Risk factors for sudden intrauterine unexplained death: epidemiologic characteristics of singleton cases in Oslo, Norway, 1986-1995

OBJECTIVE: The epidemiologic characteristics of unexplained stillbirths are largely unknown or unreliable. We define sudden intrauterine unexplained death as a death that occurs antepartum and results in a stillbirth for which there is no explanation despite postmortem examinations, and we present risk factors for this type of stillbirth in singleton gestations.Study Design: Singleton antepartum stillbirths (n = 291) and live births (n = 582) in Oslo were included and compared with national data (n = 2025 and n = 575,572, respectively). Explained stillbirths (n = 165) and live births in Oslo served as controls for the cases of sudden intrauterine unexplained death (n = 76) in multiple logistic regression analyses. RESULTS: One fourth of stillbirths remain unexplained. The risk of sudden intrauterine unexplained death (1/1000) increased with gestational age, high maternal age, high cigarette use, low education, and overweight or obesity. Primiparity and previous stillbirths or spontaneous abortions were not associated with sudden intrauterine unexplained death. CONCLUSIONS: Risk factors for sudden intrauterine unexplained death are identifiable by basic antenatal care. Adding unexplored stillbirths to the unexplained ones conceals several risk factors and underlines the necessity of a definition that includes thorough postmortem examinations.     

Totgeburt und plötzlicher Kindstod

During the last 30 years the rate of stillbirths in industrial countries has remained nearly identical, while neonatal mortality und the incidence of the sudden infant death syndrome (SIDS) has declined significantly. This observation is in contrast to the decline of stillbirths due to placental insufficiency, maternal diabetes mellitus, preeclampsia, rhesus incompatibility and fetal aneuploidy. However, the incidence of unexplained stillbirths has increased. The decrease of the incidence of the sudden infant death syndrome proves that prevention of diseases of unknown origin is possible. Smoking, obesity and an excessive increase in body weight before pregnancy are modifiable risk factors for intrauterine stillbirth. The detection and treatment of diabetes mellitus, gestational diabetes and arterial hypertension are effective measures in pregnancy to reduce the risk for stillbirth. The induction of labor at term is also effective in the reduction of stillbirths, however, the burden of elective induction with all of the possible negative effects has to be balanced against the benefit of avoiding intrauterine deaths as approximately 300 labor inductions with the corresponding disadvantages, would be necessary to avoid 1 stillbirth.     

Intrauterine Growth Restriction (IUGR): Etiology and Diagnosis

Intrauterine growth restriction (IUGR) is associated with perinatal morbidity and mortality. IUGR is defined as fetus that fails to achieve his growth potential. Antenatal small for gestational age (SGA) is defined as fetus with weight <10th percentile. IUGR and SGA are commonly used interchangeably. The identification of IUGR is important. IUGR identification begins with assessment of risk factor(s), and the diagnosis is made by ultrasound using biometry when this confirms an estimated fetal weight (EFW) of <10th percentile. The common risk factors include maternal causes (hypertension, diabetes, cardiopulmonary disease, anemia, malnutrition, smoking, drug use), fetal causes (genetic disease including aneuploidy, congenital malformations, fetal infection, multiple pregnancies), and placental causes (placental insufficiency, placental infarction, placental mosaicism). Intrauterine growth determines the perinatal, postnatal, and adult life development. IUGR is associated with increased risk of development in adult life of metabolic diseases including but not limited to hypertension, diabetes, obesity, dyslipidemia, and the metabolic syndrome.     

Life-table analysis of the risk of perinatal death at term and post term in singleton pregnancies

