• Managing the remaining weeks of the pregnancy
• Determining the outcome of the pregnancy
• Planning for possible complications with the birth process
• Planning for problems that may occur in the newborn infant
• Deciding whether to continue the pregnancy
• Finding conditions that may affect future pregnancies

There are a variety of non-invasive and invasive techniques available for prenatal diagnosis. Each of them can be applied only during specific time periods during the pregnancy for greatest utility. The techniques employed for prenatal diagnosis include:

• Ultrasonography
• Amniocentesis
• Chorionic villus sampling
• Fetal blood cells in maternal blood
• Maternal serum alpha-fetoprotein
• Maternal serum beta-HCG
• Maternal serum unconjugated estriol
• Pregnancy-associated plasma protein A
• Inhibin A

Ultrasonography

This is a non-invasive procedure that is harmless to both the fetus and the mother. High frequency sound waves are utilized to produce visible images from the pattern of the echos made by different tissues and organs, including the baby in the amniotic cavity. The developing embryo can first be visualized at about 6 weeks gestation. Recognition of the major internal organs and extremities to determine if any are abnormal can best be accomplished between 16 to 20 weeks gestation.

Although an ultrasound examination can be quite useful to determine the size and position of the fetus, the size and position of the placenta, the amount of amniotic fluid, and the appearance of fetal anatomy, there are limitations to this procedure. Subtle abnormalities may not be detected until later in pregnancy, or may not be detected at all. A good example of this is Down syndrome (trisomy 21) where the morphologic abnormalities are often not marked, but only subtle, such as increased nuchal translucency (the subcutaneous space between skin surface and underlying cervical spine).

Amniocentesis

This is an invasive procedure in which a needle is passed through the mother’s lower abdomen into the amniotic cavity inside the uterus. Enough amniotic fluid is present for this to be accomplished starting about 14 weeks gestation. For prenatal diagnosis, most amniocenteses are performed between 14 and 20 weeks gestation. However, an ultrasound examination always proceeds amniocentesis in order to determine gestational age, the position of the fetus and placenta, and determine if enough amniotic fluid is present. Within the amniotic fluid are fetal cells (mostly derived from fetal skin) which can be\ grown in culture for chromosome analysis, biochemical analysis, and molecular biologic analysis.

In the third trimester of pregnancy, the amniotic fluid can be analyzed for determination of fetal lung maturity. This is important when the fetus is below 35 to 36 weeks gestation, because the lungs may not be mature enough to sustain life following birth. This is because the lungs are not producing enough surfactant. After birth, the infant could develop respiratory distress syndrome from hyaline membrane disease. The amniotic fluid can be analyzed by looking for an appropriate number of lamellar bodies. Other tests for fetal lung maturity include: fluorescence polarization (fpol), lecithin:sphingomyelin (LS) ratio, and for phosphatidyl glycerol (PG). These tests have poor positive predictive value for respiratory distress, so the decision to do amniocentesis can be made by consideration of issues around gestational age and urgency of delivery.

Risks with amniocentesis are uncommon, but include fetal loss and maternal Rh sensitization. The increased risk for fetal mortality following amniocentesis is about 0.5% above what would normally be expected. Rh negative mothers can be treated with RhoGam. Contamination of fluid from amniocentesis by maternal cells is highly unlikely. If oligohydramnios is present, then amniotic fluid is difficulk to obtain. It is sometimes possible to instill saline into the amniotic cavity and then remove fluid for analysis.

Chorionic Villus Sampling (CVS)

In this procedure, a catheter is passed via the vagina through the cervix and into the uterus to the developing placenta under ultrasound guidance. An alternative approach is transabdominal. The introduction of the catheter allows sampling of cells from the placental chorionic villi. These cells can then be analyzed by a variety of techniques. The most common test employed on cells obtained by CVS is chromosome analysis to determine the karyotype of the fetus. The cells can also be grown in culture for biochemical or molecular biologic analysis. CVS can be safely performed between 9.5 and 12.5 weeks gestation.

CVS has the disadvantage of being an invasive procedure, and it has a small but significant rate of morbidity for the fetus; this loss rate is about 0.5 to 1% higher than for women undergoing amniocentesis. Rarely, CVS can be associated with limb defects in the fetus. The possibility of maternal Rh sensitization is present. There is also the possibility that maternal blood cells in the developing placenta will be sampled instead of fetal cells and confound chromosome analysis.

