三步法可识别大多数死产病因

旧金山——在加州大学主办的产前与产时管理会议上发表的一篇报告称，有2/3的死产可通过检查胎盘组织学、进行尸检以及染色体组型检测查出病因。


Yair J. Blumenfeld医生

斯坦福大学的Yair J. Blumenfeld医生指出，该结果提示临床医生，在下医嘱查找死产病因时或许应该采取错开法控制成本：如果尸检显示有潜在的结构异常，或是存在异常的染色体组型，医生很可能就不应该做2,000美元的血栓形成倾向和抗心磷脂抗体检查。

现在一般将死产比例上升归因于母体、胎儿或胎盘的原因，从而降低了被归类为“特发性”或不明原因的死产的比例。大多数死产为特发性这一理念目前有些过时了。尤尼斯·肯尼迪·施莱佛国家儿童健康与人类发展研究所创建了死产联合研究网，制定了一个确定死产病因的新系统，并于2006~2008年间通过一项多中心、群体性病例对照研究对其进行了检验。根据一项完整评估结果，将死产的潜在病因分为可能或很可能，评估项目包括尸检、胎盘病理学、病历、母亲访谈、染色体组型以及其他实验室检查。

研究者发现，在来自500名妇女的512次死产中，很可能的病因占61%，可能或很可能的病因占76%。在31%的死产中发现≥1种可能或很可能的病因，提示在死产病因上存在一定的重叠。尽管部分死产病因存在明显种族差异，但产前死产的第一大病因是产科并发症，占29%，其次是胎盘病理学，占23%。白人妇女或西班牙裔妇女中由产科并发症导致死产的几率(分别为22%和25%)低于黑人妇女(44%)或其他种族妇女(41%)。白人(7%)或西班牙裔(8%)因感染而死产的几率也低于黑人(25%)或其他种族(22%)。但西班牙裔和白人因脐带并发症导致死产的比例(均为13%)高于黑人(4%)或其他种族(5%)。

在死产的指定临床检查中， 胎盘组织学检查查出了52%的死产病因，尸检查出了31%的病因，染色体组型检测查出了9%的病因。8项其他筛查分别发现了0.4%~0.8%的病因，其中包括抗体筛查、毒理学检查或血糖检测；梅毒、细小病毒、狼疮抗凝物或抗心磷脂抗体检测；或胎儿母体出血中胎儿血液的检查。

目前在寻找死产病因方面，围绕着以下多个主题存在争议：染色体微阵列是否比染色体组型检测更好？是否应该下医嘱进行血栓形成倾向及抗心磷脂抗体筛查？如果家长拒绝尸检该怎么办？

在一项纳入532例死产的研究中，染色体微阵列检测往往比染色体组型检测更容易得出结果(分别占病例的87% vs. 71%)，并且更容易检测出非整倍性或拷贝数变异(分别占病例的8.8% vs. 6.5%)。但这种差异是否值得付出大概2,000美元做微阵列检测，这仍有待于观察。

在确定发生死产时是否应该做血栓形成倾向及抗心磷脂抗体检测？美国妇产医师协会的实践公告栏往往满篇都是这方面的内容，在这一问题上仍存在非常大的争议。使用尸检、染色体组型检测以及胎盘组织学检测帮助确定是否应该进行其他检测，以及是否应该与患者探讨血栓形成倾向家族史、胎盘的大体形态和其他能指导决策制定的因素，很可能是明智的做法。

此外，根据一项对460位家长、354名产科医生、21名围产期病理学家以及2,256名助产士的研究，医护人员对家长的告知方式可影响22%的家长接受或拒绝对其死产婴儿进行尸检的决定。总体来说，62%的家长同意进行尸检。对96位母亲进行的另外一项研究提示，拒绝尸检的家长仍有可能同意做“胎儿虚拟尸检”——对死产婴儿进行的一种体格检查和MRI或CT影像学检查。尽管只有62%同意做尸检，但有99%同意做胎儿虚拟尸检。在几个病例中，MRI发现了在尸检中未发现的异常。显然这并不是标准做法，但今后会看到更多对不接受尸检的母亲采取这种方法的研究。

2006年的国家统计数据提示，每1,000例活产新生儿中就有6例为死产，这一比率与先心病发生率相近。在这一年，美国20孕周后死亡的胎儿例数为25,972例。长期趋势表明，28孕周后的死产发生率已经下降，但在20~27孕周间并未下降。

Blumenfeld医生报告称无利益冲突。

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By: SHERRY BOSCHERT, Ob.Gyn. News Digital Network

SAN FRANCISCO – The cause of stillbirth can be identified in two-thirds of cases by checking the placental histology, conducting an autopsy, and karyotype testing.

That’s a "major, major take-home point" that’s "very different than what I was taught" in medical training, Dr. Yair J. Blumenfeld said at a meeting on antepartum and intrapartum management sponsored by the University of California, San Francisco.

That finding from an important 2011 study and other new data in the past 5 years suggests that perhaps clinicians should take a staggered approach when ordering tests to search for the etiology of a stillbirth. "Maybe I shouldn’t do a $2,000 workup for thrombophilia and anticardiolipin antibodies if the autopsy showed me that there’s an underlying structural abnormality, or if there’s an abnormal karyotype," he suggested.
 
