Maintenance of Early Pregnancy

Early Pregnancy Loss
The incidence of pregnancy loss after implantation is high, estimated at 25 to 40 percent. Although many losses involve genetic abnormalities, there is often no known cause. Hormonal factors, leukemia inhibiting factor, and prostanoid pathways play important parts in successful implantation. But, given the complexities of early development, it is likely that many other mechanisms are also involved (Figure 3).

Steroid Hormones
Progesterone-receptor antagonists readily induce abortion if given before seven weeks of gestation. Similarly, surgical removal of the corpus luteum, the source of progesterone, results in pregnancy loss. These data suggest that adequate progesterone production by the corpus luteum is critical to the maintenance of pregnancy until the placenta takes over this function at approximately seven to nine weeks of gestation. The corpus luteum is maintained through the continued production of chorionic gonadotropin by trophoblasts. The mode of action of progesterone is not well understood, but it appears to be partially independent of the interaction with either progesterone or glucocorticoid receptors. Analysis of serum hormone concentrations in pregnant women with spontaneous mutations in genes encoding steroidogenic enzymes or hormone receptors indicates that other hormones are important in this process. Estrogen does not have an essential role in early human pregnancy. Similarly, mineralocorticoids are not essential, and androgens are required only for sexual differentiation in the male. Whether glucocorticoids play an essential part is uncertain.

The concentrations of prostaglandins in the human decidua in early pregnancy are lower than those in the endometrium at any stage of the menstrual cycle, primarily because of a decrease in the synthesis of prostaglandins. Consequently, prostaglandin precursors rather than the biologically active compounds are the predominant forms in amniotic fluid and most uterine compartments. The administration of exogenous prostaglandins — intravenously, intra-amniotically, or vaginally — induces abortion in all species and at any stage of gestation. These data suggest that pregnancy is maintained by a mechanism that tonically suppresses uterine prostaglandin synthesis throughout gestation. Moreover, a defect in this inhibitory mechanism may be associated with early pregnancy loss.

Figure 3.  Maintenance of Early Pregnancy.

In sheep, the conceptus suppresses endometrial prostaglandin synthesis early in pregnancy through a mechanism that involves the production of interferon-{tau}. However, the same mechanism is not found in humans. Since endometrial prostaglandin production is also reduced in ectopic pregnancy, it seems likely that systemic rather than local mediators are involved. For example, progesterone decreases endometrial prostaglandin production either directly (by promoting the uptake and storage of arachidonic acid) or indirectly (by increasing the local synthesis of endogenous inhibitors of prostaglandin synthesis, such as the secretory component of IgA).

Regulation of Placental Growth and Differentiation

The maintenance of early pregnancy is inextricably linked with placental growth and differentiation. In mice, the differentiation of trophoblasts is regulated by several transcription factors. Although the placentas of mice and humans differ morphologically, many of the transcriptional regulatory mechanisms may be similar.

Growth factors also function in epithelial–mesenchymal interactions that occur during early placental development. In mice that carry homozygous mutations in the scatter factor–hepatocyte growth factor gene, trophoblast differentiation is defective. Similarly, mice lacking the hepatocyte growth factor receptor (c-met) die from placental insufficiency caused by abnormal placental morphogenesis. In humans, mesenchymal cells within the stromal cores of chorionic villi produce hepatocyte growth factor, cytotrophoblasts express c-met, and hepatocyte growth factor enhances cytotrophoblast invasion.

Immunologic Factors

One of the most interesting functions of the placenta is the regulation of the maternal immune response such that the fetal semi-allograft is tolerated during pregnancy. Trophoblasts are presumed to be essential to this phenomenon because they lie at the maternal–fetal interface, where they are in direct contact with cells of the maternal immune system. Trophoblasts do not express classic major-histocompatibility-complex (MHC) class II molecules. Surprisingly, cytotrophoblasts express more HLA-G, a MHC class Ib molecule, as they invade the uterus. This observation, and the fact that HLA-G exhibits limited polymorphism, suggests that it has functional importance. The exact mechanisms involved are not known but may include increasing the production of inhibitory immunoglobulin-like transcript 4, an HLA-G receptor that is expressed on macrophages and a subgroup of natural killer lymphocytes.

Cytotrophoblasts that express HLA-G come in direct contact with maternal lymphocytes that are abundant in the uterus during early pregnancy. Although estimates vary, a minimum of 10 to 15 percent of all cells found in the decidua are lymphocytes. Like invasive cytotrophoblasts, these lymphocytes have unusual properties. Most are CD56+ natural killer cells. However, as compared with peripheral-blood lymphocytes, decidual leukocytes have low cytotoxic activity. Human trophoblasts help recruit these unusual maternal immune cells by means of chemokines.