Maternal blood sampling for fetal DNA

This technique makes use of the phenomenon of fetal blood cells gaining access to maternal circulation through the placental villi. Ordinarily, only a very small number of fetal cells or cell free DNA enter the maternal circulation in this fashion (not enough to produce a positive Kleihauer-Betke test for fetal-maternal hemorrhage). The sequencing of maternal plasma cell-free DNA (cfDNA testing) can detect fetal autosomal aneuploidy, but without the risks that invasive procedures inherently have. Fluorescence in-situ hybridization (FISH) is another technique that can be applied to identify particular chromosomes of the fetal cells recovered from maternal blood and diagnose aneuploid conditions such as the trisomies and monosomy X. The problem with this technique is that it is difficult to get large amounts of fetal DNA. There may not be enough to reliably determine anomalies of the fetal karyotype or assay for other abnormalities.

Maternal serum alpha-fetoprotein (MSAFP)

The developing fetus has two major blood proteins–albumin and alpha-fetoprotein (AFP). Since adults typically have only albumin in their blood, the MSAFP test can be utilized to determine the levels of AFP from the fetus. Ordinarily, only a small amount of AFP gains access to the amniotic fluid and crosses the placenta to maternal blood. However, when there is a fetal defect in the body wall, such as a neural tube defect from failure of part of the embryologic neural tube to close, then there is a means for escape of more AFP into the amniotic fluid. Neural tube defects include anencephaly (failure of closure at the cranial end of the neural tube) and spina bifida (failure of closure at the caudal end of the neural tube). The incidence of such defects is less than 1 per 1000 in the United States. Also, if there is an omphalocele or gastroschisis (both are defects in the fetal abdominal wall), the MSAFP will be higher.

In order for the MSAFP test to have the greatest utility, the gestational age must be known with certainty. This is because the amount of MSAFP increasses with gestational age (as the fetal liver size and the amount of AFP produced increase). Also, the race of the mother and presence of gestational diabetes are important to know, because the MSAFP can be affected by these factors. The MSAFP is typically reported as multiples of the median (MoM). The greater the MoM, the more likely a defect is present. The MSAFP has the greatest sensitivity between 16 and 18 weeks gestation, but can still be useful between 15 and 22 weeks gestation.

However, the MSAFP can be elevated for a variety of reasons which are not related to fetal neural tube or abdominal wall defects, so this test is not 100% specific. The most common cause for an elevated MSAFP is a wrong estimation of the gestational age of the fetus.

Using a combination of MSAFP screening and ultrasonography, almost all cases of anencephaly can be found, and most cases of spina bifida. Neural tube defects can be distinguished from other fetal defects (such as abdominal wall defects) by use of the acetylcholinesterase test performed on amniotic fluid obtained by amniocentesis–if the acetylcholinesterase is elevated along with MSAFP then a neural tube defect is likely. If the acetylcholinesterase is not detectable, then some other fetal defect is suggested.

NOTE: Prevention of many neural tube defects can be accomplished by supplementation of the maternal diet with just 4 mg of folic acid per day, but this vitamin supplement must be taken a month before conception and through the first trimester.

The MSAFP can also be useful in screening for Down syndrome and other trisomies. The MSAFP tends to be lower when triosmy 21 or other chromosomal abnormalities is present.

Maternal serum beta-HCG

This test is most commonly used as a test for pregnancy. Beginning about a week following conception and implantation of the developing embryo into the uterus, the trophoblast will produce enough detectable beta-HCG (the beta subunit of human chorionic gonadotropin) to diagnose pregnancy. Thus, by the time the first menstrual period is missed, the beta-HCG will virtually always be elevated enough in maternal urine to provide a positive pregnancy test. The beta-HCG can also be quantified in serum from maternal blood, and this can be useful early in pregnancy when threatened abortion or ectopic pregnancy is suspected, because the amount of beta-HCG will be lower than expected.

Later in pregnancy, in the middle to late second trimester, the beta-HCG can be used in conjunction with the MSAFP to screen for chromosomal abnormalities, and Down syndrome in particular. An elevated beta-HCG coupled with a decreased MSAFP suggests Down syndrome.

