PRIOR EXPOSURE TO PLASMODIUM COATNEYI ON OUTCOME OF PREGNANCY: RHESUS MONKEYS

因感染疟原虫而患疟疾的孕妇 恶性疟原虫比恶性疟原虫遭受更多的不良后果。 感染恶性疟原虫的未怀孕妇女。越是普遍和严重 后遗症包括贫血和伴有中枢神经系统的严重疟疾 并发症。他们的婴儿患有宫内发育迟缓 (IUGR)、低出生体重儿(LBW)、先天性感染和高婴儿 死亡率。尽管已经从人类那里收集到了许多信息 人类的考验、条件和道德伦理的局限 对怀孕的研究排除了对该系统的操纵，并具有重要意义 由于变量混杂，数据往往无法解释。由于 它在临床和免疫学上与人类非常相似 对疟原虫的反应，非人灵长类已被广泛用作 一个研究疟疾的模型。非人灵长类也是唯一的动物 胎盘呈绒毛状，有血迹，与人类相似， 因此，在妊娠研究中应选择动物模型。在.期间 1996年，我们建立了妊娠期疟疾的模型 静脉接种10只未感染疟疾的恒河猴(Macaca Mulatta)在感染Coatneyi疟原虫的前三个月， “恶性寄生虫”。描述这些结果的手稿是 正在出版(《美国热带医学和卫生杂志》)。在……里面 作为我们模型开发的继续，我们检查了 在接下来的怀孕期间第二次接触到P.coatneyi 这些猴子，被称为“半免疫”。研究的这一方面 解决了与实际情况相关的问题 疟疾流行地区。这些地区的妇女长期暴露在 在怀孕前患上疟疾，因此会发展成某种程度的 对疟原虫免疫。要解决以下问题： 对妊娠结局的事先豁免权，所有5人之前都曾接触过 猴子在怀孕前三个月(妊娠日)接种疫苗 21-35)和每周体检、CBCS、寄生虫检测和 对胎儿进行了全程超声检查 怀孕了。只发生了低水平的寄生虫血症(276-12800/mm3) 总共5只猴子，平均为37只(第一项研究为14只) 还有几天就要出现了。新鲜接种比冷冻接种更有效 感染猴子。没有发生明显的贫血。 半免疫猴子，尽管寄生虫血症的水平和模式 与我们第一次发现的4只幼猴的低寄生虫血症相似 学习。与第一项研究不同的是，在第一项研究中，大坝在 怀孕期间，母亲的体重增加与 控制。没有早期婴儿死亡，这进一步加强了 我们在第一项研究中发现，在后一项研究中，持续性贫血 一半的怀孕与婴儿死亡率有关。尽管在那里 年无高寄生虫血症、严重贫血或婴儿死亡率 在这组中，5个婴儿中有4个发生了不良结局。宫内 1例死于胎儿吸收。宫内发育迟缓 第二个婴儿怀孕三个月，这个婴儿一直在发育。 在过去的6个月里发育迟缓。胎盘重量低、LBW和先天性 感染发生在第三名婴儿。临床问题与减肥 发生于出生后第一个月的第4名婴儿。中庸之道 该组新生儿出生体重正常。然而，这些婴儿 最初体重下降，平均体重增加继续低于 这是控制点的问题。平均值介于以下各项的平均值之间： 对照组和幼稚猴子所生的婴儿组。 发现一名婴儿先天性感染(半免疫母婴)。 20周龄，短暂的，有一次低水平的发作 寄生虫血症(12,000/mm~3)。我们第一次研究中的先天性感染 发生在11周时，有很高的寄生虫血症(120,000/mm3)，并 持续感染了22个月。暂时被感染的人 婴儿可能已经获得了更高水平的被动保护， 它的母亲是半免疫的。半免疫组的胎盘是 仍在评估中，但一般病理并不像 在幼稚的群体中观察到了这一点。再接种一只幼虫 在半免疫中使用相同接种物的原始猴 导致慢性寄生虫血症、贫血、宫内发育迟缓和 早产儿死亡。因此，结果的差异不是由于 接种量的可变性。一份手稿将提交给 美国热带医学与卫生学杂志。

Pregnant women with malaria due to infection with Plasmodium falciparum suffer more adverse consequences than P. falciparum-infected nonpregnant women. The more common and serious sequelae include anemia and severe malaria with central nervous system complications. Their infants suffer intrauterine growth retardation (IUGR), low birth weight (LBW), congenital infection and high infant mortality. Although much information has been gleaned from human trials, the conditions, and moral and ethical limitations of human studies of pregnancy preclude manipulation of the system and important data is often uninterpretable due to confounding variables. Due to its close similarity to the human in its clinical and immunological responses to Plasmodium, the nonhuman primate has been widely used as a model to study malaria. Nonhuman primates are also the only animals with a villous, hemochorial placenta like that of man and are, therefore, the animal model of choice in studies of pregnancy. During 1996, we established a model of malaria during pregnancy by intravenously inoculating 10 malaria naive rhesus monkeys (Macaca mulatta) during the first trimester with Plasmodium coatneyi, a "falciparum-type parasite". A manuscript describing these results is in press (The American Journal of Tropical Medicine and Hygiene). In a continuation of our model development, we examined the effect of a second exposure to P.coatneyi during a subsequent pregnancy in 5 of these monkeys, referred to as "semi-immune". This aspect of the study addressed questions relevant to the actual situation existing in malaria endemic areas. Women in these areas are chronically exposed to malaria prior to pregnancy and therefore develop some level of immunity to Plasmodium. To address the question of the effects of prior immunity on the outcome of pregnancy, all 5 previously exposed monkeys were inoculated early during the first trimester(gestation day 21-35) and weekly physical exams, CBCs, parasite determinations, and ultrasound examination of the fetus were performed throughout pregnancy. Only low levels of parasitemia occurred (276-12,800/mm3) in all 5 monkeys and took an average of 37 (vs. 14 in first study) days to appear. Fresh inoculum was more effective than frozen in infecting the monkeys. No significant anemia occurred in the semi-immune monkeys, despite levels and patterns of parasitemia similar to those in 4 naive monkeys with low parasitemia in our first study. Unlike the first study where dams lost weight during pregnancy, the dam's weight gain during pregnancy was the same as the controls. There was no early infant mortality, further strengthening our finding in the first study that persistent anemia during the later half of pregnancy correlates with infant mortality. Although there was no high parasitemia, significant anemia, or infant mortality in this group, adverse outcomes occurred in 4 of 5 infants. Intrauterine death with fetal resorption occurred in one infant. IUGR during the 3rd trimester occurred in a 2nd infant and this infant has been growth retarded for the past 6 mo. Low placental wt., LBW and congenital infection occurred in a 3rd infant. Clinical problems and weight loss occurred for the first month after birth in a 4th infant. The mean birth weight of the group was normal. However, these infants initially lost weight and the mean weight gain continues to be below that of the controls. The mean falls between the mean wt gain for controls and that for the group of infants born to naive monkeys. Congenital infection was identified in one infant (semi-immune dam) at 20 weeks of age and was transient, with one episode of low level parasitemia (12,000/mm3). The congenital infection in our first study occurred at 11 weeks, has had high parasitemia (120,000/mm3) and has been persistently infected for 22 months. The transiently infected infant may have received increased levels of passive protection from its semi-immune mother. The placentas from the semi-immune group are still being evaluated but the general pathology is not as severe as that observed in the naive group. Inoculation of one additional naive primigravid monkey with the same inoculum used in the semi-immune group resulted in very high chronic parasitemia, anemia, IUGR, and early infant death. Thus, the differences in outcome are not due to variability in the inoculum. A manuscript will be submitted to the American Journal of Tropical Medicine and Hygiene.