Causes of Stillbirth

Causes of Stillbirth Abstract: Feto-infant mortality is increasing worldwide. Stillbirth is defined as uterofetal death at 20 weeks of gestation or greater. Stillbirths contribute as a primary factor to the growing magnitude of feto-infant mortality. The reasons for stillbirth are usually not reported. In many cases, the specific cause of fetal death remains unknown. The key risk factors include smoking, increased maternal age, being overweight, fetal-maternal hemorrhage. Even though there has been remarkable development in prenatal and intranatal care, stillbirths have been consistently increasing and remain an important problem in obstetrics and gynecology. Current research studies focus mainly on the epidemiology of stillbirths. I review the known and suspected causes of stillbirth. It also describes the recommended diagnostic tests to evaluate definite cause of stillbirth. In this paper, I also review analysis of stillbirths in the United States (US). The National Center of Health Statistics recorded 26,359 stillbirths in 2001. The number of stillbirths can be greatly reduced if the specific reasons for stillbirth are understood. Introduction: A pregnancy ending in stillbirth can be mentally devastating to a patient and her family. The most widely accepted definition of stillbirth is death of the fetus inside the uterus at 20 weeks of gestation or greater (Cartlidge et al., 1995). Much information is available on protocols for evaluating other types of postmortem examination but little work has been done on the evaluation of the causes of stillbirths (Mirlene et al., 2004). No universally followed protocol is available to guide the evaluation of stillbirths. In part because a wide variety of causes can be involved in stillbirths and it can be difficult to designate a specific cause of death. A stillbirth might result from various diseases, infections, trauma or genetic defects in the mother or fetus (Gardosi et al., 2005). In many cases, a specific reason is not known. Even though stillbirths are a serious problem, few resources have been focused on them and most obstetricians lack a sound method of evaluating of stillbirths (Petersson, 2002). In this document, I will review the accepted causes of still birth and the suggested diagnostic tests for evaluating the reason behind stillborn infants. In the year 2001 in the US, the National Center of Health Statistics recorded 26,359 stillbirths (Ananth et al., 2005). When compared to 27,568 infant deaths were reported in the same year. More than half of the stillbirths are before 28 weeks of gestation and almost 20% are close to the term. If a history of stillbirth exists then there is a 5-fold increase for subsequent stillbirth to occur. Prominent racial discrimination occurs in the rates of stillbirths. Stillbirths are almost three times more prevalent in African Americans when compared to whites (Puza et al., 2006). In 2001, the rate of stillbirths among white mothers was 5.5 per 1000 live births and 12.1 per 1000 among the black mothers. According to an analysis of U.S. vital statistics between 1995 and 1998, the increased risk of black, compared with white, stillbirths is greatest among singleton stillbirths (Puza et al., 2006). Reduction of proportion of fetal deaths at gestation of 20weeks or longer to 4.1 per 1000 live births and also reduction of fetal deaths for all racial and ethnic groups are the objectives of U.S. National Health for 2010. Categorization of Stillbirths: Different attempts were made in order to classify causes of stillbirth. Baird and his colleagues were among the first to classify the causes of perinatal death from the available clinical information. Depending on the British perinatal mortality survey, in 1958 Butler and Bonham designed a classification scheme that included the results of postmortem examinations. The most widely used is the 9 category classification system formulated by Wigglesworth and his coworkers (Wigglesworth, 1980). A new classification scheme which does not include neonatal deaths was proposed by Gardosi and his colleagues known as the ReCoDe Classification which focuses on the relevant conditions at the time of death in the uterus. It includes factors which affect the fetus followed by the factors which affect the mother (Gardosi et al., 2005). When compared with the Wigglesworth classification, a remarkable decrease in the number of unclassified stillbirth was achieved using this classification. One of the most vital aspects is to develop a proper definition of the factors that lead to death of the fetus. The basic definition for the â€Å"cause of death† is injury or disease responsible for a death. Froendefined cause of death in stillbirth as â€Å"an event or condition of sufficient severity, magnitude, and duration for death to be expected in a majority of such cases in a continued pregnancy in the clinical setting where it was observed† (Froen, 2002). When the definition of â€Å"cause of death† is reviewed, it is observed that only a few disorders are directly responsible for fetal death while many others are not. Causes of Stillbirth: Infection: Infections such as viral, protozoal and bacterial are linked with stillbirth. Almost 10-25% of stillbirths result from feto-maternal infections in the developed countries where as bacterial infections are common in developing countries (Goldenberg et al., 2003). Stillbirths that result from infection might be due to various factors which include direct infection, placental damage, and severe maternal illness. Usually the stillbirths in the initial weeks of gestation are linked with infection. Bacterial infections caused by Escherichia coli, group B streptococci, and Ureaplasma urealyticum are a cause of stillbirth in developed countries (Goldenberg et al., 2003). If syphilis epidemic occurs in an area then it might be the cause of a considerable proportion of stillbirths. If women come in contact with a parasite like malaria for the first time then stillbirth might be attributed to it. Toxoplasma gondii, leptospirosis, Listeria monocytogenes, Q fever, and Lyme disease are associated with the occurrence of stillbirth (Goldenberg et al., 2003). The magnitude of stillbirths due to viral infections is not known mainly due to the absence of a well defined systematic evaluation of infections in stillborn infants. The problem lies behind the fact that these viruses are difficult to culture and moreover, a positive viral serological diagnostic test identifying the DNA or RNA of the virus in the fetal tissue or placental tissue does not definitely determine that infection was the reason behind death. In most of the cases, infection is linked with stillbirth in early gestational weeks around twenty weeks. If molecular diagnostic technology (DNA and RNA polymerase chain reaction [PCR]) is utilized, it will help in diagnosis of viral infections without any error. Parvovirus B-19 appears to have the strongest association with stillbirth. According to a Swedish survey, in 8%of stillbirths B-19 PCR positive tissues were observed (Enders et al., 2004). In the United States, less than 1% of all stillbirths are reported to be due to parvovirus infection Parvovirus B19 moves across the placenta spreading the infection to fetal erythropoetic tissue resulting in fetal anemia leading to fetal death (Wapner et al., 2002). Myocardial damage may also occur due to Parvovirus B19. Here the virus directly attacks the fetal cardiac tissue. Parvovirus infection that leads to stillbirth usually occurs before 20 weeks of gestation (Wapner et al., 2002). Enteroviruses which include Coxsackie A and B, echoviruses and other enteroviruses are associated with stillbirth. Coxsackie viruses can cross the placenta and lead to villous necrosis, inflammatory cell infiltration, calcific pancarditis, and hydrops. Echovirus infection begins with severe maternal illness and finally ends with stillbirth. Cytomegalovirus (CMV) belongs to herpesvirus family and it is a congenital viral infection. Initially, the mother is infected and then it is transmitted to the fetus. CMV causes placental damage leading to intrauterine fetal growth restriction, but an association with stillbirth remains controversial (Goldenberg et al., 2003). Viral infections in the mother like rubella, mumps and measles are linked with stillbirth. If the vaccinations are administered on time then the proportion of stillbirths occurring due to infections can be reduced greatly. Genetics: Genetic causes are responsible for a considerable magnitude of stillbirths. 