Very high levels of HCG suggest trophoblastic disease (molar pregnancy). The absence of a fetus on ultrasonography along with an elevated HCG suggests a hydatidiform mole. The HCG level can be used to follow up treatment for molar pregnancy to make sure that no trophoblastic disease, such as a choriocarcinoma, persists.

Maternal serum unconjugated estriol

The amount of unconjugated estriol in maternal serum is dependent upon a viable fetus, a properly functioning placenta, and maternal well-being. The substrate for estriol begins as dehydroepiandrosterone (DHEA) produced in the fetus. This is further metabolized in the placenta to estriol. The estriol crosses to the maternal circulation and is excreted by the maternal kidney in urine or by the maternal liver in the bile. The measurement of serial estriol levels in the third trimester will give an indication of general well-being of the fetus. If the estriol level drops, then the fetus is threatened and delivery may be necessary emergently. Estriol tends to be lower when Down syndrome is present or when there is adrenal hypoplasia with anencephaly.

Inhibin-A

Dimeric inhibin-A is secreted by the placenta and by the maternal ovarian corpus luteum. Dimeric inhibin-A can be measured in maternal serum. An increased level of inhibin-A is associated with an increased risk for trisomy 21. A high inhibin-A may also be associated with risk for preterm delivery.

Pregnancy-associated plasma protein A (PAPP-A)

Low levels of PAPP-A as measured in maternal serum during the first trimester may be associated with fetal chromosomal anomalies including trisomies 13, 18, and 21. In addition, low PAPP-A levels in the first trimester may predict an adverse pregnancy outcome, including a small for gestational age (SGA) baby or stillbirth. A high PAPP-A level may predict a large for gestational age (LGA) baby.

“Triple” or “Quadruple” screen

Combining the maternal serum assays may aid in increasing the sensitivity and specificity of detection for fetal abnormalities. The classic test is the “triple screen” for alpha-fetoprotein (MSAFP), beta-HCG, and estriol (uE3). The “quadruple screen” adds inhibin-A.

Approach to diagnosis of trisomy 21 can be based upon timing. In the first-trimester combined screening with measurement of nuchal translucency, PAPP-A, and beta-HCG has a high diagnostic yield. Second-trimester quadruple screening with measurement of AFP, beta-HCG, unconjugated estriol, and inhibin A has a high diagnostic yield. Both can be combined to provide high rates of detection of trisomy 21. The detection rate of trisomy 21 for the “triple screen” is about 70%, and for the “quad screen” about 80%, with false positive rates of 7% and 6% respectively. Combining the “quad screen” from the second trimester with results of PAPP-A and NT from the first trimester yields a Down syndrome detection rate of 90%, with 3% false positive rate. Without the NT test, combination of the 5 serum tests yields a detection rate for trisomy 21 of 87% with 3.2% false positive rate.

Note: the levels of these analytes may change markedly during pregnancy, so interpretation of the measurements depends greatly upon knowing the proper gestational age. Otherwise, results can be misinterpreted. Rather than absolute values, the test results are typically reported as “multiples of the median” or MoM to adjust for the effect of gestational age, as well as maternal weight and race if applicable.

Techniques for Pathologic Examination

A variety of methods can be employed for analysis of fetal and placental tissues:

Gross Examination

The most important procedure to perform is simply to look at the fetus or fetal parts. Obviously, examination of an intact fetus is most useful, though information can still be gained from examination of fetal parts.

The pattern of gross abnormalities can often suggest a possible chromosomal abnormality or a syndrome. Abnormalities can often be quite subtle, particularly the earlier the gestational age.

Consultations are obtained with clinical geneticists to review the findings. A description of the findings is put into a report (surgical pathology or autopsy).

Examination of the placenta is very important, because the reason for the fetal loss may be a placental problem.

Microscopic Examination

Microscopic findings are generally less useful than gross examination for the fetus, but microscopic examination of the placenta is important. Microscopy can aid in determination of gestational age (lung, kidney maturity), presence of infection, presence of neoplasia, or presence of “dysplasia” (abnormal organogenesis).