In general, a growing proportion of stillbirths is being attributed to maternal, fetal, or placental causes, shrinking the proportion relegated to "idiopathic" or unexplained stillbirth. The idea that most stillbirths are idiopathic is "somewhat old thinking" at this point, said Dr. Blumenfeld of Stanford (Calif.) University.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development created the Stillbirth Collaborative Research Network, which developed a new system of determining the causes of stillbirth and tested it in a multicenter, population-based case-control study in five U.S. states during 2006-2008. Potential etiologies for each stillbirth were graded as a possible or probable cause of death based on a complete evaluation including autopsy, placental pathology, medical records, maternal interview, karyotype, and other laboratory tests.

Investigators found a probable cause in 61% of the 512 stillbirths from 500 women and a possible or probable cause in 76%. More than one possible or probable cause was found in 31% of stillbirths, showing some overlap in the causes of stillbirth. The leading causes of antepartum stillbirths were obstetric complications in 29% and placental pathology in 23%, although some of the causes of stillbirth varied significantly by race (JAMA 2011;306:2459-68).

Obstetric complications were less likely to be the cause of stillbirths in white women (in 22%) or Hispanic women (25%), compared with black women (44%) or women of other races (41%). Infection as a cause of stillbirth also was less likely in whites (7%) or Hispanics (8%), compared with blacks (25%) or other races (22%). Hispanics and whites, however, had higher rates of umbilical cord complications as a cause of stillbirth (13% for each), compared with blacks (4%) or other races (5%).

Among the clinically indicated tests for stillbirths, the placental histology identified a cause of stillbirth 52% of the time. An autopsy found a cause in 31% of cases, and karyotype testing identified a cause 9% of the time. Eight other screening tests found a cause for stillbirth in 0.4%-4.8% of cases, depending on the test. These included screens for antibodies, toxicology, or blood glucose; tests for syphilis, parvovirus, lupus anticoagulant, or anticardiolipin antibody; or detection of fetal blood in fetal-maternal hemorrhage.

"I’m not saying we shouldn’t do these things, but I think in today’s health care climate, especially with health care economics, you should start to think about maybe a staggered approach" in order to control costs, Dr. Blumenfeld said.

Controversy surrounds several topics in the search for stillbirth etiologies: whether chromosomal microarrays are better than karyotype testing; whether or not to order screening for thrombophilias and antiphospholipid antibodies; and what to do if the parents reject an autopsy.

In a study of 532 stillbirths, chromosomal microarray testing yielded results more often than did karyotyping – in 87% of cases vs. 71% – and detected aneuploidy or copy number variants more often, in 8.8% of cases vs. 6.5% (New Engl. J. Med. 2012;367:2185-93). Whether that difference is worth a price tag of approximately $2,000 for microarray testing remains to be seen, but "we’re going to see a lot more studies" of stillbirths using this and other new technologies, Dr. Blumenfeld said.

Practice bulletins from the American College of Obstetricians and Gynecologists are "all over the map" when it comes to deciding whether or not to test for thrombophilias and antiphospholipid antibodies when there’s a stillbirth," he said. "It’s still very, very controversial." It’s probably wise to use the results of autopsy, karyotyping, and placental histology to help decide whether to pursue these other tests, and to talk with patients about their family history of thrombophilia, what the placenta looked like, and other factors that could guide decision-making, he added.

How health care providers counseled parents affected parents’ decision to accept or decline an autopsy of their stillborn infant in 22% of cases, according to one study of 460 parents, 354 obstetricians, 21 perinatal pathologists, and 2,256 midwives (BJOG 2012;119:987-97). Altogether, 62% of parents agreed to an autopsy.

Parents who decline an autopsy still are likely to consent to a "fetal virtuopsy" – a physical exam and MRI or CT imaging of the stillborn infant, a separate study of 96 mothers suggests. Although 62% consented to autopsy, 99% consented to a virtuopsy. In a few cases, the MRI detected abnormalities that were missed on autopsy (Ultrasound Obstet. Gynecol. 2012;39:659-65).

"Clearly, this is not standard, but I think we’re going to see a lot more studies taking this kind of approach to women who are not accepting of an autopsy," Dr. Blumenfeld said. "Go back to your home institutions, find your favorite pediatrician, geneticist, or dysmorphologist, and ask them, ‘Are you willing to come and look at this stillbirth once it is born, and try to get some information just by looking at the infant?’ I guarantee that you will be able to find somebody like that in your institution. It’s something that we do at Stanford."

National statistics from 2006 suggest that 6 of every 1,000 live births will be stillbirths, a rate similar to the prevalence of congenital heart disease, he said. In 2006, there were 25,972 fetal deaths after 20 weeks’ gestation in the United States (Natl. Vital Stat. Rep. 2012:60;1-23). Long-term trends show that the rate of stillbirths has declined after 28 weeks’ gestation but not between 20 and 27 weeks’ gestation.

Dr. Blumenfeld reported having no financial disclosures.