CHAPTER III LITERATURE REVIEW

I.

Definition Fetal death or stillbirth is a major obstetrical complication and a devastating

experience for parents and caregivers. For bereaved parents it is among the most stressful life events and it is not seldom that they show acute emotional distress and symptoms of depression. Fleurisca J. Korteweg. 2010 Nomenclature regarding Intra Uterine Fetal Death (IUFD) or stillbirth is still controversial. There is not complete uniformity internationally with regard to birth weight and gestational age criteria for reporting fetal death and perinatal mortality as a whole. ACOG.2007 The World Health Organization defines stillbirth as a death before the complete expulsion or extraction from its mother of a product of conception, irrespective of the duration of pregnancy; the death is indicated by the fact that after such separation, the fetus does not breathe or show any other evidence of life, such as beating of the heart, pulsation of the umbilical cord, or definite movement of voluntary muscles. For the purpose of statistics, however, fetal deaths are defined as pregnancy lost after 20 completed weeks of gestation. If gestational age is unknown, a birth weight of 500 g or more is considered to be a stillbirth.
2010 ACOG.2007 M.N. El-Gharib,

Based on Statistics on perinatal outcome compiled by the Centers for Disease Control and Prevention and the Vital Statistics Reports, IUFD include only those dead fetuses and neonates born at after 19 weeks, or if gestational age is not available, weighing 350 g or more. Cunningham 2010.

However, others advocate the use of 24 weeks or 28 weeks of gestation to define stillbirth. The rationale behind the use of these latter definitions is to focus on fetal deaths after viability outside of the womb and is limited in clinical relevance by changes in the limit of viability over time and according to survival potential in different countries and regions. ACOG.2007

II.

Epidemiology Worldwide an estimate of at least 3.2 million stillbirths occur each year. The

majority of these deaths occur in developing countries. In developed countries approximately 1 in 200 pregnancies ends in stillbirth. Fleurisca J. Korteweg. 2010. The worldwide IUFD rate declined by 14.5% from 22.1 IUFD per 1000 births in 1995 to 18.9 IUFDs per 1000 births in 2009. This rate varies considerably depending on the quality of medical care available in the country in question and the definitions used for classifying fetal deaths. Underreporting in developing nations is common, which makes comparisons even more difficult. In 2009, the estimated global number of IUFD was 2.64 million (uncertainty range, 2.14-3.82 million).
2012. Fleurisca J. Korteweg. 2010 James,

In 2005, data from the National Vital Statistics Report showed a US national average IUFD rate of 6.2 per 1000 births. Approximately 25.000 stillbirths are reported annually. The IUFD rate for the United States has steadily declined since 1985 from 7.8 to 6.2 per 1000 live births.Cunningham, 2010

III.

Etiology and Pathophysiology Cause of IUFD based on Cunningham, 2010 literatur are: Fetal Factor (25 to

40) percent, Placental (25 to 35) percent, Maternal (5 to 10) percent, and Unexplained (15 to 35) percent.Cunningham, 2010

Eiology of IUFD, can be classified into 3 factors based on the origin of disease, that are fetal cause, placental cause, and maternal cause. a. Fetal Causes ( 25 40%) Genetic anomalies may not only affect the development of the fetus, but the placenta as well. One recent study found an increase in apoptosis and a decrease in cell proliferation in chromosomally abnormal placentae compared to chromosomally normal placentae of spontaneous abortion specimens, which suggests that genetic abnormalities can lead to changes that affect trophoblast development and proliferation.Korteweg, 2007 Research found that a third of fetal deaths were caused by structural anomalies. Neural-tube defects, hydrops, isolated hydrocephalus, and complex congenital heart disease were the most common. Major structural anomalies, hydrops, and aneuploidy are particularly amenable to antenatal diagnosis.Cunningham, 2010 IUFD caused by fetal infection are also common, especially when ascending bacterial infections of amnionic fluid and placental sources are considered. In indigent and inner-city women, congenital syphilis can be a common cause of fetal death. Infection is a significant risk for the fetus. Ascending bacterial infections (where bacteria migrate from the vagina through the cervix into the amniotic cavity) trigger a cytokine cascade that ultimately leads to fetal damage, preterm delivery, and in severe cases, intrauterine fetal demise (IUFD). Korteweg, 2007 Other potentially lethal infections include those caused by

cytomegalovirus and parvovirus B19 which is found in 50-70 percent adults and is often asymptomatic in this population, in pregnancy is associated with fetal anemia, fetal hydrops, spontaneous abortion and IUFD. As well as rubella, varicella, listeriosis, borreliosis, toxoplasmosis, and many more.Cunningham,
;Korteweg, 2007 2010