Radiography

Standard anterior-posterior and lateral radiographic views are essential for analysis of the fetal skeleton. Radiographs are useful for comparison with prenatal ultrasound, and help define anomalies when autopsy consent is limited, or can help to determine sites to be examined microscopically. Conditions diagnosed by postmortem radiography may include:

• Skeletal anomalies (dwarfism, dysplasia, sirenomelia, etc.)
• Neural tube defects (anencephaly, iniencephaly, spina bifida, etc.)
• Osteogenesis imperfecta (osteopenia, fractures)
• Soft tissue changes (hydrops, hygroma, etc.)
• Teratomas or other neoplasms
• Growth retardation
• Orientation and audit of fetal parts (with D&E specimens)
• Assessment of catheter or therapeutic device placement

Microbiologic Culture

Culture can aid in diagnosis or confirmation of congenital infections. Examples of congenital infection include:

T – toxoplasmosis

O – other, such as Listeria monocytogenes, group B Streptococcus, syphilis

R – rubella

C – cytomegalovirus

H – herpes simplex or human immunodeficiency virus (HIV)

For many of these infections, serologic testing is available and can be performed on maternal serum. Many of them can be assayed for both IgM antibodies (suggesting recent infection that may affect the fetus) and IgG antibodies (suggesting past infection. Higher titers suggest a greater likelihood for potential fetal involvement.

Cultures for agents such as E. coli or group B streptococcus have to be appropriately obtained with the proper media and sent with the proper requisitions (“routine” includes aerobic and anaerobic bacteria; fungal and viral cultures must be separately ordered).

Viral cultures are difficult and expensive. Separate media and collection procedures may be necessary depending upon what virus is being sought.

Bacterial contamination can be a problem.

Karyotyping

Tissues must be obtained as fresh as possible for culture and without contamination.

A useful procedure is to wash the postmortem tissue samples in sterile saline prior to placing them into cell culture media.

Tissues with the best chance for growth are those with the least maceration: placenta, lung, diaphragm.

Obtaining tissue from more than one site can increase the yield by avoiding contamination or by detection of mosaicism.

FISH (performed on fresh tissue or paraffin blocks)

In addition to karyotyping, fluorescence in situ hybridization (FISH) can be useful. A wide variety of probes are available. It is useful for detecting aneuploid conditions (trisomies, monosomies).

Fresh cells are desirable, but the method can be applied even to fixed tissues stored in paraffin blocks, though working with paraffin blocks is much more time consuming and interpretation can be difficult. The ability to use FISH on paraffin blocks means that archival tissues can be examined in cases where karyotyping was not performed, or cells didn’t grow in culture.

• FISH technique, diagram
• FISH abnormalities, diagram

DNA Probes

Fetal cells obtained via amniocentesis or CVS can be analyzed for DNA sequences. In some cases, if the DNA sequence of a gene is known, a probe to a DNA sequence specific for a genetic marker is available, and the polymerase chain reaction (PCR) technique can be applied for diagnosis.

There are many kinds of birth defects, but only in a minority have particular genes been identified, and tests to detect them have been developed in some. Thus, it is not possible to detect a specific genetic abnormality for all birth defects. Moreover, testing is confounded by possible presence of different mutations in the same gene, making testing more complex.

Biochemical Analysis

Tissues can be obtained for cell culture or for extraction of compounds that can aid in identification of inborn errors of metabolism. Examples include:

• long-chain fatty acids (adrenoleukodystrophy)
• amino acids (aminoacidurias)

Flow Cytometry

Flow cytometry is useful only for determination of the amount of DNA and can yield no information about individual chromosomes with aneuploidy. Thus, the condition that flow cytometry can routinely detect is triploidy.

Very little sample (0.1 gm) is required. The technique can also be applied to fixed tissues in paraffin blocks.

Electron Microscopy (EM)

EM isarely used and requires prompt fixation with no maceration. Examples of conditions to be diagnosed with EM include:

• mitochondrial myopathies
• viral infections

Overview of Fetal-Placental Abnormalities

Chromosomal Abnormalities

The risk for chromosomal abnormalities increases with increasing maternal age, mainly because non-dysjunctional events in meiosis are more likely, and result in trisomies. The table below indicates the relative risk of having a baby with various trisomies based upon maternal age:

Maternal Age	Trisomy 21	Trisomy 18	Trisomy 13
15 – 19	1:1600	1:17000	1:33000
20 – 24	1:1400	1:14000	1:25000
25 – 29	1:1100	1:11000	1:20000
30 – 34	1:700	1:7100	1:14000
35 – 39	1:240	1:2400	1:4800
40 – 44	1:70	1:700	1:1600
45 – 49	1:20	1:650	1:1500

Listed below are some of the more common chromosomal abnormalities that can occur. The descriptions are for the completely abnormal condition in which all fetal cells contain the abnormal karyotype.