OBJECTIVE: This study was undertaken to estimate the cumulative risk of perinatal death associated with delivery at each gestational week both at term and post term. STUDY DESIGN: The numbers of antepartum stillbirths, intrapartum stillbirths, neonatal deaths, and surviving neonates delivered at between 37 and 43 weeks' gestation in Scotland, 1985-1996, were obtained from national databases (n = 700,878) after exclusion of multiple pregnancies and deaths caused by congenital abnormality. The numbers of deaths at each gestational week were related to appropriate denominators: antepartum stillbirths were related to ongoing pregnancies, intrapartum stillbirths were related to all births (excluding antepartum stillbirths), and neonatal deaths were related to live births. The cumulative probability of perinatal death associated with delivery at each gestational week was estimated by means of life-table analysis. RESULTS: The gestational week of delivery associated with the lowest cumulative risk of perinatal death was 38 weeks' gestation, whereas the perinatal mortality rate was lowest at 41 weeks' gestation. The risk of death increased more sharply among primigravid women after 38 weeks' gestation because of a greater risk of antepartum stillbirth. The relationships between risk of death and gestational age were similar for the periods 1985-1990 and 1991-1996. CONCLUSION: Delivery at 38 weeks' gestation was associated with the lowest risk of perinatal death.     

Determinants of unexplained antepartum fetal deaths

OBJECTIVE: To assess fetal, maternal, and pregnancy-related determinants of unexplained antepartum fetal death. METHODS: We conducted a hospital-based cohort study of 84,294 births weighing 500 g or more from 1961-1974 and 1978-1996. Unexplained fetal deaths were defined as fetal deaths occurring before labor without evidence of significant fetal, maternal, or placental pathology. RESULTS: One hundred ninety-six unexplained antepartum fetal deaths accounted for 27.2% of 721 total fetal deaths. Two thirds of the unexplained fetal deaths occurred after 35 weeks' gestation. The following factors were independently associated with unexplained fetal death: maternal prepregnancy weight greater than 68 kg (adjusted odds ratio [OR] 2.9; 95% confidence interval [CI] 1.85, 4.68), birth weight ratio (defined as ratio of birth weight to mean weight for gestational age) between 0.75 and 0.85 (OR 2.77; 95% CI 1.48, 5.18) or over 1.15 (OR 2.36; 95% CI 1.26, 4.44), fewer than four antenatal visits in women whose fetuses died at 37 weeks or later (OR 2.21; 95% CI 1.08, 4.52), primiparity (OR 1.74; 95% CI 1.26, 2.40), parity of three or more (OR 2.01; 95% CI 1.26, 3.20), low socioeconomic status (OR 1.59; 95% CI 1.14, 2.22), cord loops (OR 1.75; 95% CI 1.04, 2.97) and, for the 1978-1996 period only, maternal age 40 years or more (OR 3.69; 95% CI 1.28, 10.58). Trimester of first antenatal visit, low maternal weight, postdate pregnancy, fetal-to-placental weight ratio, fetal sex, previous fetal death, previous abortion, cigarette smoking, and alcohol use were not significantly associated with unexplained fetal death. CONCLUSION: In this study, we identified several factors associated with an increased risk of unexplained fetal death.     

Intrauterine growth restriction and pregnancy outcome

AIM: This prospective study was performed to evaluate perinatal outcome and maternal risk factors in pregnancies complicated by fetal intrauterine growth restriction (IUGR). METHODS: A total of 3 537 women pregnant with a singleton gestation were enrolled in the study: 219 of these pregnancies were complicated by fetal growth restriction (6.2%). Statistical analysis was performed using Wilcoxon test, Kruskall-Wallis test, c2 analysis of variance and ANOVA test. Statistical significance was set at P-value <0.05. Correlations were calculated by Spearman's coefficient. RESULTS: Ethnic group, physical demanding work, maternal smoking, alcohol abuse do not seem to be associated with lower birth weight and worse Apgar score. Sonographic assessment of fetal weight obtained by Hadlock's formula underestimate real newborn's weight. The difference between estimate weight and real weight is statistically significant. Women with intrauterine growth restriction underwent caesarean sections more often than women with appropriate fetal growth selected as controls (P<0.05). CONCLUSION: In conclusion, the obstetrician must recognize and accurately diagnose inadequate fetal growth and attempt to determine its cause (especially placental factors) in order to reduce fetal and maternal risks and establish the appropriate clinical management, timing and mode of delivery. If the growth-restricted fetus is identified and appropriate management instituted, perinatal mortality can be reduced.     

Unexplained antepartum fetal deaths: what are the determinants?

