Research Update on Immune Function 2010

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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].

Ref­er­ences

1. Mor, G. Immunol­o­gy of Preg­nan­cy. Series: Med­ical Intel­li­gence Unit. Springer. 2006.

2. Mor G. Chap­ter 19: Tro­phoblast as Immune Reg­u­la­tor, Immunol­o­gy of Preg­nan­cy. Series: Med­ical Intel­li­gence Unit. Springer. 2006.

3. Bil­ban M, Haslinger P, Prast J et al. Iden­ti­fi­ca­tion of Nov­el Tro­phoblast Inva­sion-Relat­ed Genes: Heme Oxy­ge­nase-1 Con­trols Motil­i­ty via Per­ox­i­some Pro­lif­er­a­tor-Acti­vat­ed Recep­tor {gam­ma}, Endocrinol­o­gy 150(2):1000–1013. 2009.

4. Pang, ZJ, Xing FQ. Expres­sion pro­file of tro­phoblast inva­sion-asso­ci­at­ed genes in the preeclamp­tic pla­cen­ta., British Jour­nal of Bio­med­ical Sci­ence 60(2):97–101. 2003.

5. Gomez L and Par­ry S. Tro­phoblast infec­tion with chlamy­dia pneu­mo­ni­ae indu­ce­pla­cen­tal dys­func­tion and preeclamp­sia. Amer­i­can Jour­nal of Obstet­rics and Gyne­col­o­gy 199(6):S11. 2008.

6. Arechavale­ta-Velas­co F, Ma Y, Zhang J, McGrath CM and Par­ry S. Ade­no-Asso­ci­at­ed Virus-2 (AAV-2) Caus­es Tro­phoblast Dys­func­tion, and Pla­cen­tal AAV-2 Infec­tion Is Asso­ci­at­ed with Preeclamp­sia, Amer­i­can Jour­nal of Pathol­o­gy 168:1951–1959. 2006.

7. Goncalves LF, Chai­worapongsa T, Romero R. . Intrauter­ine infec­tion and pre­ma­tu­ri­ty. Men­tal Retar­da­tion and Devel­op­men­tal Dis­abil­i­ties Research Reviews, 8(1), 3–13. 2002.

8. Weiss­ger­ber TL, Wolfe LA, Davies, GAL. The Role of Reg­u­lar Phys­i­cal Activ­i­ty in Preeclamp­sia Pre­ven­tion Med Sci Sports Exerc 36(12):2024–2031, 2004.

9. Rudra CB, Williams MA, Lee IM, Miller RS, Sorensen TK. Per­ceived exer­tion dur­ing prepreg­nan­cy phys­i­cal activ­i­ty and preeclamp­sia risk. Med­i­cine & Sci­ence in Sports & Exer­cise, 37(11), 1836–41. 2005.

10. Sorensen TK, Williams MA, Lee IM, Dashow EE, Thomp­son ML, Luthy DA. Recre­ation­al phys­i­cal activ­i­ty dur­ing preg­nan­cy and risk of preeclamp­sia. Hyper­ten­sion, 41(6), 1273–1280. 2003

11. Saft­las AF, Logs­den-Sack­ett N, Wang W, Wool­son R, Brack­en MB.  Work, leisure-time phys­i­cal activ­i­ty, and risk of preeclamp­sia and ges­ta­tion­al hyper­ten­sion. Amer­i­can Jour­nal of Epi­demi­ol­o­gy, 160(8):758–765. 2004.

13. Cowl­in AF, Bran­ca­to R, Mor G, Zel­ter­man D, DeZin­no, P. Effect of com­mu­ni­ty-based group pre­na­tal phys­i­cal activ­i­ty on preeclamp­sia risk, Poster Pre­sen­ta­tion, Soc Gyn Inves­ti­ga­tion Con­fer­ence, March 2008, and Slide Pre­sen­ta­tion, Amer Col­lege Sports Med Con­fer­ence, May 2008.

15. Juhl M, Ander­sen PK, Olsen J, Mad­sen M, Jør­gensen T, Nøhr EA, Ander­sen AN. Phys­i­cal exer­cise dur­ing preg­nan­cy and the risk of preterm birth: A study with­in the dan­ish nation­al birth cohort, Am J Epi­demi­ol. 167(7):859–856. 2008.

18. Laatikainen, T. J. Cor­ti­cotropin-releas­ing hor­mone and opi­oid pep­tides in repro­duc­tion and stress. Ann. Med. 23(5):489–496, 1991.

19. Magiak­ou MA, Mas­torakos G, Web­ster E, Chrousos GP. The hypo­thal­a­m­ic-pitu­itary-adren­al axis and the female repro­duc-tive sys­tem.  Ann. NY Acad. Sci . 816:42–56, 1997.

20. Rau­ramo I, Ander­s­son, B, Laatikaines TJ. Stress hor­mones and pla­cen­tal steroids in phys­i­cal exer­cise dur­ing preg­nan­cy.  B JObstet.Gynecol. 89:921–925, 1982.

21. Berkowitz GS, Kel­wey JL, Hol­ford TR, Berkowitz RL. Phys­i­cal activ­i­ty and risk of spon­ta­neous preterm deliv­ery.  J. Reprod.Med. 28(90):581–588, 1983.

1 Comment

  1. Dispelling Myths on Pregnancy Exercise | Dancing Thru Pregnancy® Blog
    November 12, 2014 @ 10:42 pm

    […] and pla­cen­tal devel­op­ment (see Research Updates 2001–2005, Win­ter 2005 and Win­ter 2004 and Update on Immune Func­tion). Bar­ring that, begin­ning ear­ly in preg­nan­cy is help­ful because pla­cen­tal devel­op­ment is still […]