Bear in mind that “mosaicism” can occur. A “mosaic” is a person with a combination of two cell lines with different karyotypes (normal and abnormal). When karyotyping is performed, multiple cells are analyzed to rule out this possibility. An example would be a Turner’s mosaic, with a 45,X/46,XX karyotype, with some cells having the abnormal karyotype and some cells having a normal karyotype. The mosaic condition is not as severe as the completely abnormal karyotype, and the features may not be as marked, and livebirths may be possible. Sometimes the mosaicism is confined to the placenta (“confined placental mosaicism”).

A placenta with an abnormal karyotype (confined placental mosaicism) may lead to stillbirth, even though the fetus has a normal karyotype; conversely, a placenta with a normal karyotype may allow longer survival for a fetus with a chromosomal abnormality. Rarely, a translocation of part of one chromosome to another in the parent will be passed on to the child as a partial trisomy (such as 6p+ or 16p+) which may not be as severe as a complete trisomy.

Trisomy 21: Down syndrome; incidence based upon maternal age, though translocation type is familial; features can include: epicanthal folds, simian crease, brachycephaly, cardiac defects.

• Trisomy 21 (47, XY, +21) karyotype, diagram
• Trisomy 21, facial features, gross
• Trisomy 21, abnormal creases, hands, gross
• Trisomy syndrome, cystic Hassall’s corpuscles in thymus, medium power microscopic

Trisomy 18: Features include micrognathia, overlapping fingers, horseshoe kidney, rocker bottom feet, cardiac defects, diapragmatic hernia, omphalocele.

• Trisomy 18 (47, XY, +18) karyotype, diagram
• Clenched hand with trisomy 18, gross
• Diaphragmatic hernia, gross

Trisomy 13: Features include microcephaly, cleft lip and/or palate, polydactyly, cardiac defects, holoprosencephaly.

• Trisomy 18 (47, XY, +18) karyotype, diagram
• Trisomy 18, facial features, gross
• Clenched hand with trisomy 18, gross
• Diaphragmatic hernia, gross

Trisomy 16: Seen in abortuses from first trimester. Never liveborn.

• Trisomy 16 karyotype, diagram

Monosomy X: Turner’s syndrome; can survive to adulthood; features include short stature, cystic hygroma of neck (leading to webbing), infertility, coarctation.

• Monosomy X, or Turner’s syndrome (45, X) karyotype, diagram
• Monosomy X, or Turner’s syndrome, streak ovaries in adult, gross
• Massive fetal hydrops with monosomy X, or Turner’s syndrome, gross
• Cystic hygroma with monosomy X, or Turner’s syndrome, gross

XXY: Klinefelter’s syndrome; features include elongated lower body, gynecomastia, testicular atrophy (incidence: 1/500 males)

• Klinefelters’ syndrome karyotype, diagram

Triploidy: There is often a partial hydatidiform mole of placenta. Fetal features include 3-4 syndactyly, indented nasal bridge, small size.

• Triploidy karyotype, diagram
• Partial hydatidiform mole, gross
• 3-4 syndactyly with triploidy, gross

A host of other chromosomal abnormalites are possible. In general, fetal loss earlier in gestation, and multiple fetal losses, more strongly suggests a possible chromosomal abnormality.

Neural Tube Defects

The maternal serum alpha-fetoprotein (MSAFP) is useful for screening for neural tube defects, but the gestational age must be known for proper interpretation. The frequency of neural tube defects has been shown to be reduced if women supplement their diet with folic acid (before and during pregnancy).

Anencephaly: There is absence of the fetal cranial vault, so no cerebral hemispheres develop. Anencephaly is the most common congenital malformation–about 0.5 to 2/1000 live births. Other neural tube defects are as frequent, but the incidence varies with geography.

• Anencephaly, gross
• Anencephaly, gross

Iniencephaly: Imperfect formation of the base of the skull, with rachischisis and exaggerated lordosis of the spine.

