nullHypertensive Disorders
in PregnancyHypertensive Disorders
in PregnancyTeng YinCheng
Shanghai Jiaotong University Affiliated Sixth People's Hospital, Dept of Obs & GynContentsContentsIncidence and Risk FactorsIncidence and Risk FactorsIncidence
Commonly about 5 percent
Markedly influenced by parity
Related to race and ethnicity—A genetic predisposition
Main Risk Factors
Nulliparous (初产妇)
Multiple pregnancy
History of chronic hypertension
Maternal age over 35 years
Obesity
Lower socioeconomic status
…Etiology and PathogenesisRoberts, J. M. et al. Hypertension 2005;46:1243-1249
Used with permissionTwo-stage model of the pathophysiology of preeclampsiaStage 2 develops in some, but not all women with stage 1Etiology and PathogenesisEtiology and PathogenesisEtiology and PathogenesisNormal:
vessel remodeling (血管重铸) of the decidua and myometrium
transforming into large-capacitance, low-resistance vesselsPreeclampsia:
incomplete remodeling
limited to the superficial decidua
myometrial segments remain narrow Faulty Placentation (胎盘形成不良)---Stage InullnullEtiology and PathogenesisEtiology and PathogenesisOxidative distress (氧化应激)
Incomplete vessel remodeling → Reduced placental perfusion → placenta ischemia(缺血) and hypoxemia(缺氧) → Oxidative distress → Endothelia dysfunction → affected production of Nitric Oxide/ Prostaglandins(前列腺素)
Other factors
Immune system dysfunction
Genetic predisposition
MalnutritionPathogenesis of preeclampsiaPathogenesis of preeclampsiaPhysiopathology
------ sgage IIPhysiopathology
------ sgage II
Basic change:
System Vasospasm (全身小动脉痉挛)PhysiopathologyPhysiopathologyClinical manifestationClinical manifestationHypertension
Edema
Proteinuria
Severe cases
Headache
blurred vision
nausea, vomit
right upper quadrant pain
seizure (抽搐) Usually occurs after 20 gestational weeksWHAT LINKS STAGE
1 & 2?WHAT LINKS STAGE
1 & 2?Theory exploration: Genetics/Abnormal lipid metabolism
Endocrine dysfunction
InflammationNot all women with reduced placental perfusion develop preeclampsia…
Not all women with reduced placental perfusion develop preeclampsia…
What links stages 1 and 2?
Reduced placental perfusion must interact with maternal factors to result in preeclampsia.Stage 1???Stage 2Roberts, J.M., Gammill H.S. (2005)Diverse manifestations are possible: maternal and fetal/placental factors may vary in proportion.Diverse manifestations are possible: maternal and fetal/placental factors may vary in proportion. In a woman with many predisposing factors, even a minor reduction in placental perfusion is sufficient for stage 2 to develop.
In a woman with few predisposing factors, a profound reduction in placental perfusion may be required for preeclampsia to develop.
Roberts, J.M., Gammill H.S. (2005)Predisposing factorsReduced placental perfusionMicrosoft Office 2000Could maternal genetics play a role in the link between stage 1 & 2?Could maternal genetics play a role in the link between stage 1 & 2?Stage 1Stage 2GeneticsWhat do we know? What do we know? We know that abnormalities in lipid metabolism have a genetic basis.
We have learned that preeclampsia is characterized by profound lipid abnormalities such as hypertriglyceridemia…
Gratacos, E. (2000)
Microsoft Office 2000Could abnormal lipid metabolism be a genetic factor linking the stages of preeclampsia?
Could abnormal lipid metabolism be a genetic factor linking the stages of preeclampsia?
Stage 1Stage 2Abnormal lipid metabolismPreeclampsia is characterized by metabolic abnormalities similar to those present in atherosclerosis:Preeclampsia is characterized by metabolic abnormalities similar to those present in atherosclerosis:Hypertriglyceridemia
Reduced HDL cholesterol
Predominance of small-dense LDL cholesterol which have an increased potential to cause endothelial cell damage as compared to larger, more buoyant LDL’s.
Gratacos E., 2000.
nullStage 1 Abnormal lipid metabolism Stage 2In the presence of oxidative stress and inflammation, susceptible small-dense lipoproteins may be more easily oxidized, triggering Stage 2, maternal disease.
