versión impresa ISSN 0034-9887
Rev. méd. Chile v.130 n.5 Santiago mayo 2002
Nausea and vomiting of pregnancy:
Nausea and vomiting of pregnancy, "morning sickness", is a common contemporary complaint. Many pregnant patients note alterations in smell and taste which can precipitate "morning sickness", symptoms that characterize early gestation. Epidemiologic studies suggest that pregnancies accompanied by "morning sickness" have better outcomes than asymptomatic pregnancies. The intimate connection between immunogenetic identity, chemoidentity, and chemocommunication by olfactory mechanisms suggests a relationship between maternal symptoms and maternal accommodation of paternal antigens contained in the fetoplacental unit. Most mammalian species utilize olfaction to reduce inbreeding and thus do not require an intimate placental connection between mother and fetus. The evolution of Homo sapiens included prolonged periods of small, genetically homogeneous foraging groups which limited selection of genetically heterogeneous mates. Adaptation to this circumstance included a reduction of olfactory precision in mate selection and a more intimate association between mother and fetus, the hemochorial placenta (Rev Med Chile 2002; 130: 580-84).
(Key Words: Chemoreceptors; Nausea; Pregnancy toxemias; Smell; Vomiting).
La náusea y el vómito gravídicos:
Las náuseas y vómitos al comienzo del embarazo, o "emesis gravídica", son síntomas muy frecuentes. Muchas embarazadas reconocen este estado porque perciben desde los primeros días de un embarazo alteraciones en el olfato y en el sabor que pueden precipitar una emesis gravídica. Hay estudios epidemiológicos que sugieren que los embarazos acompañados por emesis gravídica tienen una mejor evolución que los embarazos asintomáticos. La conexión íntima entre la identidad inmunogenética, la quimioidentidad y la quimiocomunicación mediante mecanismos olfatorios sugieren que existe una relación entre estos síntomas maternos y la adaptación materna a antígenos paternos contenidos en la unidad fetoplacentaria. La mayoría de las especies de mamíferos utilizan el olfato para reducir la consanguinidad y de este modo no necesitan una íntima conexión placentaria entre la madre y el feto. Durante períodos prolongados en la evolución del Homo sapiens hubo grupos pequeños de pastores genéticamente homogéneos, con una limitada posibilidad de seleccionar apareamientos heterogéneos. Su adaptación a esta circunstancia incluyó una disminución de la precisión olfatoria en la selección de apareamientos y una asociación más íntima entre la madre y el feto: la placenta hemocorial.
Manuscrito preparado por invitación de los Editores de la Revista.
Recibido el 4 de diciembre de 2001. El Dr. Lee es miembro del
Comité Asesor Internacional de la Revista Médica de Chile.
*Professor of Medicine and Pediatrics and Obstetrics; Adjunct Professor
of Anthropology and Social and Preventive Medicine. Director, Division of
Maternal & Adolescent Medicine. Director, Division of Geographic Medicine.
Department of Medicine, State University of New York at Buffalo, USA.
Chemoidentity and chemocommunication are closely linked in all living things. Mammals, including human beings, have individual identifying odors linked to the HLA alleles on chromosome 61,2. The mammalian olfactory mechanism contains receptors specific for chemo-identification as well as receptors and neurons for recognizing pheromones and aromatics. Taste and smell -the gustatory and olfactory senses- are closely linked genetically and functionally. Odors and tastes can signal danger. For example, chemosensory mechanisms are useful for identifying the contents of food. Odors can stimulate or deter appetite and trigger nausea and vomiting. Odors can signal and stimulate sexual arousal. Breeding in almost all mammals is governed by chemocommunication3. In many mammalian species where appearance is uniform, chemo-identification is necessary to establish breeding and family relationships. Mammalian mate selection is influenced by chemo-identifying odors, as is receptive readiness for sexual intercourse4. Most mammals avoid inbreeding by olfactory identification of desirable, genetically different mates and by rejection of undesirable, genetically similar mates2,3,5,6. Inbred female mice can be induced to abort conceptions by genetically identical males by exposing them only to the odors of a genetically different male.
Despite human aspirations for sophisticated high culture free of offensive odors, our species has not been able to discard the biologic equipment for and responses to smell. Indeed the long history of human use of incense and perfumes indicates our species abiding affiliation with its nose7. Human beings make pheromones, possess a vomeronasal organ, just like olfactorily more sophisticated mammals like dogs, and human beings respond emotionally and physiologically to pheromones and to other airborne chemicals7. Human females can identify the genetically determined odors of human males and report that odors of genetically dissimilar males are more appealing than those of genetically similar males2,6. Human females produce pheromones related to their menstrual cycle so that groups of women living in close contact will tend to cycle in synchrony7. As yet there is no documented influence of male odors on human ovulation or menstruation. Human males do not appear to have their sexual appetites determined by the cyclic olfactory events of human females, perhaps because of the widespread use among males and females of scents, deodorants, and antiperspirants.
