Caring for a pregnant woman is both an enormous privilege and a weighty responsibility. To meet these demands, ob/gyns must constantly keep up with new innovations in their specialty and adapt new recommendations, when they are based on solid clinical research. Unfortunately, given the complexity of human pregnancy and the lack of an adequate animal model, the discipline of clinical obstetrics—unlike specialties like cardiology and neurology—is plagued by a dearth of such studies.
As you know, there are many situations in daily practice where we find ourselves in a "data-free zone," having to make recommendations and management decisions without the benefit of sound evidenced-based data. In those circumstances, clinical experience and the art of medical practice have to take over.
Nowhere is this more apparent than in clinical obstetrics, where many basic questions remain unanswered. While cardiologists measure changes in calcium flux within a single myocardial cell and nephrologists estimate changes in osmotic gradient along a single nephron, ob/gyns continue to debate such questions as: Why is the fetus head down at the end of pregnancy? What causes labor? How do we adequately monitor fetal well-being during labor?
Our purpose here is to review a series of devices and technical innovations that are currently under development to assist clinicians in caring for a pregnant woman and her fetus. Although none of these instruments are currently in routine clinical use, it is likely that they will find their way into clinical practice within the next few years.
Biochemical tests for pPROM
Preterm premature rupture of membranes (pPROM), the rupture of the fetal membranes prior to 37 weeks' gestation, complicates up to 12% of all pregnancies.1 It also increases the risk of maternal and perinatal complications and death due to placental abruption, cord prolapse, chorioamnionitis, sepsis, and preterm labor and birth. In fact, pPROM is associated with 20% to 40% of all preterm births.2,3 Its early and accurate detection would allow for obstetric interventions that may minimize such complications (such as broad-spectrum antibiotic therapy to prolong latency); a failure to accurately diagnose pPROM may increase the risk of complications.2-5 Similarly, a false-positive diagnosis may result in inappropriate care, including unnecessary hospitalization, administration of antibiotics, tocolytics, corticosteroids, and/or induction of labor.
TABLE 1 Clinical tests to confirm the diagnosis of rupture of membranes
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Of course, if you can see amniotic fluid leaking out of the cervical os, that would confirm the diagnosis, but that rarely happens. An amnio-dye test is the gold standard for the confirmation of pPROM, but is invasive and, as such, is associated with bleeding, infection, iatrogenic rupture of membranes, and miscarriage. Other currently available tests include visible pooling of amniotic fluid in the posterior fornix, a positive "nitrazine" test, and ferning (crystallization) of vaginal fluid (Table 1). Ultrasound alone cannot confirm the diagnosis, but helps to suggest it in the appropriate clinical setting. All of these clinical tests have some limitations in terms of diagnostic accuracy, risks, cost, and technical ease.6-14 Moreover, such tests become progressively less accurate when more than 1 hour has elapsed after the membranes have ruptured.
Clearly then a rapid, accurate, and inexpensive test for pPROM is urgently needed. Several biochemical markers have been measured in vaginal fluid in an attempt to confirm the diagnosis of pPROM—including fetal fibronectin (fFN), alpha-fetoprotein, prolactin, insulin-like growth factor, and human placental lactogen—with variable results.5,15-21 One diagnostic test that is widely used in Europe and has recently been approved by the Food and Drug Administration is AmniSure (N-Dia, Inc., Cambridge, Mass.). An immunoassay that is simple, easy to perform, rapid (5-10 minutes), and noninvasive, AmniSure does not require a speculum examination.
The test identifies trace amounts of placental alpha microglobulin-1 (PAMG-1), a placental protein that is abundant in amniotic fluid (2,000–25,000 ng/mL) but is present in far lower concentrations in maternal blood (5–25 ng/mL). The protein is in even lower concentrations in cervicovaginal secretions in the absence of ruptured membranes (0.05–0.2 ng/mL). This 10,000-fold difference in concentration between amniotic fluid and cervicovaginal secretions makes PAMG-1 a very attractive marker for pPROM.22-25 The minimum detection threshold of the AmniSure immunoassay is 5 ng/mL, which should be sufficiently sensitive to detect pPROM with an accuracy of approximately 99%.25
FIGURE 1 AmniSure test for the diagnosis of pPROM: The test is designed to measure the presence of placental alpha microglobulin-1 (PAMG-1), which is abundant in amniotic fluid but in extremely small quantities in cervicovaginal fluid—in the absence of ruptured membranes. A sample of cervicovaginal fluid is collected using a sterile swab (but no speculum) and eluted into a vial containing solvent for 1 minute. The dipstick is then placed in the solvent, allowing the sample in the vial to move through the membrane by capillary reaction. The pad region of the test strip has two zones, one containing anti-PAMG-1 antibodies (the test zone) and anti-IgG (the positive control zone). If PAMG-1—the antigen in this case—is present in the sample, it will interact with the capture antibody, forming antigen-conjugate complexes that can be seen as a visible line. In the absence of antigen, no visible line will form. Results are determined by the presence or absence of the control and text lines (the intensity of these lines is not important).
