Prenatal diagnosis employs a variety of techniques to determine the health
and condition of an unborn fetus. Without knowledge gained by prenatal
diagnosis, there could be an untoward outcome for the fetus or the mother or
both. Congenital anomalies account for 20 to 25% of perinatal deaths.
Specifically, prenatal diagnosis is helpful for:
- 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:
- Chorionic villus sampling
- Fetal blood cells in maternal blood
- Maternal serum alpha-fetoprotein
- Maternal serum beta-HCG
- Maternal serum estriol
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 nuchal thickening.
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
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. This is because the lungs are not producing enough surfactant. After
birth, the infant will develop respiratory distress syndrome from hyaline
membrane disease. The amniotic fluid can be analyzed by fluorescence
polarization (fpol), for lecithin:sphingomyelin (LS) ration, and/or for
phosphatidyl glycerol (PG).
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 cannot be obtained. 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.
Alternative approaches are transvaginal and 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 blood cells
This is a new technique that 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 enter the maternal
circulation in this fashion (not enough to produce a positive Kleihauer-Betke
test for fetal-maternal hemorrhage). The fetal cells can be sorted out and
analyzed by a variety of techniques to look for particular DNA sequences, but
without the risks that these latter two invasive procedures inherently have.
Fluorescence in-situ hybridization (FISH) is one 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 many fetal
blood cells. 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 mother's blood. However, when there is a
neural tube defect in the fetus, 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 abbout 1 to 2
births per 1000 in the United States. Also, if there is an omphalocele or
gastroschisis (both are defects in the fetal abdominal wall), the AFP from the
fetus will end up in maternal blood in higher amounts.
In order for the MSAFP test to have the greates utility, the gestational age
must be known with certainty. This is because the amount of MSAFP increasses
with gestational age (as the fetus and the amount of AFP produced increase in
size). 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 mean (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: The genetic polymorphisms due to mutations in the methylene tetrahydrofolate reductase gene may increase the risk for NTDs. Folate is a cofactor for this enzyme, which is part of the pathway of homocysteine metabolism in cells. The C677T and the A1298C mutations are associated with elevated maternal homocysteine concentrations and an increased risk for NTDs in fetuses. Prevention of many neural tube defects can be accomplished by
supplementation of the maternal diet with only 4 mg of folic acid per day, but
this vitamin supplement must be taken a month before conception and through the
The MSAFP can also be useful in screening for Down syndrome and other
trisomies. The MSAFP tends to be lower when Down syndrome or other chromosomal
abnormalities is present.
Maternal serum beta-HCG
This test is most commonly used as a test for pregnancy. Beginning at 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 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 estriol
The amount of 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) made by the fetal adrenal
glands. 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 and when there is adrenal hypoplasia with anencephaly.
Inhibin is secreted by the placenta and the corpus luteum. 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 be associated with a 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.
|Neural tube defect||Increased||Normal||Normal
| Trisomy 21||Low||Low||Increased
| Trisomy 18||Low||Low||Low
| Molar pregnancy||Low||Low||Very High
| Multiple gestation||Increased||Normal||Increased
| Fetal death (stillbirth)|| Increased||Low||Low
Note: the levels of these analytes change markedly during pregnancy, so interpretation of the measurements depends greatly upon knowing the proper gestational age. Otherwise, results can be misinterpreted.
Techniques for Pathologic Examination
A variety of methods can be employed for analysis of fetal and placental tissues:
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 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).
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
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)
Cultures 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.
Tissues must be obtained as fresh as possible for culture and without contamination.
A useful procedure is to wash the 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.
Fetal cells obtained via amniocentesis or CVS can be analyzed by probes specific for DNA sequences. One method employs restriction fragment length polymorphism (RFLP) analysis. This method is useful for detection of mutations involving genes that are closely linked to the DNA restriction fragments generated by the action of an endonuclease. The DNA of family members is analyzed to determine differences by RFLP analysis.
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 genetic diseases, but only in a minority have particular genes been identified, and tests to detect them have been developed in some of these. Thus, it is not possible to detect all genetic diseases. Moreover, testing is confounded by the presence of different mutations in the same gene, making testing more complex.
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 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.
Rarely 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
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 13: Features include microcephaly, cleft lip and/or palate, polydactyly, cardiac defects, holoprosencephaly.
Trisomy 16: Seen in abortuses from first trimester. Never liveborn.
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)
Triploidy: There is often a partial hydatidiform mole of placenta. Fetal features include 3-4 syndactyly, indented nasal bridge, small size.
- 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.
Iniencephaly: Imperfect formation of the base of the skull, with rachischisis and exaggerated lordosis of the spine.
Exencephaly: Incomplete cranial vault, but the brain is present.
Meningomyelocele: Defect in the vertebral column allowing herniation of meniges and spinal cord; location and size determine severity.
Encephalocele: Herniation of brain through a skull defect.
Spina bifida: A defective closure of the posterior vertebral column. It may not be open (spina bifida occulta).
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)
The hallmark of congenital infections is fetal hydrops along with organomegaly. Diagnosis can depend upon:
- TORCH titers
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)
Renal Cystic Disease
For examples of these diseases, go to the tutorial on renal cystic disease.
Recessive Polycystic Kidney Disease (RPKD)
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. RPKD 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 RPKD.
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.
Dominant Polycystic Kidney Disease (DPKD)
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.
Such tumors are uncommon, but those that are seen most frequently include:
Teratoma. These tumors occur in midline regions (sacrococcygeal, cerebral, nasopharyngeal).
Hemangioma. About 1/3 of all soft tissue neoplasms in the first year of life are hemangiomas or lymphangiomas. Fibromatoses are also common.
Neuroblastoma. The incidence of congenital neuroblastoma is 1:8000
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.
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.
Abruptio placenta: Premature separation of the placenta near term, with retroplacental blood clot.
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.
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.
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
Hypertension: Vascular changes can be associated with pregnancy-induced hypertension (PIH) and the more severe complications of eclampsia and pre-eclampsia.