Objective The objective was to assess fetal, antenatal, and pregnancy determinants of unexplained antepartum fetal death.Methods This is a hospital-based cohort study of 34,394 births weighing 500 g or more from January 1995 to December 2002. Unexplained fetal deaths were defined as fetal deaths occurring before labor, without evidence of significant fetal, maternal or placental pathology.Results Ninety-eight unexplained antepartum fetal deaths accounted for 27.2% of 360 total fetal deaths. Two-thirds of these deaths occurred after 36 weeks gestation. The following factors are independently associated with unexplained fetal deaths: primiparity (OR 1.74; 95% CI 1.21, 2.86); parity of five or more (OR 1.19; 95% CI 1.26, 3.26); low socioeconomic status (OR 1.22; 95% CI 1.14, 2.86); maternal age 40 years or more (OR 3.62; 95% CI 1.22, 4.52); maternal age of 18 years or less (OR 1.79; 95% CI 0.82, 2.89); maternal prepregnancy weight greater than 70 kg (OR 2.20; 95% CI 1.85, 3.68); fewer than three antenatal visits in women whose fetuses died at 31 weeks or more (OR 1.11; 95% CI 1.08, 2.48); birth weight ratio (defined as ratio of birth weight to mean birth weight for gestational age) between 0.85 and 0.94 (OR 1.77; 95% CI 1.28, 4.18) or over 1.45 (OR 2.92; 95% CI 1.75, 3.21); trimester of first antenatal visit. Previous fetal death, previous abortion, cigarette smoking, fetal sex, low maternal weight, fetal-to-placenta weight, and post date pregnancy were not significantly associated with unexplained fetal deaths.Conclusion Several factors were identified that are associated with an increased risk of unexplained fetal deaths.     

Maternal and neonatal outcome of twin pregnancies complicated by single fetal death.

OBJECTIVE: To study the maternal and neonatal outcome of twin pregnancies complicated by the intrauterine death of one fetus after 20 weeks of gestation. DESIGN: Retrospective, observational study of 7 twin pregnancies out of 185 twin pregnancies with the diagnosis of a single intrauterine death over a 5-years period in a university hospital. RESULTS: The incidence of single fetal death in twin gestation after 20 weeks was 3.8% in the study population with a high incidence of intrauterine growth retardation (IUGR) of the remaining fetus and preeclampsia in the further course of pregnancy. The incidence of preterm delivery was 71% with a mean gestational age of 33.0 +/- 1.0 weeks. The median interval from diagnosis of single fetal death to delivery was 10.2 +/- 4.1 days (range 1-28 days). 5 of 7 (71%) cases were delivered by cesarean section for standard obstetrical reasons. Neither perinatal nor neonatal death of the remaining twin were observed. Two cases of neurologic injury were diagnosed after delivery by ultrasound and MRI. No maternal coagulopathy related to single fetal death occurred. CONCLUSION: Expectant management of single fetal death in twin pregnancies might be advisible under close surveillance of both, mother and the surviving fetus.     

Fetal growth restriction and consequences for the offspring in animal models

OBJECTIVE: In the present review we discuss rat models in which intra-uterine growth restriction is obtained through pharmacological (streptozotocin), dietary (global food restriction, low protein diet), or surgical (uterine artery ligation) manipulation of the maternal animal. METHODS: A MEDLINE search was performed on rat models of intrauterine growth restriction (IUGR), ie, streptozotocin, food restriction, low protein diet, or uterine artery ligation and pregnancy and fetal programming, long-term effects or adult offspring. RESULTS: We address the impact of the different maternal conditions for the fetal and neonatal development. The rat models we concentrate on were all associated with fetal hypoinsulinemia and intrauterine growth restriction. Both fetus and neonate adapt to the altered perinatal environment. Some of these adaptations may predispose the offspring to the development of insulin resistance, cardiovascular disease, obesity, and even overt diabetes in later life. CONCLUSION: The adaptations of the fetal metabolism to the altered intrauterine environment have consequences for the offspring, persisting into adulthood and into the next generation.     

Understanding perinatal mortality

The term perinatal death is used to describe antepartum and intrapartum stillbirths, and early neonatal deaths. At term, intrapartum stillbirth and neonatal death are collectively referred to as delivery related perinatal death, and the incidence in nulliparous and multiparous women is approximately one in 1000 and one in 2000 births, respectively. Associated factors include advanced maternal age, small for gestational age, fetal macrosomia, breech labour and previous caesarean delivery. The impact of obstetric interventions in labour on delivery related perinatal death, including rising rates of caesarean delivery, is complex and unclear. The incidence of overall perinatal death is falling mainly as a result of improvements in the management of premature neonates and from decreased deaths secondary to intrapartum anoxia at term. This review will provide an overview of perinatal mortality with a particular emphasis on delivery related perinatal death at term.     

