Effect of Advanced Maternal Age on Pregnancy Outcomes and Vascular Function in the Rat

Abstract

Advanced maternal age is becoming increasingly common in Western societies and is associated with increased maternal and fetal morbidity and mortality. We hypothesized that aging results in impaired vascular function in pregnancy because of increased vascular oxidative stress and resultant scavenging of nitric oxide in both uterine and systemic arteries, causing reduced uteroplacental perfusion and poor pregnancy outcomes. Using aged rats (9.5 months), we investigated the effect of a delayed first natural pregnancy on pregnancy outcomes and uterine and mesenteric artery function on gestational day 20. Delayed pregnancy in the rat reduced fertility by 46%, reduced litter size by 36%, caused fetal growth restriction, increased placental weight, and increased maternal systolic blood pressure (by 16 mm Hg). Uterine arteries from aged dams displayed reduced constriction to phenylephrine (young: 14.3±0.94 mN/mm versus aged: 11.4±0.5 mN/mm, P =0.02) and potassium chloride (124 mmol/L; young: 21.8±1.27 mN/mm versus aged: 14.2±1.7 mN/mm; P =0.01). Methacholine-induced vasodilation was similar in uterine arteries from young and aged dams. However, mesenteric arteries from aged dams had a greater nitric oxide and a reduced endothelial-derived hyperpolarization contribution to methacholine-mediated vasodilation compared with young dams. Both uterine and mesenteric arteries from aged dams had greater active myogenic responses, with area under the curve increased by 228% and 151%, in aged uterine and mesenteric arteries, respectively. These results demonstrate that vascular function is altered at an advanced maternal age and provides further insights into the risks of poor pregnancy outcomes observed in women who delay pregnancy.

Factors associated with maternal mortality at advanced maternal age: a population‐based case–control study

“…9 Thus, the weakened vascular system in older women is unable to compensate fully for the physiological demands that occur during pregnancy, which in turn increases the risk of cardiovascular events, pregnancy-induced hypertension and other complications. 23 Inadequate antenatal care was the strongest association found in this study and this finding was similar to previous published studies. 11,19 It is likely that this relationship may be partially explained by socio-economic status 18 and immigration status, 24 which were either not fully adjusted for or not available in this study.…”

Advanced Maternal Age Worsens Postpartum Vascular Function

“…Of the three main endothelium-dependent pathways, NO was maintained, EDH reduced and a vasoconstrictor prostaglandin effect uncovered. A reduction of EDH mediated vasodilation is in-line with our data in the mesenteric arteries of advanced maternal age rats at GD20 (Care et al, 2015). This suggests that a change occurs in the vasculature in response to pregnancy that persists into the postpartum period and may lead to a predisposition to cardiovascular dysfunction; even following a successful pregnancy.…”

“…As detailed in our previous publication, rats of an advanced maternal age have a significantly reduced viable pregnancy rate (Care et al, 2015). Similarly, in the current study some rats were tested positive for sperm but failed to deliver a litter at GD22 (nulliparous).…”

“…Few studies have been performed, however, to investigate whether these factors could also be responsible for increased cardiovascular risk following a pregnancy that is complicated by advanced maternal age. A previous study in our laboratory has shown that advanced maternal age in the rat resulted in reduced fertility, reduced litter size, increased maternal systolic blood pressure and altered vascular function in the peripartum period (Care et al, 2015). These data are in line with human epidemiological data which demonstrate an increased incidence of both adverse acute maternal (hypertension, diabetes, miscarriage, caesarian section) and neonatal (intrauterine growth restriction, low birth weight infants, malformations, low Apgar scores, perinatal mortality) outcomes in aging mothers (Cleary-Goldman et al, 2005; Salem Yaniv et al, 2011; Almeida et al, 2015; Schimmel et al, 2015; Traisrisilp and Tongsong, 2015).…”

Pregnancy complications and risk of preterm birth according to maternal age: A population‐based study of delivery hospitalizations in Alberta

“…For sPTB, the magnitude of age modification may be small but aligns with biological sciences research on aging‐related impairments in reproductive functioning. For example, analyses of both human and rodent data suggest that advanced maternal age is associated with uterine dysfunction (eg, reduced decidualization) and altered utero‐placental vascular function (eg, enhanced myogenic response), even when samples are restricted to pregnancies with normal outcomes . Consequently, older mothers may experience more severe physiologic responses to the incomplete spiral artery remodeling, imbalance of angiogenic factors, oxidative stress, and inflammation that characterizes preeclampsia, possibly worsening ischemia and/or triggering sPTB .…”