Cytotoxicity against semi-allogeneic trophoblasts must be selectively inhibited. The factors responsible for this localized immunosuppression are unclear but probably include cytotrophoblast-derived interleukin-10, a cytokine that inhibits alloresponses in mixed-lymphocyte reactions. Steroid hormones, including progesterone, have similar effects. The complement system may also be involved, given that the deletion of the complement regulator Crry in mice leads to fetal loss as a result of placental inflammation. Finally, pharmacologic data, also from studies in mice, suggest that trophoblasts express an enzyme, indoleamine 2,3-dioxygenase, that rapidly degrades tryptophan, which is essential for the activation of T cells. Whether this mechanism occurs in humans is not known, although human syncytiotrophoblasts express indoleamine 2,3-dioxygenase78 and maternal serum tryptophan concentrations fall during pregnancy.

Clinical Implications and Future Directions

Infertility and Assisted Reproductive Technology

Infertility may result from a failure of fertilization or from the loss of the fertilized blastocyst before implantation. The ultimate goal of understanding implantation at a molecular level is to improve the diagnosis and treatment of infertility. The most recent estimate of the likelihood of a live birth per embryo-transfer procedure with the use of standard forms of assisted reproductive technology is 27.9 percent.80 The failure of implantation remains a major problem and may result from diminished uterine receptivity,3 poor oocyte quality,3 or delayed implantation.81 The high implantation rate of donated oocytes in older women suggests that the endometrium retains normal receptivity3,82 and that oocyte quality, rather than uterine factors, determines the success of implantation. To maximize pregnancy rates after in vitro fertilization, several embryos of the two-to-eight-cell stage are transferred into the uterus, a practice that is associated with a substantial increase in higher-order multiple gestations.83 Although transferring fewer blastocyst-stage embryos may eliminate this problem, a better understanding of the mechanisms responsible for implantation will allow clinicians to maximize pregnancy rates while minimizing the incidence of multifetal gestations.

Complications of Pregnancy

At a functional level, the placenta must integrate maternal and fetal physiology, immune systems, and endocrine systems. Complications that become apparent relatively late in pregnancy may actually reflect errors that occurred much earlier in placental development.

The invasion of cytotrophoblasts to the proper depth of the uterus is a major factor in determining the outcome of pregnancy. Excessive invasion can lead to deficient development of the decidua with abnormally firm attachment of the placenta directly onto the myometrium (a condition called placenta accreta), to the extension of the placenta into the myometrium (placenta increta), or to invasion through the myometrium to the uterine serosa and even into adjacent organs (placenta percreta). Despite improvements in diagnosis and treatment, these disorders are still associated with substantial rates of maternal illness and death, primarily because of hemorrhage.

Inadequate invasion has been implicated in the pathophysiology of preeclampsia, which is the leading cause of maternal death in the industrialized world and which increases perinatal mortality by a factor of five. Although the cause of preeclampsia is unknown, the characteristic pathologic lesion is the result of shallow interstitial invasion by cytotrophoblasts and, more consistently, limited endovascular invasion.84,85 In preeclampsia, cytotrophoblasts that invade uterine vessels fail to switch their repertoire of adhesion molecules to resemble that of vascular cells.86 Thus, the uterine arterioles remain small-bore, high-resistance vessels that cannot adequately respond to the ever-increasing fetal demands for blood flow. Determining the consequences of reduced placental perfusion and how it ultimately leads to the clinical characteristics of this syndrome remains an important challenge.87

Normal implantation and placentation are critical for successful pregnancy. A better understanding of the molecular mechanisms responsible for these processes will improve clinicians’ ability to treat such disorders as infertility, early pregnancy loss, and preeclampsia.

Supported in part by grants from the Reproductive Scientist Development Program through the Association of Professors of Obstetrics and Gynecologists (to Dr. Norwitz) and the Society for Gynecologic Investigation (to Dr. Schust) and grants from the National Institutes of Health (HD00849 to Dr. Norwitz, HD00840 to Dr. Schust, and HD26732, HD30367, HL64597, and 6RT-0304 to Dr. Fisher).

We are indebted to Ms. Evangeline Leash and Dr. Linda Schust for editorial assistance, and to Dr. S.K. Dey and Dr. James Cross for their constructive comments.

Source Information

From the Divisions of Maternal–Fetal Medicine and Reproductive Endocrinology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital and Harvard Medical School, Boston (E.R.N., D.J.S.); and Department of Stomatology, University of California, San Francisco (S.J.F.).

Address reprint requests to Dr. Norwitz at the Division of Maternal–Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, or at .(JavaScript must be enabled to view this email address).


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Errol R. Norwitz, M.D., Ph.D., Danny J. Schust, M.D., and Susan J. Fisher, Ph.D.
The New England Journal of Medicine

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