Cytogenetic Studies in Perinatal Death

Following tissue culture cytogenetic studies were performed on tissue obtained from 136 fetuses who died in the perinatal period (98 stillbirths and 38 neonatal deaths). The gestational age of the stillbirths was evenly distributed between 20 and 40 weeks (1 was 42 weeks) while 74% of the neonatal deaths were term babies. Analyzable metaphases were obtained in 45 stillbirth specimens (46%) and 32 neonatal specimens (84%). Abnormal karyotypes were identified in 7 of the stillbirths (15.5%) and 8 of the neonatal deaths (25%) and all these were from babies with congenital anomalies identified at autopsy. Time delays were crucial to the success of culture from stillbirths, but specimens obtained from neonatal deaths could be grown successfully up to 3 days after death. Generally the placenta was more viable than other tissues, including skin, cartilage and muscle. Whereas growth was obtained in 69% of fresh unexplained stillbirths, no tissue from the macerated stillbirths grew. This is a group which may have a high abnormality rate. We recommend that if fetal assessment during pregnancy suggests a compromised fetus and there are no maternal factors to account for this, an amniocentesis be performed.     

Sickle cell disease in pregnancy: twenty years of experience at Grady Memorial Hospital, Atlanta, Georgia

OBJECTIVE: We compared pregnancy outcomes among women with sickle cell disease with outcomes for African American women without the disease. STUDY DESIGN: We selected 127 deliveries in women with sickle cell disease (hemoglobin SS or hemoglobin SC) that occurred between 1980 and 1999. A control group of 129 deliveries by African American women with normal hemoglobin (hemoglobin AA) was also selected. Evaluated pregnancy outcomes included low birth weight, prematurity, intrauterine growth restriction, antepartum hospital admission, preterm labor or preterm premature rupture of membranes, postpartum infection, preeclampsia, pyelonephritis, intrauterine fetal death, perinatal mortality, and maternal mortality. RESULTS: Compared with deliveries among women with hemoglobin AA, deliveries among women with hemoglobin SS or hemoglobin SC were at increased risk for intrauterine growth restriction, antepartum hospital admission, and postpartum infection. In addition, deliveries among women with Hb SS were more likely to be complicated by low birth weight, prematurity, and preterm labor or preterm premature rupture of membranes when compared with deliveries among women with hemoglobin AA. There were no significant differences among the groups (hemoglobin SS, hemoglobin SC, and hemoglobin AA) in terms of perinatal deaths; there were no maternal deaths in the study population. CONCLUSION: Those caring for women with sickle cell disease should be aware that they are at increased risk for pregnancy complications, although overall pregnancy outcome is favorable.     

Management of pregnancy complications in women of advanced maternal age

The average age of women at childbirth in high resource obstetric settings has been increasing steadily for approximately 30 years. Women aged 35 years or over have an increased risk of gestational hypertensive disease, gestational diabetes, placenta praevia, placental abruption, perinatal death, preterm labour, fetal macrosomia and fetal growth restriction. Unsurprisingly, rates of obstetric intervention are higher among older women. Of particular concern is the increased risk of antepartum stillbirth at term in women of advanced maternal age. In all maternal age groups, the risk of stillbirth is higher among nulliparous women than among multiparous women. Women of advanced maternal age (>40 years) should be given low dose aspirin in the presence of an additional risk factor for pre-eclampsia and offered serial ultrasounds for fetal growth and wellbeing. Given the increased risk of antepartum stillbirth, induction of labour from 39 weeks’ gestation should be discussed with woman.     