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The technique for performing this test is described briefly in Figure 1. Although large clinical trials using AmniSure in the diagnosis of pPROM are currently in progress, preliminary data from studies in Moscow and California, which included about 300 patients being evaluated for pPROM, suggest that the test is 99% accurate, can be used at any time in gestation (15–42 weeks), and is highly specific without interference by semen, urine, blood, or vaginal infections.22-25 In the presence of vaginal infection or nonsignificant admixture of blood, for example, levels of PAMG-1 in cervicovaginal secretions do not appear to exceed 3 ng/mL, which would not significantly interfere with the AmniSure test.25 Such biochemical tests for pPROM appear to represent the right mix of technologic innovation and practical usefulness.
Three- and four-dimensional U/S
Ultrasound has long been used in obstetrics to document fetal number, confirm gestational age, identify fetal structural anomalies and/or markers of fetal aneuploidy, and confirm fetal well-being. Compared with standard 2D U/S, 3D U/S—or 4D if one includes movement—allows for visualization of fetal structures in all three dimensions concurrently, improved depiction of complex fetal structural anomalies (such as intracranial lesions), and storage of scanned volumes and images with 3D reconstruction at a later date or remote location (telemedicine).
3D U/S consists of three steps: volume acquisition by internal (automated) or external (free-hand) scanning systems, volume display, and volume manipulation. Using multiplanar mode, 3D volume is displayed by multiple 2D slices (like CT or MR imaging) in three orthogonal planes. Using the stored volumes, images can be reconstructed and rotated in every possible plane to give the requisite views. In this way, the amount of time required for the sonographer to acquire the images from the patient can be decreased from 30–40 minutes to about 8–10 minutes (Dr. Beryl Benaceraff, personal communication).
Like 2D U/S, the quality of 3D imaging is dependent on sufficient amniotic fluid to create an adequate acoustic window. But unlike 2D U/S, 3D images are greatly influenced by fetal movements and are subject to far more interference from structures such as fetal limbs, umbilical cord, and placental tissue. Because of movement interference, it is difficult to accurately visualize the fetal heart with 3D U/S. Lastly, 3D U/S equipment is expensive and requires additional training.
FIGURE 2 Prenatal diagnosis of fetal cleft lip: (A) An adequate view of the upper lip, philtrum, and nares routinely should be acquired at the time of fetal anatomic survey at 18 to 20 weeks gestation. (B) The diagnosis of cleft lip and/or palate can be made in 26% to 72% of cases using 2D U/S, although the images can appear far more dramatic than they really are because of the inability to resolve the facial soft tissues.26-28 (C) 3D U/S can provide superior images of the fetal face to help the parents prepare psychologically for the birth of a child with a facial defect. Through the use of 3D U/S, the images of the fetal face obtained before delivery can very closely approximate the real facial appearance (D).
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Although 3D U/S has been available since the early 1990s, it has yet to live up to its billing. In addition to rapid acquisition of images that can be reconstructed and manipulated, 3D U/S has other potential advantages:
- Surface rendering mode provides clear sculpture-like images of many fetal structures. By applying transparency mode to display some subsurface structures (such as bones) at the expense of soft tissue, improved images can be obtained. Such images may make it easier to diagnose certain fetal malformations, especially craniofacial anomalies (cleft lip and palate [Figure 2], micrognathia, ear anomaly, facial dysmorphism, club foot, finger and toe anomalies), spinal anomalies, abdominal wall defects, and fetal tumors.26-28 Accurate diagnosis of cleft lip/palate will allow for careful survey for other structural anomalies, early consultation with pediatric surgery, and initiation of regular fetal testing, if indicated. 3D surface reconstruction of the fetal face will prepare the family psychologically for the birth and may facilitate bonding between the mother and fetus.27-29
- 3D transvaginal U/S may help assess early pregnancy by accurately measuring the gestational sac, yolk sac, and crown-rump length. It may also allow for a more accurate midsagittal view of the fetus for measuring nuchal translucency.
- 3D U/S can also be used to measure tissue volume. Preliminary data suggest that assessment of cervical volume may predict women at risk of cervical insufficiency and measurement of placental volume in the first trimester may predict fetuses at risk of intrauterine growth restriction.30-31
- Modern telecommunication networks allow transfer of stored volume data by 3D U/S to remote centers for re-evaluation and/or second opinion by specialists.