+ Oxidative Stress+ InflammationGratacos E., 2000 Most of the suggested linkages could contribute to or be stimulated by oxidative stress.Most of the suggested linkages could contribute to or be stimulated by oxidative stress.Oxidative stress is proposed as relevant to many diseases.
Evidence supports the presence of oxidative stress in preeclampsia:
Protein products of oxidative stress present in maternal and fetal tissues
Antibodies to oxidatively modified LDL’s present in maternal and fetal tissues
Concentrations of certain antioxidants reduced in preeclamptic women.
Roberts, J.M., Gammill H.S. (2005)In summary:In summary:Hypertriglyceridemia and predominance of small-dense LDL’s prior to pregnancy could be one predisposing factor for developing preeclampsia.
Oxidative stress and inflammation
may trigger the maternal disease. Gratacos E., (2000)
Microsoft Office 2000Could endocrine dysfunction be a factor linking Stage 1 and Stage 2?Could endocrine dysfunction be a factor linking Stage 1 and Stage 2?Stage 1Stage 2Endocrine dysfunctionThere is growing evidence suggesting that preeclampsia may be an early manifestation of the “metabolic syndrome”:
There is growing evidence suggesting that preeclampsia may be an early manifestation of the “metabolic syndrome”:
elevated triglyceride levels
hyperinsulinemia
insulin resistance
relative glucose intolerance
elevated blood pressure
These factors have been linked to the development of preeclampsia.Innes, K., Weitzel, L., Laudenslager, M. (2005)
Studies have repeatedly demonstrated that metabolic abnormalities precede the clinical signs of preeclampsia:Studies have repeatedly demonstrated that metabolic abnormalities precede the clinical signs of preeclampsia:Insulin resistance and associated hyperinsulinemia
Glucose intolerance
Hypertriglyceridemia
This suggests that insulin resistance and dyslipidemia may be factors involved in the development of preeclampsia.Innes, et al. (2005)Similarities between the risk factors for preeclampsia and cardiovascular disease include:Similarities between the risk factors for preeclampsia and cardiovascular disease include:Insulin resistance
Dyslipidemia- decreased HDL levels and
elevated triglyceride levels
These risk factors are thought to play a causal role in the development of endothelial dysfunction, a characteristic feature of preeclampsia and cardiovascular disease.
Innes, et al. (2005)
Future implications:Future implications:
Studies have demonstrated that women with a history of preeclampsia are at increased risk of developing cardiovascular disorders later in life.
Women with preeclampsia who deliver preterm or with recurrent preeclampsia are at greatest risk.
Women with preeclampsia have an approximate doubling of risk death from cardiovascular disease.
These findings suggest that pregnancy may constitute a metabolic and vascular stress test which reveals a woman’s health in later life.
Identification of maternal factors provides specific targets for prevention of preeclampsia in “at-risk” women.
Innes, et al. (2005)
Roberts, J.M., Gammill H.S. (2005)
Could inflammation be a factor linking
Stage 1 and Stage 2?Could inflammation be a factor linking
Stage 1 and Stage 2?InflammationStage 1Stage 2null“Preeclampsia is associated with an excessive inflammatory response compared with normal pregnancy.”
In a study done by Braekke, et.al (2005) inflammatory markers (calprotectin, CRP) were evaluated in maternal and fetal serum and amniotic fluid. Braekke, K., Holthe, Ml, Harsem, N., Fagerhol, M., Staff, A., 2005Inflammatory Markers:Inflammatory Markers:Calprotectin:
Is a protein released by activated neutrophils
C-reactive protein (CRP):
Is a protein produced by the liver
Production is stimulated by inflammatory cytokines
Braekke, K. et. al. (2005)Microsoft Office 2000Calprotectin and C-reactive protein (CRP), markers of inflammation, are elevated in preeclampsia.Calprotectin and C-reactive protein (CRP), markers of inflammation, are elevated in preeclampsia.The concentration of calprotectin in the maternal plasma of preeclamptic women was higher than in the control group (normal pregnant women).
No statistically significant difference in calprotectin levels was noted between women with mild and severe preeclampsia
Braekke, K. et al. (2005)C-reactive protein:C-reactive protein:Has been used to evaluate low-grade inflammation as a cardiovascular risk factor
Braekke et al. 2005Microsoft Office 2000CRP levels in the maternal plasma of pregnant women:CRP levels in the maternal plasma of pregnant women:
Correspond to a low-grade inflammation in preeclampsia and in normal pregnancy.