6- 12% of stillbirths attributed to genetic etiologies are due to karyotyping abnormalities. Due to the fact that in some of the cases cells cannot be cultured, karyotyping is not possible. Such factors alter the exact estimate of stillbirths resulting from chromosomal abnormalities. In stillborn fetuses which show apparent structural defects the probability of chromosomal abnormality is much higher when compared to normal stillborn fetuses. The usually focused abnormalities include monosomy X (23%), trisomy 21 (23%), trisomy 18 (21%), and trisomy 13 (8%). There are many instances where the karyotype of the stillborn is normal yet the cause of death is a genetic abnormality. Indeed, 25-35% of stillborn infants undergoing autopsy have intrinsic abnormalities (Wapner et al., 2002) .These include single malformations (40%), multiple malformations (40%), and deformations or dysplasia (20%) (Wapner et al., 2002). Almost 25% ofstillborns due to intrinsic defects show an abnormal karyotype whereas the rest of the 75% may have genetic defects which are not identifiable by the regular cytogenetic tests. This holds good for fetuses with multiple abnormalities. Single gene mutations may be responsible for death of the fetus in early weeks of development. Stillbirths in the midgestational weeks might be due to abnormal placental growth, development, or angiogenesis. Some autosomal recessive disorders including glycogen storage diseases and hemoglobinopathies have been reported as the cause of stillbirth (Wapner et al., 2002). In male fetuses, X-linked disorders may prove to be fatal. Many other genetic defects that are not recognized by the conventional cytogenetic diagnostics may lead to stillbirth. For example, conventional karyotype cannot identify chromosomal microdeletions that are linked with unexplained mental retardation. Confined placental mosaicism has also been associated with fetal growth impairment and stillbirth (Kalousek et al., 1994). Heritable Thrombophilia is another probable etiology of stillbirth.It is thought that placental infarction occurs due to thrombosis in the uteroplacental circulation leading to death. This poses concern over other thrombophilic defects and their effects on stillbirth. It is noteworthy that many heritable thrombophilias are common in normal individuals without a history of thrombosis or pregnancy loss (Rey et al., 2003). Even though many studies relate thrombophilias to fetal loss, most of the women with thrombophilias have healthy pregnancies with no lethal complications. It can be said that in the absence of any previous obstetric problems, thrombophilia will not result in stillbirth. Feto-maternal Hemorrhage: Feto-maternal hemorrhage has been linked to almost 3- 14% of all stillbirths which implies that it is responsible for a considerable number of stillbirths. Obstetric procedures such as external cephalic version and cesarean section lead to fetal maternal hemorrhage. Hemorrhage can also result due to placental abruption and/or abdominal trauma during pregnancy. Fetal maternal hemorrhage must be identified and quantitated using a proper dependable diagnostic test to attribute this reason behind the death of fetus. Hypoxia and anemia are indicators of death due to fetal hemorrhage. So, they should be confirmed by autopsy as in some normal cases too, few fetal cells can be seen in maternal blood. Maternal Features: Delayed child bearing or increased maternal age, prepregnancy obesity and stress are found to have their effects on the occurrence of stillbirth. The underlying mechanisms of action are unknown; however, with both obesity and delayed child-bearing on the rise, their importance as potential causes of stillbirth deserves greater attention (Cnattingius et al., 2002). Women whose only risk factor is being overweight have about a 2-fold increased risk of stillbirth (Nohr et al., 2005). Likewise, compared with women younger than 35 years of age, the stillbirth rate is increased 2- fold for women 35-39 years of age, and 3- to 4-fold for women aged 40 years old or olderwhereas some age-associated risk is due to higher rates of maternal complications, in uncomplicated pregnancies there may be a 50% increased risk associated only with maternal age 35 years or older (Nohr et al., 2005). Stress is a suspected cause of stillbirth which might occur as a result of a major life event (such as loss or poverty) (Huang et al., 2000) or through unexplained health changes related to adverse childhood experiences (Hillis et al., 2004). Different exposures are attributed to stillbirth. One of the most prevalent and preventable cause of stillbirth is cigarette smoking (Hillis et al., 2004). Smoking negatively affects fetal growth and oxygen supply to the tissues as it produces high levels of carboxyhemoglobin and decreases blood supply to the placenta. Smoking is also associated with increased risks of placenta previa and placental abruption and women who stop smoking in the first trimester have stillbirth rates equivalent to women who never smoked which indicates that quitting smoking in early pregnancy may significantly reduce the chances of occurrence of stillbirth (Hillis et al., 2004). A variety of complications result due to continuous exposure of different recreational drugs. Consumption of cocaine during pregnancy is also linked with stillbirth because it causes fetal growth restriction and/or abruption. The use of meth amphetamines leads to premature deliveries and stunted growth but its association with stillbirth remains unknown. In some cases, alcohol consumption during pregnancy has been associated with an increased risk of stillbirth (Mary et al., 2006). According to a study in Scandinavia, for women who consume less than 1 drink per week, the rate of stillbirth is 1.37 per 1000 births while the rate increases to 8.83 per 1000 births in women who consume 5 drinks or more per week. If smoking habits, caffeine intake, prepregnancy body mass index, marital status, occupational status, education, parity, and fetal gender are considered, the risk of stillbirth for women consuming 5 drinks or more per week was 2.96 (95% confidence interval 1.37 to 6.41) (Mary et al., 2006). Some studies show a protective effect on both stillbirth and fetal growth restriction rates if small amounts of alcohol are consumed during pregnancy (Mary et al., 2006). A link between pesticide exposure and stillbirth was observed by Pastore and his colleagues in 1997. Occupational exposures prove to be deleterious compared to residential exposure because the occupational exposures cause congenital abnormalities in addition to risk of stillbirth. A noteworthy fact is that the use of fertility drugs is also associated with stillbirths. This finding is problematic due to the fact that many women make use of fertility treatments to conceive. However, data on stillbirths due to exposures is obtained from retrospective studies which are prone to bias. The link between exposures and stillbirth should therefore be dealt with great attention and care. Maternal Diseases: Diabetes: There is always an increased danger of stillbirths in second and third trimester for mothers who are affected with type I or type II diabetes mellitus (DM) pregestationally. Even with modern obstetric care and diabetes management, stillbirth rates in women with type 2 DM have been reported to be 2.5-fold higher than nondiabetic women (Mary et al., 2006). The rate of stillbirth is the same between women with gestational diabetes (GDM) as well as normal women when the whole population is taken into account. The magnitude of danger involved with fetal death in women with type II DM is identical to women with GDM who in fact entered the pregnancy with undiagnosed type II DM. Therefore, women with GDM who have an undiagnosed type II DM are usually at a greater danger of encountering stillbirth. Examples of women with undiagnosed type II DM include history of GDM in previous pregnancies, high fasting glucose values;random glucose values greater than 200mg/dL or diagnosis of GDM early in pregnancy. The reason behind fetal death in late gestation in diabetic women is not known precisely. In addition to an increased risk of fetal death in diabetic women, there also exists a higher magnitude of danger associated with fetal abnormalities in these women compared to healthy women. Stress, hypertension and obesity complement each other in DM patients. In women with DM, there is a higher risk of stillbirth as it may lead to fetal abnormalities which may be either abnormally increased growth rate or retarded growth. To maintain the physiological range of the plasma glucose level, tremendous amounts of insulin is produced by the fetus resulting in fetal hyperglycemia. This fetal hyperglycemia is acquired from maternal hyperglycemia which finally results in fetal death due to excessive growth. The precise limit of plasma glucose level which poses a threat to the fetal life is not well defined. The most that could be done is to detect and deal with it using needed medications to lower the incidents of stillbirths.Many other maternal diseases have been linked to stillbirth, including thyroid disease, cardiovascular disease, asthma, kidney disease, and systemic lupus erythematosus (Simpson, 2002). These are subclinical diseases which in many cases has not been proven to be direct causes of stillbirth and women had normal pregnancies giving birth to healthy babies. Multiple Gestation and Stillbirth: Nearly 3% of all births and 10% of all stillbirths result from multiple pregnancies. According to national vital statistics, 1.8% of twin, 2.4% of triplet, 3.7% of quadruplet, and 5.6% of quintuplet fetuses suffered intrauterine fetal deaths (Salihu et al., 2003). The stillbirth rate among singleton pregnancies is approximately 0.5%. The reason behind fetal death in multiple pregnancies is difficult to be resolved when compared to singleton pregnancies. The broad causes of fetal death in multiple pregnancies include fetal growth retardation, preclamsia, abruption and cord accidents. It is vital to determine the chorionicity of multiple gestations as the rate of stillbirth is higher in monochorionic multiple gestations (Salihu et al., 2003) (Lynch et al., 2007). Assisted Reproductive Technology (ART) is an essential aspect in the occurrence of multiple pregnancies and stillbirth (Helmerhorst et al., 2004). Complications in Fetus: Fetal Growth Restriction: Some stillbirths result from fetuses which are smaller for a particular gestational age (SGA) compared to normal fetuses. Birth weight and risk of stillbirth are inversely proportional. If one increases, the other decreases. The main fact behind stillbirths in this condition is retardation of fetal growth and not the small size of fetus. An obstacle that occurs in determining the precise time of death of fetus due to SGA is the fact that the death might have occurred a long time before but the gestational age at the time of delivery is considered to be the time of death. This gives a false implication of the magnitude of stillbirths resulting from SGA. This problem can be solved by analysis of early and mid pregnancy placental hormones which are very specific for gestational periods (Smith et al., 2004). An evaluation of the amounts of these hormones relates directly to the time of death. Umbilical Cord Accidents: An increased number of stillbirths are due to â€Å"accidents† of umbilical cord like cord occlusion or blockage due to true knots, nuchal cords and compression of the cord. In almost 30% of normal healthy infant deliveries, nuchal cord and true knots in umbilical cords are observed. According to a study in Sweden, 9% of stillbirths were due to cord accidents (Petersson, 2002). Determination of cord accidents leading to fetal death by autopsy is smaller in proportion (up to 2.5%) (Horn et al., 2004). This difference indicates that in the absence of a proper cause, many times fetal death is attributed to cord entanglement. Due to the increased load of complications with live infants, little concern is expressed towards dead fetuses. In order to precisely relate a fetal death to cord accident, a clear indication of either hypoxic tissue injury or cord occlusion must be observed in autopsy. As nuchal cords are observed in normal deliveries also, the exact proportion of stillbirths due to cord accidents is biased. Obstetric Complications: Some of the obstetric complications are preclampsia, preterm premature rupture of membranes, preterm labor, cervical insufficiency, abruption, placenta previa, and vasa previa. These may either be direct or primary causes or may be indirect or secondary causes of stillbirth. Almost 10-19% of stillbirths occur due to abruption. Since cervical insufficiency or preterm labor lead to neonatal death, their role in causing stillbirth is not well defined. Evaluation of Stillbirth Stillbirth in itself may be emotionally devastating to many patients and their families. There the likelihood of carrying out genetic testing or autopsy on the fetus may not be readily agreeable from the family and culture. Lastly the procedures for evaluation must be cost effective and within reach. The two important facts that should be kept in mind while deciding which tests would prove as the most useful ones are primarily the consideration of cost of that test. It should not be beyond limits. Secondarily, if this test would be helpful in prevention of recurrent or sporadic stillbirths. In recurrent stillbirths, medical interference may prove helpful by preventing them in future. Analyzing the etiology of sporadic stillbirths might lead to reassurance and avoid irrelevant diagnostic tests in future pregnancies. The single most useful diagnostic test is a fetal autopsy (Peterson et al., 1999). Not only does the visible genetic and structural abnormalities but also an autopsy would be of great help in relating specific etiologies to stillbirth. The frequency of fetal autopsy is very less due to the fact that it is costly, not many trained pathologists are available and also it may be of great discomfort to the family and clinicians to deal with such a case. If autopsy is refused, partial autopsy or postmortem magnetic resonance imaging (MRI) scans may provide the necessary data. Embryonic membranes, placenta and umbilical cord must be physically and histologically examined while evaluating stillbirth etiology. This would give a precise cause of fetal death and might also provide clues for death due to secondary causes like infections, thrombophilia, and anemia. In most cases, families do not object on placental evaluation. In the cases where autopsy is not performed karyotyping the fetus would prove helpful. Cells and tissues from placenta (especially chorionic plate), fascia lata, skin from the nape of the neck, and tendons can be isolated and cultured and used for diagnostic tests like karyotyping. Comparative genomic hybridization shows tremendous promise for the identification of chromosomal abnormalities in stillbirths wherein fetal cells cannot be successfully cultured (Silver et al., 2006). An autopsy