C-reactive protein and ART outcomes: a systematic review

A dynamic balance between pro- and anti-inflammatory factors contributes to regulating human female reproduction. Chronic low-grade inflammation has been detected in several female reproductive conditions, from anovulation to embryo implantation failure. C-reactive protein (CRP) is a reliable marker of inflammation that is extensively used in clinical practice. Recent studies quantified CRP in the serum of infertile women undergoing ART and suggested its potential for the prediction of ART reproductive outcomes.

The first objective of this systematic review of the available literature was to evaluate the association between pre-implantation circulating CRP concentration and pregnancy rates in women undergoing ART. The second objective was to describe serum CRP concentration changes after early embryo implantation. The changes in circulating CRP throughout the ART cycle, clinical implications of CRP quantification for the management of women undergoing ART, and future therapeutic options will also be discussed.

The MEDLINE database was systematically searched from inception to March 2019 using the following key words: (C-reactive protein) AND (assisted reproductive techniques OR ovulation induction OR insemination OR in vitro fertilization). Only articles in English were considered. Studies were selected based on title and abstract. The full text of potentially relevant articles was retrieved and assessed for inclusion by two reviewers (S.B. and S.H.). The protocol was registered in the International prospective register of systematic reviews (PROSPERO; registration number: CRD148687).

In total, 10 studies were included in this systematic review. Most of these studies reported lower circulating CRP values before the window of implantation and higher circulating CRP values during the peri-implantation period in women with successful ART outcome (biochemical or clinical pregnancy) compared to women without a successful outcome. Several lifestyle factors and/or drugs that reduce the concentration of circulating CRP significantly improve ART outcomes. Subgroup analyses according to female BMI and baseline circulating CRP concentration are highly recommended in future analyses.

These findings highlight a possible detrimental impact of preconception high circulating CRP concentration on ART outcomes. However, the biochemical or clinical pregnancy rate endpoints used in the studies examined here are insufficient (there were no data on live birth outcome), and the impact of major variables that can influence CRP and/or ART, for example maternal age, BMI, number of transferred embryos, and use of anti-inflammatory drugs, were not considered in the analyses. CRP quantification may be a potential marker of ART outcome, but its predictive value still needs to be investigated in large prospective studies. In future, the quantification of circulating CRP before starting ART could help to identify patients with a poor ART prognosis, leading to ART cycle cancellation or to preconception treatment to minimize the medical risks and costs.