Although it's not likely to replace standard 2D imaging in the near future, 3D U/S is a valuable adjunct in obstetric imaging. As the technology steadily improves, it's likely that fetal U/S will evolve to look more and more like CT and MR imaging.
Advances in prenatal diagnosis
Genetic analysis is currently being offered to most pregnant women to assess their age-related risk of carrying a fetus with a chromosomal disorder, the most common of which is trisomy 21 (Down syndrome). To date, the only way to collect fetal cells for definitive analysis is by amniocentesis or chorionic villus sampling. Although these invasive tests are accurate and reliable, they carry risks, including bleeding, infection, iatrogenic rupture of membranes, and miscarriage. The procedure-related risk of losing a pregnancy from routine second trimester genetic amniocentesis at 15 to 20 weeks is 0.2% to 0.5%.32 The risk of losing a pregnancy with CVS is 1% to 2%.33
To minimize these risks, investigators are trying to develop noninvasive tests for definitive genetic testing for fetal aneuploidy. Fetal cells are present in the maternal circulation at a concentration of about 1 cell for every 10,000 maternal cells.34 Free fetal DNA has also been found in significant concentrations in the maternal circulation throughout pregnancy. Indeed, 3% to 6% of all free DNA in maternal serum is of fetal origin, but that figure may be as high as 20% during preeclampsia or feto-maternal hemorrhage. Free fetal DNA may be superior to cells for genetic analysis because it's relatively abundant, does not require excessive purification, and the short half-life of free DNA effectively precludes contamination from a prior pregnancy.35 However, recent attempts at identifying and isolating fetal cells, fetal DNA, or both from maternal circulation for use in genetic testing for aneuploidy have been largely unsuccessful.36,37
Around the time of implantation (7 to 10 days after conception), the embryo differentiates into a trophectoderm layer that becomes the placenta and fetal membranes and an inner cell mass that becomes the embryo proper. Around the third week after conception, trophoblast cells are shed from the anti-implantation pole of the embryo into the uterine cavity and drain into the cervical mucus. Several investigators have attempted to isolate these trophoblast cells from the cervicovaginal discharge of women in early pregnancy, and use these cells for definitive genetic testing.38-41 Preliminary studies have shown that it is indeed possible to isolate trophoblast cells from the cervix by lavage of the cervical canal at 7 to 10.5 weeks' gestation.38
A more recent study has shown that trophoblast cells can also be identified and isolated from the external cervical os of women at 5 to 12 weeks' gestation using a cytobrush, a procedure sometimes called a genetic Pap smear.41 In the latter study, trophoblast cells were isolated from 86% (195/227) of samples by immunocytochemistry with trophoblast-specific antibodies, and genetic analysis agreed with placental tissue karyotyping by CVS in 95% (186/195) of cases.41 The ability to successfully collect trophoblast cells from the cervicovaginal discharge of women in early pregnancy and subject them to genetic analysis (analogous to an early CVS) may provide a simple, reliable, noninvasive, yet definitive genetic test for fetal aneuploidy in a singleton pregnancy without placing the mother or fetus at risk.
Applying proteomic technology to obstetrics
Preterm birth complicates 7% to 10% of all deliveries and is responsible for over 85% of all perinatal mortality and morbidity.42-44 Preterm labor is probably a syndrome rather than a single disorder since its causes vary so widely. Approximately 20% of all preterm deliveries are iatrogenic and are performed for maternal or fetal indications. Of the remaining cases, around 20% to 25% result from chorioamnionitis, 30% occur in the setting of pPROM, and the remaining 25% to 30% are unexplained.45,46
Intra-amniotic infection remains a clinical diagnosis, as evidenced by fetal tachycardia, maternal tachycardia, uterine tenderness, and/or maternal fever. Elevated amniotic fluid levels of glucose, white cell counts, and selective cytokines (such as Interleukin-6) or a positive Gram's stain can suggest the diagnosis, but are not definitive. The gold standard for diagnosing the disorder is a positive amniotic fluid culture. Unfortunately, this takes several days to return, by which time the clinical condition is typically quite apparent. Early identification of intra-amniotic inflammation would enable ob/gyns to expedite delivery, thereby removing the fetus from a hostile intrauterine environment. To this end, researchers have recently used proteomic technology to identify intra-amniotic inflammation in amniotic fluid.47-49
Proteomics refers to the study of the protein complement of a fluid compartment, tissue, or cell line by means of proteome analytic technologies, such as 2D protein gel electrophoresis or mass spectrometry- and/or protein microarray-based protein identification techniques. Proteomics has emerged as a promising new technology in reproductive science, with the potential to better define the pathophysiology of pregnancy-related complications, to improve the diagnosis of pregnancy-related conditions such as intra-amniotic infection and preeclampsia, and to monitor disease progression. For example, investigators have recently used SELDI-TOF-MS (surface enhanced laser desorption/ionization – time-of-flight – mass spectroscopy) to identify discriminatory protein biomarkers in the cerebrospinal fluid and urine of women with preeclampsia.50,51
Mass spectrometry separates proteins according to their mass-to-charge (m/z) ratio, and can identify proteins present in a complex biologic solution in extremely small concentrations (10-12 M). SELDI-TOF-MS is a newly developed proteomic technology that combines chromatography with mass spectrometry. The advantage of this approach is its technical simplicity, speed of screening, and ability to use small amounts (2-10 μL) of crude biologic solutions. Each protein molecule within the biologic sample is ionized, the ions are propelled into a mass analyzer by an electric field, and separated according to their m/z ratio.