followed by a careful histological examination might help in relating stillbirths that result due to infections from the bacteria or virus. Parvovirus serology may be useful because this virus has been implicated in a meaningful proportion of cases (Erik et al., 2002). Diagnostic tests are performed for the detection of syphilis also since it contributes to the list of accepted causes of stillbirth. For various viral and protozoal agents like toxoplasmosis, rubella, cytomegalovirus (CMV) and herpes simplex virus (HSV) {TORCH}, serological screening is carried out. For bacterial and viral infections in the fetus, nucleic acid based tests are more helpful when compared to tissue cultures. Feto-maternal hemorrhage can be detected using Kleihauer – Betke test (KBT). Most laboratories use manual KBT which is prone to error. It has been found that flow cytometry is a better tool in detecting fetal erythrocytes in maternal blood. In order to eliminate red cell alloimmunization as an etiology of stillbirth, an indirect Coomb’s test is performed. Autopsy and examination of placenta are helpful in this situation. During the initial prenatal visits, if the antibody screen comes out to be negative then there is a need for recurrent testing. Diagnostic tests for conditions like diabetes and heritable thrombophilias must be carried out on a regular basis to prevent any complications which may lead to stillbirth. The treatment of such conditions at the appropriate time may prevent similar complications in subsequent pregnancies. Heritable thrombophilia might be of concern in the cases where there is recurrent fetal loss or there is a history of thrombosis or with complications involving placental insufficiency like placental infarction and intrauterine growth restriction. Administration of illicit drugs through various modes may be a cause of stillbirth in many cases. Toxicological examination may reveal the results for women who are subjected to such exposures. A simple urinary examination may prove helpful. The advanced and cost effective technology like ELISA (Enzyme Linked Immuno Sorbent Assay) can be used to detect a variety of metabolites like steroids in various tissues like blood, hair, and homogenized umbilical cord. Conclusion: Many medical and nonmedical agents govern the best approach to evaluate a stillbirth. The obstacles faced by obstetricians in solving these issues include the fact that in most of the cases the reason behind fetal death is unknown. Also the magnitude of stillbirths resulting from a single cause is not known precisely. Here there arises a need for population based studies to attribute stillbirths to their specific etiologies. There is a clear cut need of experts in the field of perinatal pathology and the required funding should be provided at the national level to promote it. Moreover, the clinician should be aware of the history of pregnant women in better evaluation. In cases where the local clinicians cannot reach a conclusion, the tissue samples must be sent to senior pathologists who have a thorough command on the subject and can help in reaching decisive conclusions. A universally accepted protocol is required for a systematic evaluation of stillbirths. Due to its absence a difference of opinion occurs among the obstetricians and gynecologists. The institutions like Stillbirth Collaborative Research Network should formulate guidelines for the proper judgement of stillbirth etiologies. The responsibility lies in the hands of the clinicians to do the best they can to reach a definite conclusion from the available data. It is noteworthy that the proportion of stillbirths that are â€Å"explained† is much higher in centers using systematic evaluations for recognized causes and potential causes of stillbirth (Petersson, 2002) (Horn et al., 2004). In conclusion, autopsy, placental evaluation, karyotype, Kleihauer-Betke, antibody screen, and serologic test for syphilis are useful in evaluating the etiologies of stillbirth. Depending on the case, other relative tests should be performed. The approach towards the testing of potential causes of stillbirth is not clear if it should be very specific and sequential or should it be comprehensive which means that it is targeted towards a broad spectrum of causes. Each of these has its own advantage. Sequential testing avoids false positive results and is directed to a specific cause and more over, it is cost effective. Comprehensive testing may prove helpful in cases where more than one factor is responsible for stillbirth. The problem with autopsy, placental evaluation, karyotype, screen for fetal-maternal hemorrhage, and toxicology screen is that they are dependant on time, that is, these tests should be performed immediately after the delivery. Autopsy cannot be delayed because death of the fetus already occurred and this would lead to physiological changes in the whole body and decay begins. The necessary evidence for stillbirth is easily available from fresh samples of placenta and also for toxicology screen. As the time since death increases, the physiology of fetus also changes leading to false positive or false negative results. If the time of fetal examination is delayed, fetal hemorrhage may be mistaken for postmortem lividity. Therefore a serious call for action is expected from institutions like Stillbirth Collaborative Research Network (SCRN) which would help in creating the most applicable diagnostic setting for evaluation of stillbirth (Silver et al., 2006). SCRN was developed by the National Institute of Child Health and Human Development to target the range of etiologies of stillbirth in the U.S. The aim of SCRN is to focus on the following objectives. The use of standardized surveillance in a geographic catchment area will show that the stillbirth rates are greater than those reported in the vital statistics catchment. The use of a prospectively implemented, standardized, postmortem, and placental examination protocols will improve diagnosis of fetal or placental conditions that cause or contribute to stillbirth. Maternal biologic and environmental risk factors in combination with genetic predisposition increase the risk for stillbirth. This is a population based study which is carried out in different counties of different states in the U.S. This study would take into account all the stillbirths and live births occurring in rural as well as urban areas in different racial groups. Even though occurrence of stillbirths cannot be stopped completely, yet attempts of such sort can be made atleast to prevent them to a maximum extent. Glossary Abruptio placenta totalis A placental abruption is a serious condition in which the placenta partially or completely separates from the uterus before the baby is born. Achondrogenesis Dwarfism characterized by various bone aplasias and hypoplasias of the extremities and a short trunk with delayed ossification of the lower spine. Alloimmunization Development of antibodies in response to alloantigens; antigens derived from a genetically dissimilar animal of the same species. Angiogenesis The formation of new blood vessels. Anomaly abnormality Autosome a chromosome other than the X and Y sex-determining chromosomes. Camptomelia bending of the limbs that produce a permanent curving or bowing. Cholestasis a condition caused by rapidly developing or long-term interruption in the excretion of bile (a digestive fluid that helps the body process fat). Chondrodysplasia Congenital dwarfism similar to but milder than achondroplasia, not familial and not evident until mid-childhood, in which the skull and facial features remain normal. Chorioamnionitis Inflammation of the fetal membranes. Dystocia Difficult delivery or parturition. Erythema infectiosum mild infectious disease occurring mainly in early childhood, marked by a rosy-red maculopapular rash on the cheeks, often spreading to the tr