• Iniencephaly, gross
• Iniencephaly, gross

Exencephaly: Incomplete cranial vault, but the brain is present.

• Exencephaly, gross

Meningomyelocele: Defect in the vertebral column allowing herniation of meniges and spinal cord; location and size determine severity.

• Meningomyelocele, gross
• Meningomyelocele, gross

Encephalocele: Herniation of brain through a skull defect.

• Occipital encephalocele, radiograph
• Occipital encephalocele with iniencephaly, gross

Spina bifida: A defective closure of the posterior vertebral column. It may not be open (spina bifida occulta).

Hydrops Fetalis

There are many causes for fetal hydrops, and in about 25 to 30% of cases, no specific cause for hydrops can be identified. Multiple congenital anomalies can also be associated with hydrops, though the mechanism is obscure for everything except cardiac anomalies that produce heart failure.

Hydrops can be classified as immune and non-immune. Immune causes such as Rh incompatibility between mother and fetus are now uncommon. Non-immune causes can include:

• Congenital infections
• Cardiac anomalies
• Chromosomal abnormalities
• Fetal neoplasms
• Twin pregnancy
• Fetal anemia
• Other anomalies (pulmonary, renal, gastrointestinal)

Congenital Infections

The hallmark of congenital infections is fetal hydrops along with organomegaly. Diagnosis can depend upon:

TORCH titers

Tissue culture

Histologic examination

Disruptions

It is becoming increasingly recognized that many fetal abnormalities result from problems with embryogenesis early on. Some of these abnormalities may involve problems with vascular supply. The result is abnormal formation of a body region or regions. Such disruptions are generally asymmetric. Examples may include:

Limb-Body Wall Complex (amnionic band syndrome)

• Omphalocele, gross
• Gastroschisis, gross
• Amnionic bands, gross
• Limb-body wall (LBW) complex, gross
• Limb-body wall (LBW) complex, gross

Sirenomelia

• Sirenomelia, gross
• Sirenomelia, gross

Hydranencephaly

• Hydranencephaly, gross

Renal Cystic Disease

For examples of these diseases, go to the tutorial on renal cystic disease.

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

This condition is inherited in an autosomal recessive pattern, giving a 25% recurrence risk for parents having subsequent children. The kidneys are affected bilaterally, so that in utero, there is typically oligohydramnios because of poor renal function and failure to form significant amounts of fetal urine. The most significant result from oligohydramnios is pulmonary hypoplasia, so that newborns do not have sufficient lung capacity to survive, irrespective of any attempt to treat renal failure. ARPKD may be termed “Type I” cystic disease in the Potter’s classification. A helpful finding at autopsy is the presence of congenital hepatic fibrosis, which accompanies ARPKD.

Multicystic Renal Dysplasia

This condition has a sporadic inheritance pattern. It is perhaps the most common form of inherited cystic renal disease. It results from abnormal differentiation of the metanephric parenchyma during embryologic development of the kidney. However, in many cases it can be unilateral, so the affected person survives, because one kidney is more than sufficient to sustain life. In fact, with absence of one functional kidney from birth, the other kidney undergoes compensatory hyperplasia.

Multicystic renal dysplasia is often the only finding, but it may occur in combination with other anomalies and be part of a syndrome (e.g., Meckel-Gruber syndrome), in which case the recurrence risk will be defined by the syndrome. If this disease is bilateral, the problems associated with oligohydramnios are present.

Multicystic renal dysplasia was termed “Type II” in the Potter classification. There are two main subgroups. If the affected kidney is large, then it is termed “Type IIa”. If the affected kidney is quite small, it can be termed “hypodysplasia” or “Type IIb”. Different combinations are possible, so that only one kidney or part of one kidney can be affected and be either larger or small; both affected kidneys can be large or both can be small, or one can be larger and the other small. It is quite common for asymmetry to be present.

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

This condition is inherited in an autosomal dominant pattern, so the recurrence risk in affected families is 50%. However, this disease rarely manifests itself before middle age. It may begin in middle aged to older adults to cause progressive renal failure as the cysts become larger and the functioning renal parencyma smaller in volume. This is the “Type III” cystic disease in the Potter classification, but it is rarely manifested prenatally or in children.