FIGURE 3 SELDI-TOF-MS technology: An undiluted biologic sample (in this case, amniotic fluid) is placed on a spot of a ProteinChip array and the proteins within the fluid allowed to bind to the surface. Proteins are co-crystallized with energy-absorbing molecules (overlay matrix), ionized, propelled into a mass spectral analyzer by an electric field, and resolved by mass spectroscopy according to their m/z ratio. The mass spectrometry data are then interpreted by computer program, generating a tracing like the one illustrated in Figure 4.
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A time-of-flight analyzer is based on the principle that, when accelerated by a constant voltage, the velocity with which an ion reaches the detector is determined by its mass. The ability of this technology to separate out the individual proteins is enhanced with the help of the various active surfaces of the ProteinChip arrays that have the ability to interact differentially with proteins, based on hydrophobic interactions, ion-exchange interactions, metal affinity, or antibody-antigen interactions.
FIGURE 4 Representative SELDI-TOF-MS tracing: Four protein peaks are evident in the diseased tracing. These discriminatory protein peaks (labeled P1–P4) suggest the presence of compounds in the amniotic fluid that signal the presence of intrauterine inflammation. They are not found in the "normal" or "background" tracings. Two protein peaks are present in the "diseased" and "normal" tracings, but not the "background" tracing. These are the reference peaks (labeled R1 and R2).
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In brief, an undiluted biological sample is placed on a small area (spot) on a ProteinChip array and proteins are allowed to bind to the surface. The proteins are then subjected to mass spectrometry after co-crystallization with energy-absorbing molecules or matrix (Figure 3). SELDI-TOF-MS outputs are Cartesian sequences of numbers with m/z ratios on the X-axis and peak intensity on the Y-axis. A representative SELDI-TOF-MS tracing is shown in Figure 4. Using this technology, researchers have recently identified distinct biomarkers in the amniotic fluid of women with preterm labor-related intrauterine inflammation that appears to be predictive of preterm birth and fetal damage.49-51 Although further studies are required to confirm these results, SELDI-TOF-MS may provide an accurate, rapid (10–15 minutes), and reproducible technique for the diagnosis of early intra-amniotic inflammation in the setting of preterm labor and/or pPROM.
Although we aim to give our patients a positive birth experience, the primary goal of antepartum and intrapartum care is a healthy mother and a healthy baby. The development of new devices and technologies will likely improve the ability of obstetric care providers to achieve each of these goals in the years to come.
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Article at a glance
- AmniSure may offer a rapid, inexpensive test for pPROM. The test identifies trace amounts of placental alpha microglobulin-1, a protein abundant in amniotic fluid but found in much smaller amounts in cervicovaginal secretions—in the absence of ruptured membranes.
- Although 3D U/S is not likely to replace standard 2D U/S in the near future, it is a valuable adjunct in obstetric imaging. As the technology improves, it's likely that fetal U/S will evolve to look more like CT and MR imaging.
- Several investigators have attempted to isolate trophoblast cells from the cervicovaginal discharge of women in early pregnancy and use these cells for genetic testing. Analogous to an early CVS, this technology may provide a simple, reliable, noninvasive test for fetal aneuploidy in a singleton pregnancy.
- Proteomics has the potential to improve the diagnosis of intra-amniotic infection and preeclampsia. Researchers have recently used SELDI-TOF-MS (surface enhanced laser desorption/ionization – time-of-flight – mass spectroscopy) to identify protein biomarkers in the cerebrospinal fluid and urine of women with preeclampsia.