Causes of Stillbirth Causes of Stillbirth Abstract: Feto-infant mortality is increasing worldwide. Stillbirth is defined as uterofetal death at 20 weeks of gestation or greater. Stillbirths contribute as a primary factor to the growing magnitude of feto-infant mortality. The reasons for stillbirth are usually not reported. In many cases, the specific cause of fetal death remains unknown. The key risk factors include smoking, increased maternal age, being overweight, fetal-maternal hemorrhage. Even though there has been remarkable development in prenatal and intranatal care, stillbirths have been consistently increasing and remain an important problem in obstetrics and gynecology. Current research studies focus mainly on the epidemiology of stillbirths. I review the known and suspected causes of stillbirth. It also describes the recommended diagnostic tests to evaluate definite cause of stillbirth. In this paper, I also review analysis of stillbirths in the United States (US). The National Center of Health Statistics recorded 26,359 stillbirths in 2001. The number of stillbirths can be greatly reduced if the specific reasons for stillbirth are understood. Introduction: A pregnancy ending in stillbirth can be mentally devastating to a patient and her family. The most widely accepted definition of stillbirth is death of the fetus inside the uterus at 20 weeks of gestation or greater (Cartlidge et al., 1995). Much information is available on protocols for evaluating other types of postmortem examination but little work has been done on the evaluation of the causes of stillbirths (Mirlene et al., 2004). No universally followed protocol is available to guide the evaluation of stillbirths. In part because a wide variety of causes can be involved in stillbirths and it can be difficult to designate a specific cause of death. A stillbirth might result from various diseases, infections, trauma or genetic defects in the mother or fetus (Gardosi et al., 2005). In many cases, a specific reason is not known. Even though stillbirths are a serious problem, few resources have been focused on them and most obstetricians lack a sound method of evaluating of stillbirths (Petersson, 2002). In this document, I will review the accepted causes of still birth and the suggested diagnostic tests for evaluating the reason behind stillborn infants. In the year 2001 in the US, the National Center of Health Statistics recorded 26,359 stillbirths (Ananth et al., 2005). When compared to 27,568 infant deaths were reported in the same year. More than half of the stillbirths are before 28 weeks of gestation and almost 20% are close to the term. If a history of stillbirth exists then there is a 5-fold increase for subsequent stillbirth to occur. Prominent racial discrimination occurs in the rates of stillbirths. Stillbirths are almost three times more prevalent in African Americans when compared to whites (Puza et al., 2006). In 2001, the rate of stillbirths among white mothers was 5.5 per 1000 live births and 12.1 per 1000 among the black mothers. According to an analysis of U.S. vital statistics between 1995 and 1998, the increased risk of black, compared with white, stillbirths is greatest among singleton stillbirths (Puza et al., 2006). Reduction of proportion of fetal deaths at gestation of 20weeks or longer to 4.1 per 1000 live births and also reduction of fetal deaths for all racial and ethnic groups are the objectives of U.S. National Health for 2010. Categorization of Stillbirths: Different attempts were made in order to classify causes of stillbirth. Baird and his colleagues were among the first to classify the causes of perinatal death from the available clinical information. Depending on the British perinatal mortality survey, in 1958 Butler and Bonham designed a classification scheme that included the results of postmortem examinations. The most widely used is the 9 category classification system formulated by Wigglesworth and his coworkers (Wigglesworth, 1980). A new classification scheme which does not include neonatal deaths was proposed by Gardosi and his colleagues known as the ReCoDe Classification which focuses on the relevant conditions at the time of death in the uterus. It includes factors which affect the fetus followed by the factors which affect the mother (Gardosi et al., 2005). When compared with the Wigglesworth classification, a remarkable decrease in the number of unclassified stillbirth was achieved using this classification. One of the most vital aspects is to develop a proper definition of the factors that lead to death of the fetus. The basic definition for the â€Å"cause of death† is injury or disease responsible for a death. Froendefined cause of death in stillbirth as â€Å"an event or condition of sufficient severity, magnitude, and duration for death to be expected in a majority of such cases in a continued pregnancy in the clinical setting where it was observed† (Froen, 2002). When the definition of â€Å"cause of death† is reviewed, it is observed that only a few disorders are directly responsible for fetal death while many others are not. Causes of Stillbirth: Infection: Infections such as viral, protozoal and bacterial are linked with stillbirth. Almost 10-25% of stillbirths result from feto-maternal infections in the developed countries where as bacterial infections are common in developing countries (Goldenberg et al., 2003). Stillbirths that result from infection might be due to various factors which include direct infection, placental damage, and severe maternal illness. Usually the stillbirths in the initial weeks of gestation are linked with infection. Bacterial infections caused by Escherichia coli, group B streptococci, and Ureaplasma urealyticum are a cause of stillbirth in developed countries (Goldenberg et al., 2003). If syphilis epidemic occurs in an area then it might be the cause of a considerable proportion of stillbirths. If women come in contact with a parasite like malaria for the first time then stillbirth might be attributed to it. Toxoplasma gondii, leptospirosis, Listeria monocytogenes, Q fever, and Lyme disease are associated with the occurrence of stillbirth (Goldenberg et al., 2003). The magnitude of stillbirths due to viral infections is not known mainly due to the absence of a well defined systematic evaluation of infections in stillborn infants. The problem lies behind the fact that these viruses are difficult to culture and moreover, a positive viral serological diagnostic test identifying the DNA or RNA of the virus in the fetal tissue or placental tissue does not definitely determine that infection was the reason behind death. In most of the cases, infection is linked with stillbirth in early gestational weeks around twenty weeks. If molecular diagnostic technology (DNA and RNA polymerase chain reaction [PCR]) is utilized, it will help in diagnosis of viral infections without any error. Parvovirus B-19 appears to have the strongest association with stillbirth. According to a Swedish survey, in 8%of stillbirths B-19 PCR positive tissues were observed (Enders et al., 2004). In the United States, less than 1% of all stillbirths are reported to be due to parvovirus infection Parvovirus B19 moves across the placenta spreading the infection to fetal erythropoetic tissue resulting in fetal anemia leading to fetal death (Wapner et al., 2002). Myocardial damage may also occur due to Parvovirus B19. Here the virus directly attacks the fetal cardiac tissue. Parvovirus infection that leads to stillbirth usually occurs before 20 weeks of gestation (Wapner et al., 2002). Enteroviruses which include Coxsackie A and B, echoviruses and other enteroviruses are associated with stillbirth. Coxsackie viruses can cross the placenta and lead to villous necrosis, inflammatory cell infiltration, calcific pancarditis, and hydrops. Echovirus infection begins with severe maternal illness and finally ends with stillbirth. Cytomegalovirus (CMV) belongs to herpesvirus family and it is a congenital viral infection. Initially, the mother is infected and then it is transmitted to the fetus. CMV causes placental damage leading to intrauterine fetal growth restriction, but an association with stillbirth remains controversial (Goldenberg et al., 2003). Viral infections in the mother like rubella, mumps and measles are linked with stillbirth. If the vaccinations are administered on time then the proportion of stillbirths occurring due to infections can be reduced greatly. Genetics: Genetic causes are responsible for a considerable magnitude of stillbirths. 