Epidemiologic Study of Placental Abruption

在正常妊娠中，胎盘在出生后立即分离，而在伴有早剥的妊娠中，胎盘较早开始分离。早剥是早产和围产期死亡的重要和潜在可预防的原因。胎盘早剥并发症约占妊娠的1%，但高达50%的早产可归因于这种情况。值得注意的是，在一次妊娠中发生早剥会使随后妊娠的风险增加20-30倍。我们假设，这种非常高的复发风险反映了可能具有遗传易感性的生理异常，并与遗传性血栓症相关。为了验证这些假设，我们提出了一个早剥的病例对照研究。我们将登记在分娩时出现早剥的妇女作为病例。对照将包括未发生早剥的妇女，并将根据胎次（0、1、2+）和种族/民族（高加索、非裔美国人、西班牙裔、其他）与病例（1:1）匹配。建议在4.5年期间（2002年4月至2006年9月）从新泽西州圣彼得大学医院招募235名病例和235名对照者，将提供足够的数据来检验这一假设。同意的患者将在分娩后接受采访，以获得详细的社会、行为、生殖和产科病史。将查询所有病例妇女和对照妇女分娩的医疗记录。将对病例和对照组的胎盘进行组织学检查。访谈结束后（出院前），将立即从病例和对照中采血，从中提取DNA并检测基因突变和多态性，包括因子V Leiden （1691G产生A）、凝血酶原基因（20210G产生A）、677C产生T和1298A产生C多态性的5,10-亚甲基四氢叶酸还原酶（MTHFR）、蛋氨酸合成酶还原酶（MTRR） 66A产生G多态性。甜菜碱-同型半胱氨酸甲基转移酶（BHMT）突变和高同型半胱氨酸血症。我们还将检测获得性（也可能是暂时性）凝血异常，如狼疮抗凝血和抗心磷脂抗体，以及其他遗传性血栓性疾病，包括蛋白C缺乏、活化蛋白C抵抗、因子VIII和因子XI凝血异常。此外，我们还将评估两种MTHFR、MTRR和BHMT基因异常与叶酸代谢和维生素B12缺乏之间是否存在基因-环境相互作用，从而导致高同型半胱氨酸血症，从而导致胎盘血管病变。这项研究将提供可靠的数据，这对于建立异常高复发风险的遗传假设至关重要。它还将为几种遗传性血栓形成和早剥风险之间的关联提供大量新证据。

In normal pregnancies, placental separation occurs immediately after birth, while in pregnancies complicated by abruption the placenta begins to detach earlier. Abruption is an important and potentially preventable cause of premature delivery and perinatal mortality. Placental abruption complicates approximately 1 percent of pregnancies, but up to 50 percent of premature births are attributable to this condition. Remarkably, the occurrence of abruption in one pregnancy confers a 20-30-fold increased risk in subsequent pregnancies. We hypothesize that this very high recurrence risk reflects physiological abnormalities that may have a genetic predisposition, and are associated with heritable thrombophilias. To test these hypotheses we propose a case-control study of abruption. We will enroll as cases women who develop abruption at the time of labor/delivery. Controls will comprise women who do not develop abruption, and will be matched to cases (1:1) based on parity (0, 1, 2+) and race/ethnicity (Caucasian, African-American, Hispanic, other). A proposed recruitment of 235 cases and 235 controls over 4.5 years from Saint Peter's University Hospital, NJ (April 2002 to September 2006) will provide adequate data to test the hypothesis. Consenting patients will be interviewed following their delivery to obtain detailed social, behavioral, reproductive and obstetric histories. Medical records will be sought for all deliveries of case and control women. Placentas from cases and controls will be examined for histologic lesions. Blood will be obtained from cases and controls immediately following the interview (prior to discharge from the hospital) from which DNA will be extracted and assayed for genetic mutations and polymorphisms, including those for factor V Leiden (1691G yields A), prothrombin gene (20210G yields A), the 677C yields T and 1298A yields C polymorphisms in 5,10- methylenetetrahydrofolate Reductase (MTHFR), methionine synthase reductase (MTRR) 66A yields G polymorphism, betaine-homocysteine methyltransferase (BHMT) mutation and hyperhomocysteinemia. We will also test for acquired (and perhaps transitory) coagulation abnormalities such as lupus anticoagulant and anticardiolipin antibodies, as well as other heritable thrombophilias including protein C deficiency, activated protein C resistance, factors VIII and XI coagulation abnormalities. In addition, we will also evaluate if there exists a gene-environment interaction between the two MTHFR , MTRR, and BHMT gene abnormalities and deficiencies of folate metabolism and vitamin B12, leading to hyperhomocysteinemia, and consequently, placental vasculopathy. This study will provide credible data that is critical to building a genetic hypothesis for the extraordinarily high recurrence risk. It will also add substantial new evidence for associations of several genetic thrombophilias and abruption risk.