Cystic Change with Obstruction

In the fetus and newborn with urinary tract obstruction, it is possible for cystic change to occur in the kidneys, in addition to hydroureter, hydronephrosis, and bladder dilation. Depending upon the point of obstruction, either or both kidneys may be involved. For example, posterior urethral valves in a male fetus, or urethral atresia in a male or female fetus, will cause bladder outlet obstruction so that both kidneys are involved. With bladder outlet obstruction, there will be oligohydramnios and the appearance of pulmonary hypoplasia.

Grossly, this form of cystic disease may not be apparent. The cysts may be no more than 1 mm in size. Microscopically, the cysts form in association with the more sensitive developing glomeruli in the nephrogenic zone so that the cysts tend to be in a cortical location. Thus, “cortical microcysts” are the hallmark of this form of cystic disease, which is “Type IV” in the Potter’s classification. There are no accompanying cystic changes in other organs in association with this disease.

Congenital Neoplasms

Such tumors are uncommon, but those that are seen most frequently include:

Teratoma. These tumors occur in midline regions (sacrococcygeal, cerebral, nasopharyngeal).

• Nasopharyngeal teratoma, gross
• Teratoma, low power microscopic
• Immature teratoma, medium power microscopic

Hemangioma. About 1/3 of all soft tissue neoplasms in the first year of life are hemangiomas or lymphangiomas. Fibromatoses are also common.

• Hemangioma, gross
• Hemangioma, microscopic

Neuroblastoma. The incidence of congenital neuroblastoma is 1:8000

• Neuroblastoma, gross
• Neuroblastoma, microscopic

Size and location are important, for even histologically benign neoplasms can obliterate normal tissues, be difficult to resect, or recur with incomplete resection. Malignant neoplasms have the capacity for invasion and metastases.

Skeletal Abnormalities

Ultrasound may reveal long bones that are shortened. There are several possibilities, including short-limbed dwarfism, osteogenesis imperfecta, and short rib-polydactyly syndrome. The various forms of short-limbed dwarfism, which can be lethal, are more difficult to diagnose specifically. The features of these various conditions may not be well-developed at 20 weeks gestation or less, making diagnosis more difficult. Limitation of survival is often due to pulmonary hypoplasia because the chest cavity is too small.

Achondroplasia is a form of short-limbed dwarfism that is inherited in an autosomal dominant fashion, though in most cases there is no affected parent and the disease is due to a new mutation. The homozygous form of the disease is lethal. The heterozygous form is not lethal, and affected persons can live a normal life. They have short extremities, but a relatively normal sized thorax and normal sized head.

Thanatophoric dysplasia (TD) is a lethal condition. The long bones are short and curved, with femora that have a “telephone receiver” appearance on radiograph because of the curvature. The vertebrae have marked platyspondyly with widened disc spaces. There are two forms, TD 1 and TD 2, with the latter distinguished by the appearance of a “cloverleaf” pattern to the skull.

Osteogenesis imperfecta occurs in several forms. There is a lethal perinatal form in which fractures appear in long bones even in utero. This condition is due to an abnormal synthesis of type 1 collagen that forms connective tissues, including bone matrix.

• Thanatophoric dysplasia, radiograph
• Osteogenesis imperfecta, radiograph

Placental Abnormalities

Abruptio placenta: Premature separation of the placenta near term, with retroplacental blood clot.

• Abruptio placenta, gross

Placenta previa: Low-lying implantation site can lead to hemorrhage during delivery.

Velamenous insertion: Cord vessels splay out in the membranes before reaching the placental disk and predispose to traumatic rupture.

• Velamentous insertion, gross

Long – short cord: Umbilical cord length is determined by the amount of fetal movement. More movement increases cord length. A long cord can become entangled with the baby or more easily prolapse.

• Nuchal cord, gross
• True knot of umbilical cord, gross

Twin placenta: Monozygous twinning is associated with increased risk for both abnormalities and accidents. A twin-twin transfusion syndrome can occur when a vascular anastomosis is present

• Vascular anastomosis in placenta, gross
• Vascular anastomosis in placenta, gross

Hypertension: Vascular changes can be associated with pregnancy-induced hypertension (PIH) and the more severe complications of eclampsia and pre-eclampsia.

• Decidual arteriopathy, microscopic