Pregnancy is a delicate balance of angiogenic factors. Adverse pregnancy outcomes in the form of placental insufficiency occur when antiangiogenic factors predominate, which manifests as maternal-placental syndrome (MPS). Women with rheumatic disease are at increased risk of MPS. Endothelial damage from circulating antiangiogenic factors and other inflammatory molecules in combination with preexisting maternal vascular risk factors is the likely underlying pathophysiological process for MPS. It is likely that these changes persist, and additional “insults” from ongoing inflammation, medications, and disease damage contribute to the development of accelerated cardiovascular disease seen in young women with rheumatic disease.
Key points
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Adverse pregnancy outcomes are more common in women with rheumatic diseases, and the pathophysiology is likely multifactorial; hence, sole reliance on biomarkers to predict preterm delivery or other adverse outcomes may not be possible or advisable.
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Preterm (or classic) preeclampsia is a manifestation of placental insufficiency, which may also lead to fetal growth restriction, placental abruption, and stillbirth: collectively known as maternal-placental syndrome (MPS).
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Pregnancy is a delicate balance of circulating angiogenic factors of which antiangiogenic factors, for example, soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) predominate when there is MPS.
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Commercially available biomarkers, such as placental growth factor, sFlt-1, and sEng have the same diagnostic accuracy and prognostic significance in women with rheumatic diseases and chronic kidney disease as in healthy pregnant women.
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In the long term, the effect of these antiangiogenic biomarkers and the inflammatory cascade triggered by MPS, combined with preexisting metabolic risk factors, is likely contributory to the accelerated cardiovascular disease seen in young women with rheumatic diseases, especially systemic lupus erythematosus.
Definitions of adverse outcomes in pregnancy
Most autoimmune rheumatic diseases disproportionately affect women of childbearing ages, and when pregnant, these women are at an increased risk of adverse pregnancy outcomes. Much of the published literature focuses on preeclampsia, a heterogeneous disorder identified by a common phenotype of hypertension and proteinuria. The crux of the disorder is the placenta, a highly vascular structure, and it is placental ischemia and insufficiency that gives rise to the recognized clinical manifestations. Therefore, future vascular disease is likely to initially manifest with clinical features of placental dysfunction or insufficiency. These features include the following:
- i.
Preeclampsia: new-onset hypertension and proteinuria in excess of 0.3 g/24 hours or ≥30 mg/mL on a spot urinary protein:creatinine urine sample after 20 weeks’ gestation. It affects 3% to 5% of all pregnancies.
- ii.
Fetal growth restriction: slowing or cessation of fetal growth while in utero.
- iii.
Small-for-gestational age (SGA) neonates: neonatal weight is lower than the 10th percentile of that expected for the population.
- iv.
Placental abruption: pathologic separation of the placenta from the uterus.
- v.
Stillbirth.
These features are often collectively known as maternal-placental syndrome (MPS). The individual features are not exclusive to MPS but also can occur for a variety of reasons, such as fetal chromosomal abnormalities or multiple pregnancies. Nevertheless, women with underlying rheumatic disease have a much higher incidence of these complications.
Risk factors for preeclampsia and subsequent development of placental insufficiency are summarized in Box 1 .
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Nulliparity
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Extremes of maternal age younger than 18 years or older than 35 years
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Immunologic:
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Multiparous women who have changed partner from previous pregnancies
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Short interval between first coitus and conception
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“Dangerous” father: man who has previously fathered preeclamptic pregnancies in a different woman.
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Artificial reproductive therapy, especially with donor ovum
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Genetic: “familial clustering”: inheritability of preeclampsia in twin studies is 22% to 47%
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Metabolic and vascular risk factors: for example, diabetes, obesity, chronic hypertension, renal dysfunction
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Thrombophilias, especially antiphospholipid syndrome
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Underlying autoimmune inflammatory diseases; for example, systemic lupus erythematosus, scleroderma
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Past factors:
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Previous severe early-onset preeclampsia
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Maternal preterm delivery
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Maternal low birth weight
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Hypoxia:
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Multifetal gestation
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High altitude
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Prolonged gestation: placental growth outstrips the vascular supply
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In 2014, the International Society for the Study of Hypertension in Pregnancy revised the definition of preeclampsia to also include both maternal and fetal factors. The consequences of placental insufficiency can be best summarized in Fig. 1 . The presence of proteinuria is not necessarily a diagnostic requirement if other systemic features of placental dysfunction (see Fig. 1 ) are present. There is evidence that women who develop nonproteinuric preeclampsia are more likely to have severe hypertension and exhibit other features of placental insufficiency leading to preterm deliveries. Moreover, the severity of proteinuria has limited prognostic implications for pregnancy outcomes, and therefore quantification of proteinuria should not be repeated once the diagnosis of preeclampsia is established.
