal/fetal out­comes. Instead, all of these con­di­tions are medi­ated by inflam­ma­tory responses that can result in preeclamp­sia, pre­ma­ture labor, utero­pla­cen­tal insuf­fi­cien­cies, and down­stream car­dio­vas­cu­lar and meta­bolic health prob­lems for mother and off­spring. Some com­po­nents of exer­cise help reduce the risk for and sever­ity of adverse con­di­tions medi­ated by inflam­ma­tion. Immune sys­tem bio­mark­ers pro­vide cues as to how exer­cise func­tions to enhance mater­nal immune func­tion and help pre­vent or ame­lio­rate the sever­ity of these conditions.

In a study exam­in­ing whether exer­cise type was asso­ci­ated with sys­temic mark­ers of inflam­ma­tion, a sig­nif­i­cant lower like­li­hood of ele­vated inflam­ma­tory mark­ers C-reactive pro­tein, fib­rino­gen, and white blood cell lev­els, was found among jog­gers and aer­o­bic dancers [14].  While the researchers also looked at swim­ming, cycling, cal­is­then­ics, weight lift­ing and gar­den­ing, and ini­tially found dif­fer­ences, these dif­fer­ences were not sig­nif­i­cant when con­trolled for pos­si­ble con­found­ing fac­tors such as age, race, sex, body mass index, smok­ing and health sta­tus. How­ever, dura­tion and inten­sity may have accounted for some vari­a­tion among the forms of exer­cise stud­ied. Immune sys­tem pro­tec­tion pro­vided by phys­i­cal activ­ity likely has a quan­ti­ta­tive thresh­old for pro­tec­tion, even if it per­mits a broad range of activ­ity types [15].

On the other hand, fre­quent stren­u­ous bouts of pro­longed exer­cise are known to be asso­ci­ated with depressed immune cell func­tion, which may be com­pounded by inad­e­quate nutri­tion [16]. Preg­nant patients with extremely high lev­els of activ­ity need to be espe­cially care­ful to eat an ade­quate diet and to include ade­quate fluid and elec­trolyte replace­ment dur­ing stren­u­ous activ­ity. Such women can be cau­tioned to shorten, make less intense, or per­form fewer stren­u­ous weekly work­outs, as well as eat in accor­dance with their needs as an ath­lete dur­ing pregnancy.

Dur­ing phys­i­cal activ­ity, mus­cle release of cytokine IL-6 dif­fers from its release dur­ing an inflam­ma­tory response, in which it is a com­po­nent of the pro-inflammatory response. IL-6 is a piv­otal cytokine that helps stim­u­late the cas­cade of anti-inflammatory bio­mark­ers. Mus­cle release of IL-6 occurs in the absence of the pro-inflammatory marker tumor necro­sis fac­tor alpha, while stim­u­lat­ing the anti-inflammatory cas­cade [17]. Although research remains to be done to gain a bet­ter under­stand­ing of exer­cise and immune func­tion in preg­nancy, it appears that ade­quate activ­ity pro­motes appro­pri­ate immune responses in preg­nancy that may help pre­vent or reduce the sever­ity of dis­or­ders that are medi­ated by inflammation.

There is a rela­tion­ship between the medi­a­tion of stress by cor­ti­cotropin releas­ing hor­mone (CRH) and opi­oid pep­tides, and the effect of stress on dis­turbed repro­duc­tive function–disrupted men­stru­a­tion, par­tu­ri­tion and lactation–via inhi­bi­tion of gonadotropins and oxy­tocin [18,19].  Dur­ing labor, cor­ti­cotropin and beta-endorphins are found at lev­els of those in ath­letes dur­ing max­i­mal exer­cise; in addi­tion, the pla­centa pro­duces increas­ing amounts of CRH toward the end of preg­nancy, sig­nal­ing it may be involved in adap­tive stress mech­a­nisms to help mother and fetus with­stand the stress of labor [18].  In a small sam­ple, researchers found the responses of stress hor­mones and pla­cen­tal steroids in late preg­nancy exer­cis­ers to be sim­i­lar to those of non-pregnant exer­cis­ers [20].  Although the researchers found some inci­dence of uter­ine con­trac­tions brought on by increased lev­els of nor­ep­i­neph­rine, the increase in epi­neph­rine mit­i­gates this effect and reg­u­lar con­trac­tions did not start in any sub­jects [20].  Other stud­ies have found that women who par­tic­i­pated in recre­ational aer­o­bic activ­i­ties had a decreased risk of spon­ta­neous preterm birth [13,21].