The evolutionary history of Homo sapiens includes a prolonged period of small foraging groups: groups characterized by genetic homogeneity8. During this process of adaptation our primate olfactory equipment was reduced in size but not eliminated, and it was during this same time that the hemochorial placenta emerged. In widely dispersed foraging groups opportunities for outbreeding would be rare so that a certain amount of inbreeding with consequent reproductive and survival disadvantage might occur. Recent research indicates that Homo sapiens is the most genetically homogeneous species of all the primates, with less genetic variability than chimpanzees, bonobos, and gorillas9. The homogeneity of mitochondrial DNA in present day human beings suggests that the human placenta and nose originated in only a small group of breeding primates and were retained as descendants grew in number and migrated, ultimately to inhabit virtually all of the earths lands. In this setting genetically heterogeneous matings chosen by chemo-identification using the olfactory mechanism would become less essential, perhaps even a disadvantage, by too severely restricting mate selection.
If mate selection becomes less biologically precise and restrictive, and thus advantageous, then some adaptation of the maternal-fetal relationship, allowing for survival of a fetus with little genetic difference from the mother, would become useful. Maternal recognition that the conception has occurred is essential to successful implantation and placentation10,11. The smaller the genetic differences between mother and embryo, the greater the risk that implantation will fail and the fetus will be aborted. The hemochorial placenta allows for such intimate contact between maternal and fetal tissue that even small immunogenetic differences between mother and fetus can be recognized and accommodated. Successful completion of gestation depends upon selective maternal accommodation and tolerance of paternal antigens contained in the fetoplacental unit until expulsion of the fetus after time sufficient for neonatal survival. It is a characteristic of the benign nausea and vomiting of human pregnancy that it is most intense during implantation and placentation, and subsides after maternal accommodation of the placenta is completed and the placenta is sufficiently formed and functional to allow fetal survival and growth3,10,11.
The continuous receptiveness of both males and females for sexual intercourse and the disminution in olfactory perception are rather successful adaptations to our biologic need for imprecision in mate selection and the consequent propensity for inbreeding. Human evolution has produced reproductive mechanisms highly adaptive for small populations with limited genetic heterogeneity. I reckon that the evolution of Homo sapiens included a necessary dampening of chemosensory precision and rejection of genetically similar mates as well as a necessary modification of the placenta to enhance fetal survival when successful mating between genetically similar parents occurred. Nevertheless, human reproduction continues to be remarkable for the high rate of spontaneous abortions, perhaps a consequence of our background of genetic homogeneity.
There are many hypotheses for explaining the origin and meaning of gestational nausea and vomiting, "morning sickness". Attempts have proliferated to find something beneficial, to assuage the common misery of this uniquely human discomfort. Alterations in perception of aromas and tastes are a common feature of early pregnancy; the majority of women, when asked, report that once pleasant odors and tastes become unpleasant and that cravings begin even before they recognize that they have missed a menstrual period and are indeed pregnant. A variety of studies have found that pregnancies accompanied by early gestational nausea and vomiting have fewer miscarriages, fewer preterm deliveries, and fewer low infant birth weights than asymptomatic pregnancies. Huxley suggests that maternal nutritional restriction reduces levels of maternal insulin and insulin growth factor-1 (IFG-1) and suppresses maternal anabolic metabolism thus ensuring nutrient partitioning that favors early placental growth12. Animal studies in rodents and sheep and human epidemiologic studies document lower placental and infant birth weights in females given high carbohydrate and high caloric diets early in gestation. Another prominent theory is that maternal nausea and vomiting early in pregnancy protect the fetus from teratogens in the mothers food and water. The difficulty with this theory is that the conceptus is most at risk for teratogenesis before there is a full functioning placenta, and the fact that in some settings nausea and vomiting of pregnancy are indeed detrimental to both mother and fetus13. It is important to recognize that alterations in maternal chemosensory function occur very early, often coincident with the realization of a missed menstrual period. The idea that gestational nausea and vomiting are biologic features of human gestation that begin only after four to six weeks gestation misses the importance of the links between chemosensory function, immunogenetic identity, and implantation of the embryo.
