Prenatal Inflammation and Perinatal Outcomes

BACKGROUND

Preventing poor perinatal outcomes is the goal of all prenatal care, yet just who will go on to develop preeclampsia or have a growth-restricted baby is notoriously difficult to predict. A growing body of evidence suggests inflammatory markers can help predict poor outcomes, even prior to, and beyond, the current pregnancy. C-reactive protein (CRP) is manufactured by the liver in response to an immune provocation, and helps activate the complement system. Because it is easily assayed via phlebotomy and the less invasive capillary blood spot collection, it is a favoured marker to study inflammation in fields as diverse as immunology, obstetrics and gynecology, primary care, anthropology, and epidemiology. Pregnancy is a pro-inflammatory state, and reproductive physiology studies have shown that CRP is higher in pregnant women than in age-matched non-pregnant women, and higher still in viable pregnancies than in spontaneous abortions or ectopic pregnancies. But a look at the ecology of CRP variation shows trends with clinical relevance.

CRP is higher in obese pregnant women than in their leaner counterparts, and is positively correlated with body fat, waist-hip ratio, and HDL. While CRP does not appear to be related to insulin sensitivity in non-diabetic pregnant women, for pregnant women with type I diabetes mellitus, CRP is positively correlated with higher HgBA1C and progression of retinopathy. CRP rises with prenatal iron therapy, during labour, and during the post-partum period. It is higher for women who have had Cesarean sections than for women who delivered vaginally. And physiologic states are not the only variables associated with CRP variation. In a study of 52 women in Denver, Colorado, higher CRP was associated with higher second-trimester life stress scores and lower third-trimester social support scores. In a study of 775 women in North Carolina, higher CRP was associated with self-reported black race, qualifying for food stamps, lack of private insurance, being unmarried, previous preterm birth, and maternal weight. Does an elevated inflammatory marker also correspond to maternal or fetal morbidity?

Most research suggests it does. While one study of 32 Finnish women showed no difference in CRP between who had premature prelabour rupture of membranes (PPROM) and gestational age-matched controls, and one study of pregnant teens in New York showed CRP was associated with neither gestational age at birth nor birth weight, most studies of women in the USA, Ecuador, Colombia, the Netherlands, Hungary, Turkey, India, and South Korea have shown that higher third-trimester CRP is associated with increased risk for preeclampsia, intrauterine growth restriction, and preterm delivery. It also appears that elevated inflammatory markers may be associated with long-term maternal and infant morbidity. When CRP was tested in a prospective cohort of post-partum women who underwent diabetes screening at 3 months and 12 months post-partum, those women who developed diabetes had higher CRP at 3 months. And in Spain, high maternal CRP in the first trimester was associated with greater risk of infant wheezing and respiratory tract infections at 14 months (controlling for sex, birth weight, prematurity, maternal smoking and alcohol consumption, parity, maternal pre-pregnancy BMI, maternal total IgE, daycare attendance, and breastfeeding.

So while data on the prognostic value of CRP during pregnancy has been accumulating for more than a decade, this variable is not widely investigated in clinical obstetrics practice. Furthermore, most research has focused on static measures of CRP, not on a woman's dynamic response to an immune challenge during pregnancy because of the myriad ethical concerns with clinical trials involving pregnant women: it is possible that a woman's inflammatory response to a challenge is more clinically relevant than her baseline CRP level.