American Journal of Obstetrics & Gynecology
Volume 191, Issue 4 , Pages 1059-1060, October 2004

Maternal corticotropin-releasing hormone, fetal growth, and preterm birth

  • John R.G. Challis, FRCOG, FRSC

      Affiliations

    • Corresponding Author InformationReprint requests: John R. G. Challis, FRCOG, FRSC, University of Toronto, Simcoe Hall, Room 109, 27 Kings College Circle, Toronto, Ontario, M5S 1A1, CANADA.

University of Toronto, Toronto, Ontario, Canada

Article Outline

 

In this issue of the journal, Wadhwa et al1 report the remarkable observation that a single measurement of maternal corticotropin-releasing hormone (CRH) concentration at 33 weeks of pregnancy predicts fetal birth weight and may have relevance in the diagnosis of the patient at risk of preterm labor. A value of CRH that was higher than the norm was associated with impaired fetal growth and a further increment in CRH predicted, in addition, premature delivery. Many other groups have discussed the possibility of using a prospective diagnostic marker such as CRH in this way, but none appears to have shown such a clear relationship as the current study.

Previous work by Goland et al2 reported elevated cord CRH concentrations in pregnancies with intrauterine growth restrictive (IUGR) infants. Others3., 4. have shown that the progressive rise in CRH through normal gestation is accelerated with risk of PTL and in preeclampsia, but clinical trials have hitherto failed to show that this single measurement is of clinical usefulness. Korebrits et al5 suggested that maternal CRH was elevated significantly in women presenting in preterm labor who went on to deliver prematurely, but not in those who continued to deliver at term. Importantly, this relationship did not hold in those presenting initially at less than 28 weeks, where the incidence of infection-driven preterm labor was much higher. It seems likely that the later sampling time in the current study1 is crucial in diminishing an effect of infection on labor. Indeed, CRH appeared much more predictive than other clinical risk factors, but a larger scale prospective study will be required to determine the clinical usefulness of this relationship. The validity of CRH in this context may be enhanced by other measures, including CRH-BP, oncofetal fibronectin, cervical dimensions, and maternal cortisol values.

Finally, it is of interest to speculate on the physiologic relationships between maternal CRH, fetal size at birth, and preterm labor that might underlie the present findings. A fundamental question that remains unresolved is whether the changes in CRH are a cause of preterm labor and fetal growth restriction, or sequelae of an underlying pathophysiology? Is CRH a uterotonin in the circumstances described, or an inhibitor of uterine contractility through stimulation of adenyl cyclase or inhibition of intracellular Ca2+? It has been suggested that the primate fetus responds to an adverse intrauterine circumstance through activation of fetal hypothalamic-pituitary adrenal function, and that increased output of fetal adrenal cortisol upregulates placental CRH expression.6., 7. Inappropriate elevations in fetal cortisol impair normal fetal growth, and even lead to predisposition to later life disease. This relationship is exacerbated in circumstances of placental or uteroplacental compromise. One can imagine that stress-induced increases in maternal cortisol could affect this axis similarly, particularly in circumstances in which the 11b hydroxysteroid dehydrogenase activity of the placenta is impaired, and more maternal cortisol crosses to the fetus. Inappropriate levels of fetal cortisol generate a common pathway to growth restriction and to elevations in placental CRH output. Paradoxically, the stimulus to CRH could serve to generate a protective inhibition of myometrial contractions, yet its increasing concentrations in maternal plasma might also predict the patient at risk of preterm labor. The study of Wadhwa et al1 raises the potential clinical applicability in exploiting this relationship to the diagnosis of preterm labor and to the recognition of fetal compromise.

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References 

  1. Wadhwa PD, Garite TJ, Porto M, Glynn L, Chicz-DeMet A, Dunkel-Schetter C, et al. Placental corticotropin-releasing hormone (CRH), spontaneous preterm birth and fetal growth restriction: a prospective investigation. Am J Obstet Gynecol. 2004;191:1063–1069
  2. Goland RS, Jozak S, Warren WB, Conwell IM, Stark RI, Troper PJ. Elevated levels of umbilical cord plasma corticotrophin-releasing hormone in growth-retarded fetuses. J Clin Endocrinol Metab. 1993;77:1174–1179
  3. Florio P, Severi FM, Ciarmela P, Fiore G, Calonaci G, Merola A, et al. Placental stress factors and maternal-fetal adaptive response: the corticotropjn-releasing factor family. Endocrine. 2002;19:91–102
  4. McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R. A placental clock controlling the length of human pregnancy. Nat Med. 1995;1:460–463
  5. Korebrits C, Ramirez MM, Watson L, Brinkman E, Bocking AD, Challis JRG. Maternal CRH is increased with impending preterm birth. J Clin Endocrinol Metab. 1998;83:1585–1591
  6. Challis JRG, Matthews SG, Gibb W, Lye SJ. Endocrine and paracrine regulation of birth at term, and preterm. Endocr Rev. 2000;21:514–550
  7. Robinson BG, Emanuel RL, From DM, Majzoub JA. Glucocorticoid stimulates expression of corticotrophin-releasing hormone gene in human placenta. Proc Natl Acad Sci U S A. 1988;85:5244–5248

PII: S0002-9378(04)00686-6

doi:10.1016/j.ajog.2004.06.071

Refers to article:

  • Placental corticotropin-releasing hormone (CRH), spontaneous preterm birth, and fetal growth restriction: A prospective investigation

    Pathik D. Wadhwa, Thomas J. Garite, Manuel Porto, Laura Glynn, Aleksandra Chicz-DeMet, Christine Dunkel-Schetter, Curt A. Sandman
    American Journal of Obstetrics & Gynecology October 2004 (Vol. 191, Issue 4, Pages 1063-1069)

American Journal of Obstetrics & Gynecology
Volume 191, Issue 4 , Pages 1059-1060, October 2004

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