Definitions of adverse outcomes in pregnancy
Most autoimmune rheumatic diseases disproportionately affect women of childbearing ages, and when pregnant, these women are at an increased risk of adverse pregnancy outcomes. Much of the published literature focuses on preeclampsia, a heterogeneous disorder identified by a common phenotype of hypertension and proteinuria. The crux of the disorder is the placenta, a highly vascular structure, and it is placental ischemia and insufficiency that gives rise to the recognized clinical manifestations. Therefore, future vascular disease is likely to initially manifest with clinical features of placental dysfunction or insufficiency. These features include the following:
- i.
Preeclampsia: new-onset hypertension and proteinuria in excess of 0.3 g/24 hours or ≥30 mg/mL on a spot urinary protein:creatinine urine sample after 20 weeks’ gestation. It affects 3% to 5% of all pregnancies.
- ii.
Fetal growth restriction: slowing or cessation of fetal growth while in utero.
- iii.
Small-for-gestational age (SGA) neonates: neonatal weight is lower than the 10th percentile of that expected for the population.
- iv.
Placental abruption: pathologic separation of the placenta from the uterus.
- v.
Stillbirth.
These features are often collectively known as maternal-placental syndrome (MPS). The individual features are not exclusive to MPS but also can occur for a variety of reasons, such as fetal chromosomal abnormalities or multiple pregnancies. Nevertheless, women with underlying rheumatic disease have a much higher incidence of these complications.
Risk factors for preeclampsia and subsequent development of placental insufficiency are summarized in Box 1 .
- •
Nulliparity
- •
Extremes of maternal age younger than 18 years or older than 35 years
- •
Immunologic:
- ○
Multiparous women who have changed partner from previous pregnancies
- ○
Short interval between first coitus and conception
- ○
“Dangerous” father: man who has previously fathered preeclamptic pregnancies in a different woman.
- ○
Artificial reproductive therapy, especially with donor ovum
- ○
- •
Genetic: “familial clustering”: inheritability of preeclampsia in twin studies is 22% to 47%
- •
Metabolic and vascular risk factors: for example, diabetes, obesity, chronic hypertension, renal dysfunction
- •
Thrombophilias, especially antiphospholipid syndrome
- •
Underlying autoimmune inflammatory diseases; for example, systemic lupus erythematosus, scleroderma
- •
Past factors:
- ○
Previous severe early-onset preeclampsia
- ○
Maternal preterm delivery
- ○
Maternal low birth weight
- ○
- •
Hypoxia:
- ○
Multifetal gestation
- ○
High altitude
- ○
Prolonged gestation: placental growth outstrips the vascular supply
- ○
In 2014, the International Society for the Study of Hypertension in Pregnancy revised the definition of preeclampsia to also include both maternal and fetal factors. The consequences of placental insufficiency can be best summarized in Fig. 1 . The presence of proteinuria is not necessarily a diagnostic requirement if other systemic features of placental dysfunction (see Fig. 1 ) are present. There is evidence that women who develop nonproteinuric preeclampsia are more likely to have severe hypertension and exhibit other features of placental insufficiency leading to preterm deliveries. Moreover, the severity of proteinuria has limited prognostic implications for pregnancy outcomes, and therefore quantification of proteinuria should not be repeated once the diagnosis of preeclampsia is established.
Pathophysiology of preeclampsia
The classic hypothesis for preeclampsia is that it occurs as a result of defective placentation from ineffective spiral artery remodeling leading to placental hypoxia and the downstream cascade of all other clinical features, including fetal growth restriction with resultant infants who are SGA (see Fig. 1 ). Therefore, raised midgestational uterine artery Doppler studies are a useful marker for predicting preeclampsia-associated placental insufficiency. Nevertheless, the origins of classic preeclampsia are postulated to occur much earlier, even before conception, via paternal contribution (of semen or sperm) to impaired maternal immunotolerance. Professor Redman subdivides the pathophysiological stages of classic or preterm preeclampsia into at least 6 steps ( Table 1 ). Women with rheumatic diseases are predisposed to poor placentation, and are therefore more likely to develop “classic” or preterm preeclampsia along with the vascular compromise and resultant fetal growth restriction.
| Stage 1 | Before conception | Short interval between coitus to conception leads to lack of maternal immunotolerance to paternal antigens found in sperm or semen. |
| Stage 2 (<8 wk) | Implantation | Development of the embryo (little evidence of this at this stage). |
| Stage 3 (8–18 wk) | Defective placentation | Inadequate spiral artery remodeling and ischemic reperfusion and oxidative stress. |
| Stage 4 (>20 wk) | Oxidatively stressed placenta | Impaired production of placental-derived factors. |
| Stage 5 | Overt clinical signs | Clinical manifestations of preeclampsia from placental insufficiency. The earlier the onset of stage 5, the more severe the fetal growth restriction. |
| Stage 6 | Worsening preeclampsia with further compromise of uteroplacental perfusion | Acute atherosis (similar to atherosclerotic disease in later life) of the spiral arteries leading thrombosis and placental infarction/abruption. |
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