Advanced maternal age

The average age of women at childbirth in industrialised nations has been increasing steadily for approximately 30 years. Women aged 35 years or over have an increased risk of gestational hypertensive disease, gestational diabetes, placenta praevia, placental abruption, perinatal death, preterm labour, fetal macrosomia and fetal growth restriction. Unsurprisingly, rates of obstetric intervention are higher among older women. Of particular concern is the increased risk of antepartum stillbirth at term in women of advanced maternal age. In all maternal age groups, the risk of stillbirth is higher among nulliparous women than among multiparous women. Women of advanced maternal age (>40 years) should be given low dose aspirin (in the presence of an additional risk factor for pre-eclampsia) and offered serial ultrasounds for fetal growth and wellbeing; given the increased risk of antepartum stillbirth, induction of labour from 39 weeks’ gestation should be discussed with the woman.     

Fetal growth restriction due to placental disease

Normal fetal growth depends on the genetically predetermined growth potential and its modulation by the health of the fetus, placenta and the mother. Fetuses that are small because of intrauterine growth restriction (IUGR) are at higher risk for poor perinatal and long-term outcome than those who are appropriately grown. Of the many potential underlying processes that may result in IUGR, placental disease is clinically the most relevant. Fetal cardiovascular and behavioral responses to placental insufficiency and the metabolic status are interrelated. The concurrent evaluation of fetal biometry, amniotic fluid volume, heart rate patterns, arterial and venous Doppler, and biophysical variables therefore allow the most comprehensive fetal evaluation in IUGR. In the absence of successful intrauterine therapy, the timing of delivery is perhaps the most critical aspect of the antenatal management. A discussion of the fetal responses to placental insufficiency and a management protocol that accounts for multiple Doppler and biophysical parameters as well as gestational age is provided in this review.     

A combined historic and sonographic score for the detection of intrauterine growth retardation

Sonographic analysis of fetal biometry has been useful in the antepartum detection of intrauterine growth retardation (IUGR). Little attention, however, has been focused upon elements of the maternal and fetal history that may significantly affect the likelihood of IUGR. To define more precisely both the clinical and sonographic parameters associated with IUGR, we studied the following variables: routine fetal biometry (biparietal diameter, head circumference, abdominal circumference, and femur length), fetal weight percentile, amniotic fluid volume, and an antenatal scoring system for IUGR. One hundred one consecutive fetuses with an estimated fetal weight at or below the tenth percentile for gestational age formed the study population. The results of multiple logistic regression analysis indicated that weight percentile was the single most important sonographic parameter in the detection of IUGR. Maternal history and femur length were also found to be important independent predictors of IUGR.     

The risks of spontaneous preterm delivery and perinatal mortality in relation to size at birth according to fetal versus neonatal growth standards

OBJECTIVE: The aim of this study was to test the null hypothesis that size at birth relative to fetal or neonatal growth standards is not a significant variable related to the risk of spontaneous preterm delivery. STUDY DESIGN: This was a hospital-based cohort study of consecutive births at a tertiary care perinatal center from January 1, 1985, to December 31, 1996. A total of 37,377 pregnancies met the following inclusion criteria: (1) singleton gestation, (2) 25 to 40 weeks' gestation, and (3) no anomalies. Neonates were divided into 5 birth weight categories according to either fetal (uncorrected for sex) or neonatal (corrected for sex) growth standards, as follows: (1) intrauterine growth restriction, birth weight <3rd percentile; (2) borderline intrauterine growth restriction, birth weight > or = 3rd percentile and <10th percentile; (3) appropriate for gestational age, birth weight from 10th percentile through 90th percentile; (4) borderline large for gestational age, birth weight >90th percentile but < or = 97th percentile, and (5) large for gestational age, birth weight >97th percentile. Logistic regression analysis was used to estimate the independent effect of birth weight category on the risk of preterm delivery after spontaneous onset of labor, with the appropriate-for-gestational-age group serving as a reference. RESULTS: When fetal growth standards were applied, there was a significant increase in the risk of spontaneous preterm delivery when birth weight was outside the appropriate-for-gestational-age range (odds ratios of 2.5, 1.4, 1.2, and 1.9 for intrauterine growth restriction, borderline intrauterine growth restriction, borderline large-for-gestational age, and large-for-gestational-age groups, respectively). In contrast, when neonatal growth standards were applied, the risks of spontaneous preterm delivery in intrauterine growth restriction, borderline intrauterine growth restriction, and large-for-gestational-age groups were significantly lower (odds ratios of 0.5, 0.7, and 0.7 for intrauterine growth restriction, borderline intrauterine growth restriction, and large-for-gestational-age groups, respectively) because of an underestimation in the number of fetuses with abnormal size at birth delivered prematurely. With both fetal and neonatal growth standards there was a 5-to 6-fold greater risk of perinatal death for both preterm and term fetuses with intrauterine growth restriction. CONCLUSION: Fetal growth standards are more appropriate in predicting the impact of birth weight category on the risk of spontaneous preterm delivery than are neonatal growth standards. When fetal standards are applied, the risks of preterm birth in both extreme abnormal birth weight categories (intrauterine growth restriction and large for gestational age) are 2- to 3-fold greater than the risk among appropriate-for-gestational-age infants.     