Based On a case control Study about Factors Associated with Intrauterine Fetal Deaths in Nottingham, United Kingdom on 2004, describe about the fetal Characteristics below:Sawas, 2004 Table 2.Fetal Characteristics of IUFDSawas, 2004
Characteristic Missing Values (%) 5 (0.8%) IUFD Live Births 3.4 (0.86 4.88) 40 (27.6 43) 40 (0100) 70 (14.7%) 65 (13.6%) 50 (10.6%) 57 (12%) 44 (9.3%) 43 (9%) 29 (6.2%) 38 (7.9%) 43 (9%) 37 (7.7%) 247 (49.9%) P Value Odds Ratio 95% Confidence Interval

Median birth weight in kg (range) Median gestational age (range) Median customized birth weight percentile (range) 0th10th percentile 11th20th percentile 21st30th percentile 31st40th percentile 41st50th percentile 51st60th percentile 61st70th percentile 71st80th percentile 81st90th percentile 91st100th percentile Fetal sex (male)

2.06 (0.11 5.3) 35 (2443) 12 (0100) 78 (48.4%) 15 (9.3%) 18 (11.2%) 12 (7.4%) 6 (3.7%) 8 (5%) 2 (1.2%)

< .0001

4 (0.6%)

< .0001

23 (3.5%)

< .0001 2.610.7 0.52.5 0.83.9 1.0 0.221.7 0.32.7 0.071.56 0.372.7 0.372.68 0.181.69 0.992.03

< .0001 .83 .20 1.0 .42 .80 .15

5.3 1.1 1.71 1.0 0.65 0.88 0.33

8 (5%) 5 (3.2%) 9 (5.6%) 6 (0.9%) 93 (58.5%)

1.0 .23 .76 .059

1.0 0.55 0.16 1.41

b. Placental Causes (25 35%) Placental abruption is the most common single identifiable cause of fetal death. Research proved that abruption is the cause of death in 14 percent of stillborns. At Parkland Hospital, approximately 10 percent of third-trimester IUFDs are from abruption.Cunningham, 2010

Significant placental and membrane infection is usually associated with fetal infection. Exceptions include tuberculosis and malaria. In some cases, microscopic examination of the placenta and membranes may help to identify an infectious cause.Cunningham, 2010 Cause of death is explained by a placental pathological abnormality supported by the clinical findings 1. Placental bed pathology. Inadequate spiral artery remodeling and/or spiral artery pathology is leading to uteroplacental vascular insufficiency such as placental infarction and abruption.Korteweg, 2007 The major pathologic processes observable in the placenta that can adversely affect pregnancy outcome include intrauterine bacterial infections, decreased blood flow to the placenta from the mother and immunologic attack of the placenta by the mothers immune system.Harvey, 2000 2. Placental pathology. Placental pathology originated during development of the placenta itself, abnormalities in the parenchyma or localisation of the placenta.Korteweg, 2007 Development. Morphologic abnormalities arise because of abnormal developmental processes. Examples: placenta circumvallata, vasa praevia, villus immaturity, and placenta hypoplasia.Korteweg, 2007 Marginal insertions only occur 5 to 7 percent of the time, but may be more prone to vessel rupture or compression, thereby resulting in fetal death.Velamentous insertion, which occurs in about 1 percent of singleton births, is the insertion of the umbilical cord vessels into the external membranes prior to their penetration into the placenta. These vessels are not surrounded by the protective Whartons and are therefore susceptible to folding, torsion rupture and exposure to inflammation if they traverse the internal cervical os.Harvey, 2000 Parenchyma. Acquired placenta parenchyma disorders of the villi or intervillous space. \Korteweg, 2007