Braekke et al. 2005
Microsoft Office 2000No inflammatory response was noted in the fetal circulation.No inflammatory response was noted in the fetal circulation.
Concentrations of calprotectin in both arterial and venous umbilical plasma, and amniotic fluid were much lower than in maternal plasma
CRP levels in fetal circulation were 1/100 of maternal CRP levels.
Braekke et al. 2005
Theoretically,Theoretically,“Calprotectin concentrations could play a role in the pathophysiology of preeclampsia through augmented placental cell death or reduced trophoblast invasion (stage 1)”Braekke et al. 2005What stimulates the inflammatory response (activates the neutrophils) in preeclampsia?What stimulates the inflammatory response (activates the neutrophils) in preeclampsia?Researchers have been unable to determine why or exactly where the neutrophils become activated.
Maternal or placenta factors triggering maternal inflammation do not appear to be transferred into the fetal circulation.
Braekke et al. 2005
Future implications:Future implications:Further research is needed to evaluate the role of calprotectin in pregnancy or pregnancy complications.
Will calprotectin concentrations be used
to predict preeclampsia before the onset of clinical symptoms or as a marker of the clinically established disease?
Braekke et al. 2005
ClassificationClassificationGestational Hypertension
BP ≥ 140/90 mmHg for first time during pregnancy
No proteinuria
BP return to normal < 12 weeks’ postpartum
Final diagnosis made only postpartum(产后)
Preeclampsia
BP ≥ 140/90 mmHg after 20 weeks’ gestation
Proteinuria 300 mg/24 hours or ≥ 1+ dipstick
Eclampsia
Seizures that cannot be attributed to other causes in a woman with preeclampsiaClassificationClassificationPreeclampsia Superimposed on Chronic Hypertension
New-onset proteinuria ≥ 300 mg/24 hours in hypertensive women but no proteinuria before 20 weeks’ gestation
A sudden increase in proteinuria or blood pressure or platelet count < 100×109/L
Chronic Hypertension in Pregnancy
BP ≥ 140/90 mmHg before pregnancy or diagnosed before 20 weeks’ gestation
Or
Hypertension first diagnosed after 20 weeks’ gestation and persistent after 12 weeks’ postpartumDiagnosis Diagnosis History
Hypertension
Proteinuria
Edema
Assistant examinationDiagnosis of severe preeclampsiaDiagnosis of severe preeclampsiaManagementManagementPrinciples
Sedation(镇静)
Antihypertension (降压)
Antispasm (解痉)
Diuresis (利尿)
Termination of pregnancyManagementManagementGeneral management
Bed rest
Frequent fetal and maternal monitoring
Sedation
Diazepam (地西泮,安定)
Hibemation (冬眠药物)
pathidine派替啶, chlorpromazine氯丙嗪
promethazine异丙嗪ManagementManagementAntispasm(解痉) : To prevent seizures
Magnesium sulfate (硫酸镁)
Mechanism
Dose regimen
loading dose : 5 g, 5-10 minutes
continuous infusion: 20 -25 g, 1-2 g/hour
total daily dose: 25-30 g
Toxicity: Mg++
Therapeutic effective concentration: 1.7~3 mmol/L
Minimum toxic concentration: > 3 mmol/L
Notes: knee reflex, respiratory rates, urine flowManagementManagementAntihypertension
To prevent maternal cerebrovascular complications
Labetalol: 拉贝洛尔
α,β -adrenaline receptor blocker
Nifedipine: 硝苯地平
calcium channel blocker
Hydrelazine: 肼屈嗪
ACE (angiotensin-converting enzyme inhibitors):
血管紧张素转换酶抑制剂, contraindicated (禁用)ManagementManagementDiuresis (利尿)
Indication
Generalized edema
Acute heart failure
Pulmonary edema
Plasma volume expansion (扩容治疗)
Indication
Severe hypoproteinemia
AnemiaManagementManagementDelivery– an ultimate treatment
Timing
maternal safety fetal safety (premature)
Indications
Delivery methods
Vaginal delivery: induced labor
Cesarean section (剖宫产)Management of eclampsia Management of eclampsia General care
Control seizure:
MgSO4, Diazepam (安定), mannitol (甘露醇)
Supply of oxygen
Anti-acidosis (纠正酸中毒)
Anti-hypertension
Delivery:
2 hours after seizure controlled Thank you!Thank you!