Genetic,metabolic and endocrine aspect of intrauterine growth restriction: an update

Intrauterine growth restriction (IUGR) is defined as growth of fetus below its in-utero growth potential. Small for gestational age (SGA) is defined as newborn with birth weight less than 10th centile as per the gestational age, sex and race. There exists major difference between IUGR and SGA. IUGR infants have multiple short-term and long-term complications and IUGR is a silent cause of various morbidities and mortalities in these infants. IUGR/SGA is usually end results of maternal, placental, fetal and genetic causes. With the advance of molecular biology, the list genetic cause of IUGR is increasing and these genetic causes include maternal, placental and fetal genes. Several metabolic and endocrinal causes are also responsible to cause IUGR. In this review, we will try to cover genetic, metabolic and endocrinal factors that are responsible for IUGR.     

Prediction and prevention of the macrosomic fetus

Fetal macrosomia is associated with significant maternal and neonatal morbidity. In the long term, infants who are large for gestational age are more likely than other infants to be obese in childhood, adolescence and early adulthood, and are inherently at higher risk of cardiovascular and metabolic complications in adulthood. With over one billion adults in the world now overweight and more than 600 million clinically obese, preventing the vicious cycle effect of fetal macrosomia and childhood obesity is an increasingly pertinent issue. Fetal growth is determined by a complex interplay of various genetic and environmental influences. Consequently the prediction of pregnancies at risk of pathological overgrowth is difficult. Many risk factors for fetal macrosomia, such as maternal obesity and advanced maternal age, are also conversely associated with intrauterine growth restriction. Sonographic detection of fetal macrosomia is notoriously fraught with difficulties, with dozens of formulas for estimated fetal weight proposed but few with sufficient sensitivity to alter clinical practice. This calls into question policies of elective delivery based on projected estimated fetal weight cut-offs alone. More recently the identification of markers of fetal adiposity and maternal serum biomarkers are being investigated to improve the antenatal detection of the large for gestational age fetus. Prevention of fetal macrosomia is entirely dependent upon correct identification of those at risk. Maternal weight, gestational weight gain and glycaemic control are the risk factors for fetal macrosomia that are most amenable to intervention, and have potential maternal health benefits beyond pregnancy and childbirth. The ideal method of optimising maternal weight and glucose homeostasis is yet to be elucidated, though a number of promising advances are recently being reported. In this review we outline the contemporary evidence for the prediction and prevention of fetal macrosomia, which is indeed a contemporary dilemma.     

Sildenafil citrate therapy for severe early-onset intrauterine growth restriction

Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG 2011;118:624-628. Currently, there is no effective therapy for severe early-onset intrauterine growth restriction (IUGR). Sildenafil citrate vasodilates the myometrial arteries isolated from women with IUGR-complicated pregnancies. Women were offered Sildenafil (25 mg three times daily until delivery) if their pregnancy was complicated by early-onset IUGR [abdominal circumference (AC)< 5th percentile] and either the gestational age was <25(+0) weeks or an estimate of the fetal weight was <600 g (excluding known fetal anomaly/syndrome and/or planned termination). Sildenafil treatment was associated with increased fetal AC growth [odds ratio, 12.9; 95% confidence interval (CI), 1.3, 126; compared with institutional Sildenafil-naive early-onset IUGR controls]. Randomised controlled trial data are required to determine whether Sildenafil improves perinatal outcomes for early-onset IUGR-complicated pregnancies.