Abnormal localisation. Examples: placenta praevia.Korteweg, 2007

3. Umbilical cord complication. If the knot is loose and fetal circulation is maintained the fetus can survive, but if the knot is tightened, then there can be constriction of the blood vessels and fetal circulation can not be maintained. Korteweg, 2007 ; Harvey, 2000

c. Maternal Causes (5 10%) Some pathologies with a strong maternal componentfor example, placental abruption or isoimmunizationoften are attributed to placental or fetal causes. Hypertensive disorders and diabetes are the two most commonly cited maternal diseases and are associated with 5 to 8 percent of IUFD. Extremes of reproductive ageeven when adjusted for known associations such as anomalies and maternal medical disordersare complicated by a higher fetal death rate. In developing countries, and intuitively so in developed nations, the IUFD rate may be increased manyfold with severe maternal morbidities Cunningham, 2010 Lupus anticoagulant and anticardiolipin antibodies are associated with decidualvasculopathy, placental infarction, fetal-growth restriction, recurrent abortion, and fetal death. Although women with these autoantibodies and other thrombophilias clearly are at increased risk for adverse pregnancy outcomes, very few otherwise unexplained IUFD can be attributed solely to such antibodies.Cunningham, 2010 Based On a case control Study about Factors Associated with Intrauterine Fetal DeathsIn City Hospital, Nottingham, United Kingdom on 2004, describe about the maternal Characteristics below.Sawas, 2004 Table 3 Maternal Characteristics of IUFDSawas, 2004
Characteristic Maternal age Median (range) Body mass index Mean (range) Missing Values IUFD 29 (1644) 25 (1956) Live Births 27 (1542) 24 (1744) P Value .001 < .001 Odds Ratio 95% Confidence Interval

Smoking in pregnancy (%) Blood group (%) B or AB A O Rhesus D positive Parity (%) 0 1

61 33 (5%)

30 (27%)

130 (26.6%) 64 (13.6%) 207 (44%) 201 (42.4%) 393 (83.3%) .58 219 (44.3%) 167 (33.8%) 65 (13.2%) 32 (6.5%) 11 (2.2%) 464 (93%) 14 (2.8%) 7 (1.4%) 10 (2%)

.933 .009 1.0 .29 .014 .44

1.02

0.641.6

12 (7%) 56 (36.1%) 87 (56.1%) 124 (80.5%) 76 (48.1%) 51 (32.3%) 15 (9.5%) 10 (6.3%) 6 (3.8%) 6 (0.9%) 143 (89%) 8 (5%) 6 (3.7%) 2 (1.2%)

1.0 1.44 2.31

1 0.732.85 1.184.49 0.751.9

34 (5.2%) 8 (1.2%)

1.0 .54

1.0 0.88

1 0.581.32 0.361.23 0.421.92 0.564.4 1 0.928.4 0.764.5 0.651.4

2 3 4 or more Race (%) Caucasian Indian/Pakistani West Indian Other

.12 .79 .39 .15 1.0 .07 .17 .58

0.67 0.9 1.56 1.0 2.8 1.9 0.65

Diabetes is often the cause of complications during pregnancy for the fetus as well as the mother which the rate of fetal death occurring between 20 and 28 weeks increases 2.5 fold in women with Type 2 diabetes.Harvey, 2000 Prepregnancy body mass index more than 25.0 has been studied in correlation with poor pregnancy outcome which is related with higher rate of hypertensive disorders.Harvey, 2000

Based on Institute of Obstetricians and Gynaecologists Royal College of Physicians of Ireland and Directorate of strategy and Clinical Programmes, Health Service Executive October 2011. The Causes of IUFD describe below:Royal College, 2011 Table 1. The Causes of IUFD Royal College, 2011

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Definition of Terms MAJOR CONGENITAL ANOMALY: Any genetic or structural defect arising at conception or during embryogenesis incompatible with life or potentially treatable but causing death

Subcategory Central Nervous system Cardiovascular system Respiratory system Gastrointestinal system Musculoskletal anomalies Multiple anomalies Chromosomal disorders Metabolic diseases Urinary tract Other Pregnancy induced hypertension Preeclampsia HELLP Syndrome Eclampsia

2.

HYPERTENSIVE DISORDERS OF PREGNANCY

3.

ANTEPARTUM OR INTRAPARTUM HAEMORRHAGE. After 20 weeks gestasion whether revealed or not. If associated with PET, APH, will be a secondary diagnosis. Ignor minor degrees of haemorrhage (e.g Shows cervical polyp, etc). Reccurent bleeding of uncertain origin followed by preterm labour should not be ignored MECHANICAL. Any death attributed to uterine ruptured, death from the birth trauma or intrapartum asphyxia associated with problems in labour such as cord compression, malpresentasion, shoulder dystosia, etc Antepartum deaths associated with cord enlargement in the absence of strong circumstansial evidence that cord compression caused death should be classified as having no associated factor MATERNAL DISORDER. Specify hypertensive disease present before pregnancy or any other maternal disease or condition sufficient to jeopardise the baby such as diabetes, cardiac disease etc Infection is classified separately

Praevia Abruption Uncertain

Cord Compression Prolapse cord Cord around neck Other cord enlargement or knot Uterine rupture Before Labour During Labour Malpresentation Breech / Transverse Face / Compound Other Shoulder dystosia Pre existing hypertensive disease Diabetes Other endocrine conditions Thromphilias Obstetric Cholestasis Drug Misuse Uterine anomalies Connective tissue disorders / Other Maternal Infection Bacterial / viral diseases

INFECTION. Confirmed by Microbiology / placental history.