6- 12% of stillbirths attributed to genetic etiologies are due to karyotyping abnormalities. Due to the fact that in some of the cases cells cannot be cultured, karyotyping is not possible. Such factors alter the exact estimate of stillbirths resulting from chromosomal abnormalities. In stillborn fetuses which show apparent structural defects the probability of chromosomal abnormality is much higher when compared to normal stillborn fetuses. The usually focused abnormalities include monosomy X (23%), trisomy 21 (23%), trisomy 18 (21%), and trisomy 13 (8%). There are many instances where the karyotype of the stillborn is normal yet the cause of death is a genetic abnormality. Indeed, 25-35% of stillborn infants undergoing autopsy have intrinsic abnormalities (Wapner et al., 2002) .These include single malformations (40%), multiple malformations (40%), and deformations or dysplasia (20%) (Wapner et al., 2002). Almost 25% ofstillborns due to intrinsic defects show an abnormal karyotype whereas the rest of the 75% may have genetic defects which are not identifiable by the regular cytogenetic tests. This holds good for fetuses with multiple abnormalities. Single gene mutations may be responsible for death of the fetus in early weeks of development. Stillbirths in the midgestational weeks might be due to abnormal placental growth, development, or angiogenesis. Some autosomal recessive disorders including glycogen storage diseases and hemoglobinopathies have been reported as the cause of stillbirth (Wapner et al., 2002). In male fetuses, X-linked disorders may prove to be fatal. Many other genetic defects that are not recognized by the conventional cytogenetic diagnostics may lead to stillbirth. For example, conventional karyotype cannot identify chromosomal microdeletions that are linked with unexplained mental retardation. Confined placental mosaicism has also been associated with fetal growth impairment and stillbirth (Kalousek et al., 1994). Heritable Thrombophilia is another probable etiology of stillbirth.It is thought that placental infarction occurs due to thrombosis in the uteroplacental circulation leading to death. This poses concern over other thrombophilic defects and their effects on stillbirth. It is noteworthy that many heritable thrombophilias are common in normal individuals without a history of thrombosis or pregnancy loss (Rey et al., 2003). Even though many studies relate thrombophilias to fetal loss, most of the women with thrombophilias have healthy pregnancies with no lethal complications. It can be said that in the absence of any previous obstetric problems, thrombophilia will not result in stillbirth. Feto-maternal Hemorrhage: Feto-maternal hemorrhage has been linked to almost 3- 14% of all stillbirths which implies that it is responsible for a considerable number of stillbirths. Obstetric procedures such as external cephalic version and cesarean section lead to fetal maternal hemorrhage. Hemorrhage can also result due to placental abruption and/or abdominal trauma during pregnancy. Fetal maternal hemorrhage must be identified and quantitated using a proper dependable diagnostic test to attribute this reason behind the death of fetus. Hypoxia and anemia are indicators of death due to fetal hemorrhage. So, they should be confirmed by autopsy as in some normal cases too, few fetal cells can be seen in maternal blood. Maternal Features: Delayed child bearing or increased maternal age, prepregnancy obesity and stress are found to have their effects on the occurrence of stillbirth. The underlying mechanisms of action are unknown; however, with both obesity and delayed child-bearing on the rise, their importance as potential causes of stillbirth deserves greater attention (Cnattingius et al., 2002). Women whose only risk factor is being overweight have about a 2-fold increased risk of stillbirth (Nohr et al., 2005). Likewise, compared with women younger than 35 years of age, the stillbirth rate is increased 2- fold for women 35-39 years of age, and 3- to 4-fold for women aged 40 years old or olderwhereas some age-associated risk is due to higher rates of maternal complications, in uncomplicated pregnancies there may be a 50% increased risk associated only with maternal age 35 years or older (Nohr et al., 2005). Stress is a suspected cause of stillbirth which might occur as a result of a major life event (such as loss or poverty) (Huang et al., 2000) or through unexplained health changes related to adverse childhood experiences (Hillis et al., 2004). Different exposures are attributed to stillbirth. One of the most prevalent and preventable cause of stillbirth is cigarette smoking (Hillis et al., 2004). Smoking negatively affects fetal growth and oxygen supply to the tissues as it produces high levels of carboxyhemoglobin and decreases blood supply to the placenta. Smoking is also associated with increased risks of placenta previa and placental abruption and women who stop smoking in the first trimester have stillbirth rates equivalent to women who never smoked which indicates that quitting smoking in early pregnancy may significantly reduce the chances of occurrence of stillbirth (Hillis et al., 2004). A variety of complications result due to continuous exposure of different recreational drugs. Consumption of cocaine during pregnancy is also linked with stillbirth because it causes fetal growth restriction and/or abruption. The use of meth amphetamines leads to premature deliveries and stunted growth but its association with stillbirth remains unknown. In some cases, alcohol consumption during pregnancy has been associated with an increased risk of stillbirth (Mary et al., 2006). According to a study in Scandinavia, for women who consume less than 1 drink per week, the rate of stillbirth is 1.37 per 1000 births while the rate increases to 8.83 per 1000 births in women who consume 5 drinks or more per week. If smoking habits, caffeine intake, prepregnancy body mass index, marital status, occupational status, education, parity, and fetal gender are considered, the risk of stillbirth for women consuming 5 drinks or more per week was 2.96 (95% confidence interval 1.37 to 6.41) (Mary et al., 2006). Some studies show a protective effect on both stillbirth and fetal growth restriction rates if small amounts of alcohol are consumed during pregnancy (Mary et al., 2006). A link between pesticide exposure and stillbirth was observed by Pastore and his colleagues in 1997. Occupational exposures prove to be deleterious compared to residential exposure because the occupational exposures cause congenital abnormalities in addition to risk of stillbirth. A noteworthy fact is that the use of fertility drugs is also associated with stillbirths. This finding is problematic due to the fact that many women make use of fertility treatments to conceive. However, data on stillbirths due to exposures is obtained from retrospective studies which are prone to bias. The link between exposures and stillbirth should therefore be dealt with great attention and care. Maternal Diseases: Diabetes: There is always an increased danger of stillbirths in second and third trimester for mothers who are affected with type I or type II diabetes mellitus (DM) pregestationally. Even with modern obstetric care and diabetes management, stillbirth rates in women with type 2 DM have been reported to be 2.5-fold higher than nondiabetic women (Mary et al., 2006). The rate of stillbirth is the same between women with gestational diabetes (GDM) as well as normal women when the whole population is taken into account. The magnitude of danger involved with fetal death in women with type II DM is identical to women with GDM who in fact entered the pregnancy with undiagnosed type II DM. Therefore, women with GDM who have an undiagnosed type II DM are usually at a greater danger of encountering stillbirth. Examples of women with undiagnosed type II DM include history of GDM in previous pregnancies, high fasting glucose values;random glucose values greater than 200mg/dL or diagnosis of GDM early in pregnancy. The reason behind fetal death in late gestation in diabetic women is not known precisely. In addition to an increased risk of fetal death in diabetic women, there also exists a higher magnitude of danger associated with fetal abnormalities in these women compared to healthy women. Stress, hypertension and obesity complement each other in DM patients. In women with DM, there is a higher risk of stillbirth as it may lead to fetal abnormalities which may be either abnormally increased growth rate or retarded growth. To maintain the physiological range of the plasma glucose level, tremendous amounts of insulin is produced by the fetus resulting in fetal hyperglycemia. This fetal hyperglycemia is acquired from maternal hyperglycemia which finally results in fetal death due to excessive growth. The precise limit of plasma glucose level which poses a threat to the fetal life is not well defined. The most that could be done is to detect and deal with it using needed medications to lower the incidents of stillbirths.Many other maternal diseases have been linked to stillbirth, including thyroid disease, cardiovascular disease, asthma, kidney disease, and systemic lupus erythematosus (Simpson, 2002). These are subclinical diseases which in many cases has not been proven to be direct causes of stillbirth and women had normal pregnancies giving birth to healthy babies. Multiple Gestation and Stillbirth: Nearly 3% of all births and 10% of all stillbirths result from multiple pregnancies. According to national vital statistics, 1.8% of twin, 2.4% of triplet, 3.7% of quadruplet, and 5.6% of quintuplet fetuses suffered intrauterine fetal deaths (Salihu et al., 2003). The stillbirth rate among singleton pregnancies is approximately 0.5%. The reason behind fetal death in multiple pregnancies is difficult to be resolved when compared to singleton pregnancies. The broad causes of fetal death in multiple pregnancies include fetal growth retardation, preclamsia, abruption and cord accidents. It is vital to determine the chorionicity of multiple gestations as the rate of stillbirth is higher in monochorionic multiple gestations (Salihu et al., 2003) (Lynch et al., 2007). Assisted Reproductive Technology (ART) is an essential aspect in the occurrence of multiple pregnancies and stillbirth (Helmerhorst et al., 2004). Complications in Fetus: Fetal Growth Restriction: Some stillbirths result from fetuses which are smaller for a particular gestational age (SGA) compared to normal fetuses. Birth weight and risk of stillbirth are inversely proportional. If one increases, the other decreases. The main fact behind stillbirths in this condition is retardation of fetal growth and not the small size of fetus. An obstacle that occurs in determining the precise time of death of fetus due to SGA is the fact that the death might have occurred a long time before but the gestational age at the time of delivery is considered to be the time of death. This gives a false implication of the magnitude of stillbirths resulting from SGA. This problem can be solved by analysis of early and mid pregnancy placental hormones which are very specific for gestational periods (Smith et al., 2004). An evaluation of the amounts of these hormones relates directly to the time of death. Umbilical Cord Accidents: An increased number of stillbirths are due to â€Å"accidents† of umbilical cord like cord occlusion or blockage due to true knots, nuchal cords and compression of the cord. In almost 30% of normal healthy infant deliveries, nuchal cord and true knots in umbilical cords are observed. According to a study in Sweden, 9% of stillbirths were due to cord accidents (Petersson, 2002). Determination of cord accidents leading to fetal death by autopsy is smaller in proportion (up to 2.5%) (Horn et al., 2004). This difference indicates that in the absence of a proper cause, many times fetal death is attributed to cord entanglement. Due to the increased load of complications with live infants, little concern is expressed towards dead fetuses. In order to precisely relate a fetal death to cord accident, a clear indication of either hypoxic tissue injury or cord occlusion must be observed in autopsy. As nuchal cords are observed in normal deliveries also, the exact proportion of stillbirths due to cord accidents is biased. Obstetric Complications: Some of the obstetric complications are preclampsia, preterm premature rupture of membranes, preterm labor, cervical insufficiency, abruption, placenta previa, and vasa previa. These may either be direct or primary causes or may be indirect or secondary causes of stillbirth. Almost 10-19% of stillbirths occur due to abruption. Since cervical insufficiency or preterm labor lead to neonatal death, their role in causing stillbirth is not well defined. Evaluation of Stillbirth Stillbirth in itself may be emotionally devastating to many patients and their families. There the likelihood of carrying out genetic testing or autopsy on the fetus may not be readily agreeable from the family and culture. Lastly the procedures for evaluation must be cost effective and within reach. The two important facts that should be kept in mind while deciding which tests would prove as the most useful ones are primarily the consideration of cost of that test. It should not be beyond limits. Secondarily, if this test would be helpful in prevention of recurrent or sporadic stillbirths. In recurrent stillbirths, medical interference may prove helpful by preventing them in future. Analyzing the etiology of sporadic stillbirths might lead to reassurance and avoid irrelevant diagnostic tests in future pregnancies. The single most useful diagnostic test is a fetal autopsy (Peterson et al., 1999). Not only does the visible genetic and structural abnormalities but also an autopsy would be of great help in relating specific etiologies to stillbirth. The frequency of fetal autopsy is very less due to the fact that it is costly, not many trained pathologists are available and also it may be of great discomfort to the family and clinicians to deal with such a case. If autopsy is refused, partial autopsy or postmortem magnetic resonance imaging (MRI) scans may provide the necessary data. Embryonic membranes, placenta and umbilical cord must be physically and histologically examined while evaluating stillbirth etiology. This would give a precise cause of fetal death and might also provide clues for death due to secondary causes like infections, thrombophilia, and anemia. In most cases, families do not object on placental evaluation. In the cases where autopsy is not performed karyotyping the fetus would prove helpful. Cells and tissues from placenta (especially chorionic plate), fascia lata, skin from the nape of the neck, and tendons can be isolated and cultured and used for diagnostic tests like karyotyping. Comparative genomic hybridization shows tremendous promise for the identification of chromosomal abnormalities in stillbirths wherein fetal cells cannot be successfully cultured (Silver et al., 2006). An autopsy