It is also clear that coexisting conditions can exacerbate pregnancy nausea and vomiting. For example, Helicobacter pylori infection was found in 89% of Puerto Rican women suffering severe nausea and vomiting4,5. Concomitant viral and parasitic infections during gestation can also lower the threshold for and exacerbate the symptoms of gestational nausea and vomiting. The presence of a comorbid condition does not explain how it is that women during the first two to three weeks of gestation develop sensory dysphoria, nausea, vomiting, and pica4,5. The mechanisms by which the mothers chemosensory function is altered are not addressed by any of the present hypotheses but increased estrogens produced by the placenta have been proposed as the stimulus4,5,8,14,15.
Infection, transplantation, immunosuppression, and gestation are manipulators of immune function and all are accompanied by changes in chemosensory function, especially olfaction. I believe that the biologic linkage between chemoidentity, immunity, and olfaction ¾an evolutionary heritage¾ is the origin of altered maternal taste and smell and thus the trigger for nausea and vomiting that occur during human gestation. A growing number of studies indicate that normal human gestation is associated with activation of maternal immune and inflammatory functions. Preeclampsia is associated with a further increase in circulating quantities of inflammatory cytokines such as tumor-necrosis-factor (TNF) and interleukin-6 (IL-6)16,17. The source of these inflammatory cytokines may be more from the mothers immune/inflammatory response and not so much from the placenta itself. Successful pregnancy in Homo sapiens is a complex voyage between the Scylla of inadequate immune and inflammatory response and the Charybdis of too much immune response and inflammation. The adaptation of the hemochorial placenta and alterations of the olfactory system would have been essential for the preservation of emergent Homo sapiens and its future expansion. The maternal immunomodulation required for successful human gestation is intensified by the hemochorial placenta, the extraordinarily intimate connection between fetus and mother. The presence of fetal cells in the maternal circulation is, for example, a characteristic of human gestation.
Human gestation is accompanied both by altered smell (chemoidentity) and altered olfactory perception (chemorecognition)3. In humans, maternal adaptation for the implanting fetus is clinically signaled by alterations in olfactory sense including the occasional finding that wives complain that their husbands odors are offensive and the common observation that previously pleasing aromas become repugnant, precipitants of nausea and vomiting3-5. Women who own or work with animals note that animals respond differently to them soon after they conceive. Indeed patients have complained to me that their dogs seem not to recognize them or that their horses are not responsive to usual commands.
When the success of the human animal resulted in large populations, living close together, using cultural not biologic governance of mate selection to discourage inbreeding, the evolutionary adaptations to a long history of existence as a small genetically homogenous foraging group became a source of symptoms. In contemporary, widely dispersed foraging groups such as the Bushmen of Southwestern Africa and of some Amazonian Amerindian tribes with well-documented genetic homogeneity, nausea and vomiting of pregnancy are vanishingly rare. In contrast, similar groups living in stable, sessile villages with larger populations and wider contacts to outside people, resulting in diverse, more complex choices for genetically heterogeneous mate selection, nausea and vomiting of pregnancy become common and may progress to maternal morbidity and mortality, and pregnancy failure. Recorded history is a product of urbanized Homo sapiens and is about 5,000 years old. It is of interest that the oldest of histories and medical writings do not describe "morning sickness", the symptoms of nausea and vomiting during early pregnancy. Genesis says only that women shall labor and deliver in pain, nothing about the immediate distress of conception. With the growth of cities and the hybridization of urbanized human populations, nausea and vomiting of pregnancy have emerged as a common phenomenon. Nowadays, implantation and placentation occur in gestations where immunogenetic differences between mother and fetus are not as subtle as they once were in small, genotypically homogeneous tribal groups. Maternal immunomodulation necessary for successful survival of the fetus is no longer asymptomatic but associated with sensory dysphoria and what we have come to accept as normal "morning sickness". Conception has become easier to recognize but harder to accommodate. Protection from teratogenic or toxic substances and improved early placental growth are indeed useful adaptations, but to me it appears likely they are by products of the more fundamental adaptations required for successful reproduction in a genetically homogeneous and constricted population.
The question remains: is "morning sickness" beneficial?18 The answer, of course, is: it depends! Whether morning sickness is beneficial depends upon the circumstances and the preconception health of the mother. Altered taste and smell, often triggering nausea and vomiting, signify maternal recognition that conception has occurred and that implantation is proceeding. That human gestation is accompanied by altered chemosensory function is, as my grandmother used to say, a fact of life.
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Address correspondence to: Richard V Lee, MD 7664 East Quaker Road, Orchard Park, NY 14127, USA. Phone/fax (716) 667-3304; E-mail: firstname.lastname@example.org