Specify maternal infections sufficient to have compromised the baby which may be associated with congenital infection of the baby. Transplacental transmission may have occurred such as CMV, Toxoplasmosis, etc Specify only those ascending infections that are a significant factor in death. Chorioamnionitis sufficient to cause preterm birth may be specified for some neonates but evidence of fetal infection may be required as an explanation of IUFD 7 SPECIFIC FETAL CONDITIONS. Document only those specific conditions arising in the fetal period

Syphilis / Group B streptococcus Protozoa Other Ascending infection Chorioamnionitis Other

Twin-twin transfusion Fetomaternal hemorrhage Non immune hydrops Isoimmunisation Other Placental infarction Retroplacentalhaemorrhage Thrombosis in fetal circulation Chorioamnionitis Vilitis Fetal vasculitis Massive perivillous fibrin deposition Vasa praevia / Velamentous insertion Other Suspected antenatally Observed at delivery Observed at post mortem

SPECIFIC PLACENTAL CONDITIONS. Specific Placental Conditions sufficient to cause death or be associated with fetal compromise such as IUGR. These will often be secondary to other maternal conditions e.g PET Cord problembs associated with compression will normally be classified under Mechanical

INTRAUTERINE GROWTH RESTRICTION DIAGNOSIS MADE. IUGR May be suspected antenatally by abdominal circumference (AC) less than the centile threshold used to define IUGR locally, or decreased AC growth velocity, +/- oligohydramnios ASSOCIATED OBSTETRIC FACTORS Factors recforded as other Associated Obstetric Factors will be important clinical or pathological features of the pregnancy or baby but will not be an explanation of the death; they will often be secondary to other maternal or fetal conditions. Birth trauma and/or intrapartum asphyxia should normally be classified primarily by the underlying cause (e.g Mechanical). Birth trauma and/or other antenatal/intrapartum factors can be recorded here either as a secondary factor or when there is no underlying explanation

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Birth Trauma Intracranial haemorrhage Birth injury to scalp Fracture Other Intrapartum fetal blood sampel< 7.25 Other Polyhidramnios Oligohydramnios Premature ruptures of membranes Spontaneous premature labour Other

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NO ANTECEDENT OR ASSOCIATED OBSTETRIC FACTORS.

Death with no explanation or significant associated labour

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UNCLASSIFIED Cases where little or nothing is known about pregnancy or delivery and which cannot be fitted into any of the above categories. Use as sparingly as possible

IV.

Diagnosis Fetal death may be associated with a cessation of previously perceived fetal

movements or a decrease in pregnancy-related symptoms such as nausea. The absence of fetal heart sounds remains the mainstay of clinical diagnosis supported by lack of fetal movements and regression of uterine size and reported lack of fetal movement by the mother may be unreliable. In some cases, women will present with bleeding, cramping, or labor. However, many patients with fetal death have no bleeding or contractions, and fetal death may precede clinical symptoms by a variable and often extended period of time. ACOG.2007 A definitive diagnosis is made by real-time ultrasonography confirming the presence of a fetus and the absence of fetal heart pulsations. US diagnosis of death is recognized by an absent fetal heart pulsation, skull collapse and retraction of brain tissue. ACOG.2007.
Malik, 2012

Clinical assessment and laboratory tests should be recommended to assess maternal wellbeing and to determine the cause of death, the chance of recurrence and possible means of avoiding further pregnancy complications. Even identification of a sporadic cause can bring emotional closure and facilitate parental recovery.Royal College,
2011

At the time of diagnosis Maternal and family history Ultrasound scan +/- Amniocentesis

After delivery External examination Infant blood tests

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Maternal blood tests Maternal toxicology Maternal microbiology

Infant microbiology Placenta, membrane and histopathology Cytogenetic investigations Postmortem examination Postmortem Radiological imaging

cord

V.