followed by a careful histological examination might help in relating stillbirths that result due to infections from the bacteria or virus. Parvovirus serology may be useful because this virus has been implicated in a meaningful proportion of cases (Erik et al., 2002). Diagnostic tests are performed for the detection of syphilis also since it contributes to the list of accepted causes of stillbirth. For various viral and protozoal agents like toxoplasmosis, rubella, cytomegalovirus (CMV) and herpes simplex virus (HSV) {TORCH}, serological screening is carried out. For bacterial and viral infections in the fetus, nucleic acid based tests are more helpful when compared to tissue cultures. Feto-maternal hemorrhage can be detected using Kleihauer – Betke test (KBT). Most laboratories use manual KBT which is prone to error. It has been found that flow cytometry is a better tool in detecting fetal erythrocytes in maternal blood. In order to eliminate red cell alloimmunization as an etiology of stillbirth, an indirect Coomb’s test is performed. Autopsy and examination of placenta are helpful in this situation. During the initial prenatal visits, if the antibody screen comes out to be negative then there is a need for recurrent testing. Diagnostic tests for conditions like diabetes and heritable thrombophilias must be carried out on a regular basis to prevent any complications which may lead to stillbirth. The treatment of such conditions at the appropriate time may prevent similar complications in subsequent pregnancies. Heritable thrombophilia might be of concern in the cases where there is recurrent fetal loss or there is a history of thrombosis or with complications involving placental insufficiency like placental infarction and intrauterine growth restriction. Administration of illicit drugs through various modes may be a cause of stillbirth in many cases. Toxicological examination may reveal the results for women who are subjected to such exposures. A simple urinary examination may prove helpful. The advanced and cost effective technology like ELISA (Enzyme Linked Immuno Sorbent Assay) can be used to detect a variety of metabolites like steroids in various tissues like blood, hair, and homogenized umbilical cord. Conclusion: Many medical and nonmedical agents govern the best approach to evaluate a stillbirth. The obstacles faced by obstetricians in solving these issues include the fact that in most of the cases the reason behind fetal death is unknown. Also the magnitude of stillbirths resulting from a single cause is not known precisely. Here there arises a need for population based studies to attribute stillbirths to their specific etiologies. There is a clear cut need of experts in the field of perinatal pathology and the required funding should be provided at the national level to promote it. Moreover, the clinician should be aware of the history of pregnant women in better evaluation. In cases where the local clinicians cannot reach a conclusion, the tissue samples must be sent to senior pathologists who have a thorough command on the subject and can help in reaching decisive conclusions. A universally accepted protocol is required for a systematic evaluation of stillbirths. Due to its absence a difference of opinion occurs among the obstetricians and gynecologists. The institutions like Stillbirth Collaborative Research Network should formulate guidelines for the proper judgement of stillbirth etiologies. The responsibility lies in the hands of the clinicians to do the best they can to reach a definite conclusion from the available data. It is noteworthy that the proportion of stillbirths that are â€Å"explained† is much higher in centers using systematic evaluations for recognized causes and potential causes of stillbirth (Petersson, 2002) (Horn et al., 2004). In conclusion, autopsy, placental evaluation, karyotype, Kleihauer-Betke, antibody screen, and serologic test for syphilis are useful in evaluating the etiologies of stillbirth. Depending on the case, other relative tests should be performed. The approach towards the testing of potential causes of stillbirth is not clear if it should be very specific and sequential or should it be comprehensive which means that it is targeted towards a broad spectrum of causes. Each of these has its own advantage. Sequential testing avoids false positive results and is directed to a specific cause and more over, it is cost effective. Comprehensive testing may prove helpful in cases where more than one factor is responsible for stillbirth. The problem with autopsy, placental evaluation, karyotype, screen for fetal-maternal hemorrhage, and toxicology screen is that they are dependant on time, that is, these tests should be performed immediately after the delivery. Autopsy cannot be delayed because death of the fetus already occurred and this would lead to physiological changes in the whole body and decay begins. The necessary evidence for stillbirth is easily available from fresh samples of placenta and also for toxicology screen. As the time since death increases, the physiology of fetus also changes leading to false positive or false negative results. If the time of fetal examination is delayed, fetal hemorrhage may be mistaken for postmortem lividity. Therefore a serious call for action is expected from institutions like Stillbirth Collaborative Research Network (SCRN) which would help in creating the most applicable diagnostic setting for evaluation of stillbirth (Silver et al., 2006). SCRN was developed by the National Institute of Child Health and Human Development to target the range of etiologies of stillbirth in the U.S. The aim of SCRN is to focus on the following objectives. The use of standardized surveillance in a geographic catchment area will show that the stillbirth rates are greater than those reported in the vital statistics catchment. The use of a prospectively implemented, standardized, postmortem, and placental examination protocols will improve diagnosis of fetal or placental conditions that cause or contribute to stillbirth. Maternal biologic and environmental risk factors in combination with genetic predisposition increase the risk for stillbirth. This is a population based study which is carried out in different counties of different states in the U.S. This study would take into account all the stillbirths and live births occurring in rural as well as urban areas in different racial groups. Even though occurrence of stillbirths cannot be stopped completely, yet attempts of such sort can be made atleast to prevent them to a maximum extent. Glossary Abruptio placenta totalis A placental abruption is a serious condition in which the placenta partially or completely separates from the uterus before the baby is born. Achondrogenesis Dwarfism characterized by various bone aplasias and hypoplasias of the extremities and a short trunk with delayed ossification of the lower spine. Alloimmunization Development of antibodies in response to alloantigens; antigens derived from a genetically dissimilar animal of the same species. Angiogenesis The formation of new blood vessels. Anomaly abnormality Autosome a chromosome other than the X and Y sex-determining chromosomes. Camptomelia bending of the limbs that produce a permanent curving or bowing. Cholestasis a condition caused by rapidly developing or long-term interruption in the excretion of bile (a digestive fluid that helps the body process fat). Chondrodysplasia Congenital dwarfism similar to but milder than achondroplasia, not familial and not evident until mid-childhood, in which the skull and facial features remain normal. Chorioamnionitis Inflammation of the fetal membranes. Dystocia Difficult delivery or parturition. Erythema infectiosum mild infectious disease occurring mainly in early childhood, marked by a rosy-red maculopapular rash on the cheeks, often spreading to the tr