This study was possible due to careful curation of data from a large cohort of pregnant women enrolled in our center’s ongoing Obstetric Registry, allowing a detailed evaluation of placental pathology and birthweight outcomes in relation to maternal BMI and associated comorbidities. Our results confirm some previously reported associations between maternal obesity and placental pathology, but also identify novel associations and confounders, pointing to specific underlying pathophysiologic mechanisms of obesity-related patterns of injury. Specifically, maternal obesity was associated with higher rates of placental inflammation, particularly high-grade CV, as well as underlying maternal vascular disease (as evidenced by DV), poor maternal circulation within the placenta (as evidenced by IVT), fewer SGA placentas, and decreased placental efficiency (as defined by FPR). These findings suggest that, while maternal obesity is generally associated with increased birthweight, the placentas of women with obesity may have underlying pathologies leading to decreased efficiency, which may prevent their fetuses from attaining their full growth potential. At the same time, our study confirmed previous findings linking maternal obesity to both an increased rate of preterm delivery, as well as increased birthweight percentile and LGA infants.(3, 16, 31, 32) However, while multiple placental lesions (including MVM, FVM, and increased perivillous fibrin deposition) were associated with decreased birthweight percentile, only MVM-I had a differential effect across maternal BMI groups, causing a more significant lowering of birthweight percentile in the obese group. These results suggest that, apart from concurrent severe underlying maternal vascular disease, the placenta is able to preserve fetal growth in the setting of maternal obesity.
Previous studies have shown obese women to present with chronically higher levels of inflammatory cytokines during pregnancy.(7, 10) This long-standing inflammatory state could extend to the maternal-fetal interface, and subsequently show signs in the placenta, in the form of chronic villitis (CV) as in our previous and current study.(18, 22) This same increase has been shown in smaller studies, including a study by Brouwers, et al that looked exclusively at uncomplicated pregnancies. (18, 22) Low-grade CV is not uncommon in normal, healthy placentas; however, high-grade CV is less common in this setting, and has a significant association with fetal growth restriction, with a higher recurrence of increasingly severe villitis in subsequent pregnancies.(33–35) Our previous study showed a trend of decreased birthweight in babies with placentas affected by CV, but this was not replicated in the current analysis; in fact, even high-grade CV was not associated with altered birthweight percentile. It is possible that the effect of placental inflammation is small, and, particularly in the setting of maternal obesity, requires larger sample sizes to confirm an effect on birthweight.
Interestingly, based on our previous study, we expected to see more CV in placentas of obese women who delivered female babies; instead, only high-grade CV showed such sexual dimorphism, appearing to be more common in placentas of male babies born to obese women in our current study. This may be due to differences in the two study designs; our previous study included only births ≥ 35 weeks gestational age, whereas the current study included all births (> 23 weeks gestational age). The current study also included, not just obese, but also overweight patients, and in fact, this latter population did show a ~ 4-fold increase in high-grade CV in placentas of female (vs. male) fetuses. We conclude that the relationship between maternal BMI, placental inflammation, and fetal sex is complex, and thus warrants further investigation in larger cohorts.
While there is no broadly accepted standard for “placental function,” fetal to placental weight ratio (FPR), as well as its inverse, are widely used as markers of “placental efficiency”.(36–38) Placental efficiency varies significantly within the population but is known to change with alterations in uterine blood flow, oxygen availability, the intake and composition of the maternal diet, as well as nutrient transfer across the placenta.(29, 38) Because of this, it is thought that changes in placental efficiency are a reflection, not just of in utero conditions, but also an attempt (by the placenta and fetus) to adapt to those conditions.(29, 38) Our analysis showed decreased placental efficiency in the obese group, suggesting that there is a difference in the in-utero environment in pregnancies complicated by obesity. One such condition could be hypoxic stress, as reflected by the significant increase in normoblastemia (aRR 1.25; 95% CI 1.03, 1.52) within the obese placentas. Interestingly, while FPR was generally higher in the placentas of male infants, it was more severely affected in this (male) cohort in the setting of maternal obesity. This is consistent with previous studies, showing that placentas belonging to male fetuses are less able to adapt to environmental stressors.(38–40) Since inflammation (particularly high-grade CV) was more common in placentas of male fetuses, we investigated whether this was contributing to the significantly decreased FPR. However, we found that, not only was this not the case, but in fact, overall, CV was associated with increased FPR, regardless of maternal BMI status. This has also been noted by Brouwers et al., who noted that of their 4 patients with high-grade CV, 3 had FPR’s above the 90th percentile, and delivered normal weight babies, despite the small size of the placentas.(18) Future studies are needed to study in more detail the relationship between placental inflammation and FPR, particularly in relation to mechanisms of placental adaptation to stress and fetal growth.
In our analysis of placental histopathologic findings, we initially defined MVM as a small placenta with one of four lesions associated with maternal vascular abnormalities (MVM-I), as previous publications have suggested, and as we have defined this lesion in our own studies.(30, 41, 42) However, given the effect of BMI on placental size, we had to re-think the definition in this study. When redefined to include placentas of any size with two or more maternal vascular lesions (MVM-II), MVM was in fact noted to be more prevalent in the obese group, and, as expected, associated with lower birthweight.(41, 43) However, the increased prevalence of MVM in the setting of obesity was largely driven by maternal hypertensive disease, and as such, it is likely that the effect of maternal obesity on lower birthweight is mediated by new-onset or worsened hypertension during pregnancy. In fact, obesity has long been known to be associated with hypertension, including during pregnancy.(44, 45) While not associated with maternal obesity, MVM-I was the only placental lesion that caused a more dramatic decrease in birthweight percentile within the Ob group, potentially suggesting that severe maternal vascular disease can in fact compromise placental adaptation in the setting of maternal obesity.
Our study has many strengths, including the large sample size and the amount of available clinical data, which allowed for identification and control of possible confounders. Our cohort also included placental pathology for healthy, uncomplicated pregnancies, rather than just placentas that met criteria for clinical examination. It is also notable that the pathologic examination was done by a single pathologist, decreasing variability that may be seen with multiple examiners. However, our study also had limitations, the mainly that the population recruited for our Obstetric Registry is enriched in high-risk pregnancies, as expected for a tertiary care center. Thus, despite controlling for several comorbidities, results from this cohort may have diminished generalizability to all populations.