Delivery of the Fetus

Most women prefer to proceed with delivery of the fetus after diagnosis of fetal death. It is emotionally stressful to carry a nonviable fetus, especially late in gestation. Nonetheless, there is no medical urgency to effect delivery and for some women a delay is emo-tionally desirable. For example, some women prefer to grieve with their families and do not feel up to a medical procedure immediately after diagnosis. Other couples may even prefer prolonged expectant management, usually prompted by a desire to avoid induction of labor. It is important to offer both the options of delivery and expectant management to women experiencing fetal death. Risks of expectant management include intrauter-ine infection and maternal coagulopathy. These risks are poorly characterized due to the relative infre-quency of expectant management. Older reports state that 8090% of women will spontaneously labor within two weeks of fetal death.32 However, this latency period may be substantially longer. It seems prudent to perform surveillance for infection and coagulopathy in women undergoing expectant care. Examples include serial assessment of maternal temperature, abdominal pain, bleeding, and labor. Reg-ular office visits (eg, weekly) may be useful for emo-tional support and medical surveillance. Some authorities advise serial (eg, weekly) determination of complete blood count, platelet count, and fibrinogen level. The usefulness of this is uncertain. A consumptive coagulopathy has been reported in 25% of pa-tients who retain a dead fetus for more than 4 weeks, but the condition is

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rare in clinical practice and is not usually associated with clinical sequelae. A fibrinogen level of less than 100 mg/dL is considered evidence of coagulopathy. Patients should be advised to immediately report symptoms such as fever, pain, bleeding, contractions, leaking fluid, or foul discharge. Depending upon gestational age, evacuation of the uterus may be accomplished medically or surgically. Ideally, the choice of delivery method should be made by the parents based on personal preference. Some women prefer surgical evacuation of the uterus because the procedure is rapid and they may receive a general anesthetic. Others choose induction of labor so that they may experience labor and deliver an intact fetus. In experienced hands, dilation and evacuation in the early second trimester is as safe as medical induction of labor. This procedure becomes technically more difficult in the later second and third trimesters. At more advanced gestational ages, labor induction is safer and dilation and evacuation should be reserved for physicians with more extensive experience and skills in this procedure. Induction of labor has been greatly aided by the availability of prostaglandin preparations. There is considerable experience with the use of prostaglandin E2 (PGE2) to induce labor in women with fetal demise. During the past decade, misoprostol has largely replaced PGE2 for induction of labor in cases of fetal death due to similar efficacy with fewer side effects.

Adverse effects of prostaglandins include fever, nausea, eme-sis, and diarrhea, particularly if a PGE2 preparation is used. Pretreatment with antiemetics, antipyretics, and antidiarrheals may reduce symptoms. Misoprostol may be administered orally as a lozenge or vaginally in the posterior fornix. Dosing of misoprostol is influenced by the size of the uterus and several approaches have been published. If the uterus is less than 28 weeks size, our approach is to place 200mg of misoprostol in the posterior fornix every 4 hours until delivery of the fetus and placenta. The dose could be increased to 400 mg every 2 hours, but delivery is not hastened compared with 200 mg every 4 hours. The oral dose (taken as a lozenge) is 200400 mg every 24 hours. The interval to delivery is less when the drug is administered vaginally compared with orally, but some women may prefer to take the drug by mouth. If the uterus is greater than 28 weeks size, we administer an

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initial dose of 25 mg of misoprostol in the posterior fornix, followed by 2550 mg every 4 hours. Alterna-tively, it may be given orally at a dosage of 25 mg every 4 hours. Prostaglandin E2should not be used in women with active cardiac, pulmonary or renal disease, and glaucoma. All prostaglandins for medical induction of labor should be avoided in cases of prior cesarean if uterine size is greater than 26 weeks of gestation at the time of induction. In such cases we use oxytocin (low dose if the cervix is unfavorable). Risks of uterine rupture must be weighed against the desire to avoid hysterotomy in women with fetal death. Although uter-ine rupturemay occur, misoprostol has been used safely for second trimester induction of labor in women with prior cesarean delivery.

In cases of fetal death in the second trimester, especially at less than 20 weeks of gestation, there is an increased risk for retained placenta. Allowing the placenta to deliver spontaneously without pulling on the umbilical cord can greatly reduce this risk. Additional doses of misoprostol may be administered (at appropriate intervals) to promote uterine contractility between delivery of the fetus and placenta. The use of misoprostol may reduce the incidence of retained placenta to less than 5%, which seems to be lower than seen with oxytocin or PGE

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