3 Fetal medicine

Congenital abnormalities affect approximately 2% of newborn babies in the UK, and account for around 21% of perinatal and infant deaths, as well as causing significant disability and morbidity later in life. Although some pregnancies are known to be at high risk, e.g. for mothers with type I diabetes or parents with a previously affected child, the vast majority of congenital defects occur unexpectedly in otherwise uncomplicated pregnancies. Prenatal identification in such situations can help in a multitude of ways:

The news that there is a problem with their unborn child is often devastating for parents. How they respond to the situation will vary with such factors as age, social background, and religious belief. Not all parents will wish to terminate the pregnancy: many will choose to go on, even in the face of abnormalities incompatible with life. Some parents report that the opportunity to hold their child enabled them to grieve. Counselling must be supportive, informative, and non-directional. Care must also be taken to counsel adequately before any screening tests. If parents have no intention of having the riskier diagnostic tests performed then there is little benefit in screening and much anxiety may be generated. Detailed written information should always be provided beforehand.

Commonest identifiable cause of learning disability. Usually occurs as a result of non-disjunction of chromosome 21 at meiosis (95%). May also be due to balanced translocation in parents (4%). 1% estimated due to mosaicism. Variable penetrance, which explains wide range of features and characteristics seen in people with Down’s syndrome. Around 50% will have one or more serious congenital abnormality. Around 10% will die before age of 5yrs, and current life expectancy is 50–55yrs.

Down Syndrome Medical Interest Group.  www.dsmig.org.uk

Second-most common autosomal trisomy. Most due to non-disjunction at meiosis. Vast majority will die soon after birth; survival to 1yr is anecdotal.

Least common autosomal trisomy; ~75% due to non-disjunction. Babies die soon after birth.

See  www.rarechromo.org

This affects only females and is due to the loss of an X chromosome. It is one of the few chromosomal abnormalities that does not result in mental impairment. Almost all women with Turner’s syndrome will have short stature and loss of ovarian function, but the extent of the other features varies enormously.

See  www.tss.org.uk

Affects only males and caused by non-disjunction of the X chromosomes. The individual is almost always sterile and may have hypogonadism. They are phenotypically tall with occasionally reduced IQ. Incidence 1:700 live male births.

Ideally, screening should be offered to all women at the time of booking. In the UK, almost all units use the ‘combined test’ to screen for Down’s syndrome, the most common chromosomal abnormality. This has a detection rate of 75% with a false +ve rate (FPR) of no more than 3%. This means that a risk of 1 in 150 or less is considered ‘high risk’.

Detailed, unbiased, written information should be provided about the condition itself, types of test available, and the implications of the results. It is important for a woman to understand that a negative result does not guarantee that her baby does not have an abnormality.

Screening relies on the integration of different independent risk factors, such as maternal age, blood hormone levels, and scan findings. These findings are slightly dependent on other factors including maternal weight, ethnicity, IVF pregnancies, smoking, multiple pregnancy, and diabetes, and calculations are modified according to these.

In recent years, fetal cells in the maternal circulation can be detected and tested for chromosomal, and even some single gene, abnormalities. Maternal blood is taken from 10wks; the test is therefore virtually risk-free. The sensitivity approaches 100%, so this test will be diagnostic. Currently expensive, the anticipated cost reductions are likely to render the need for invasive testing (amniocentesis and CVS) virtually redundant.

Scan and blood test at 11–13+6wks.

Calculated by multiplying the background maternal age and gestation-related risk by a likelihood ratio derived from the nuchal translucency (NT) measurement and the two blood tests.

Blood tests at 16wks.

Best screening test (see Table 3.1), but expensive and seldom used.

Blood test at 10wks, then again at 15wks.

Less operator dependent (scan) than the combined test and probably as accurate; not recommended despite this (see Table 3.1).

This should be offered to all women in the UK at the time of booking and usually takes the form of the ‘anomaly scan’, a detailed USS undertaken at around 18–21wks gestation. The aim is to identify specific structural malformations.

The detection of malformations may vary and is dependent on:

Craniospinal defects occur early in development when the neural tube fails to close properly. Type and severity depend on degree and site of defect. There is growing evidence that prevalence is declining, possibly due to increased use of folate supplementation.

Absence of skull vault and cerebral cortex. It is incompatible with life, with babies rarely living more than a few hours if they are not stillborn.

Incomplete fusion of vertebrae potentially allowing herniation of all or part of spinal cord. The malformation falls into three categories:

Cardiac defects are the most common major malformation in children, with an estimated incidence of 6–8:1000. They may be associated with a chromosomal abnormality, commonly trisomy 21 or 18, and with many other congenital abnormalities. Where isolated, many can be surgically corrected at birth, leading to a good quality of life. The most commonly seen abnormalities are VSDs (Fig. 3.3).

Estimated mortality rate 71–95%.

Postnatal surgery in asymptomatic cases is contentious.

Some ultrasound features at 20wks may themselves be of little significance, but are nevertheless slightly more common in chromosomally abnormal fetuses. They have therefore been used to modify the risk of aneuploidy. However, these features may cause considerable parental anxiety as they are often, mistakenly, seen as abnormalities. Furthermore, they may increase the false +ve rate of screening.

See  www.fetalanomaly.screening.nhs.uk/fetalanomalyresource/whats-in-the-hexagons1/about-the-scan/normal-variant-screening.

Non-invasive prenatal testing will soon render these tests virtually redundant (see p. 111).

Diagnostic test usually performed between 10 and 13wks and involves aspiration of some trophoblastic cells. The amount of tissue obtained is small, but sufficient for karyotyping, and with the development of fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR), rapid analysis is possible (see Fig. 3.9). It requires ultrasound guidance and is usually performed transabdominally, occasionally transcervically.

Allows 1st trimester TOP if an abnormality is detected:

This is only undertaken from 15wks onwards. It involves aspiration of amniotic fluid which contains fetal cells shed from the skin and gut. It is performed transabdominally with ultrasound guidance (see Fig. 3.10).

Fetal hydrops is the abnormal accumulation of serous fluid in two or more fetal compartments. This may be pleural or pericardial effusions, ascites, skin oedema, polyhydramnios, or placental oedema. It may be divided into non-immune and immune causes.

The mechanism for the development of hydrops appears to be due to an imbalance of interstitial fluid production and inadequate lymphatic return. This can result from congestive heart failure, obstructed lymphatic flow, or decreased plasma osmotic pressure.

Occurs in ~1:2000 births.

The prognosis depends on the underlying cause. Where treatment is not possible, the option of TOP should be discussed. In the 3rd trimester, delivery may be a better alternative than in utero treatment.

If severe polyhydramnios is present, removal of excess amniotic fluid (amnioreduction) may reduce the risk of preterm labour. Consider giving steroids before the procedure as it carries a small risk of triggering preterm labour.

Occurs when a maternal antibody response is mounted against fetal red cells. These immunoglobulin (IgG) antibodies cross the placenta and cause fetal red blood cell destruction. The ensuing anaemia, if severe, precipitates fetal hydrops, which is often referred to as immune hydrops.

Consists of three linked gene pairs; one allele of each pair is dominant—C/c, D/d, and E/e. There are only five antigens (d is not an antigen; it merely implies absence of D). Inheritance is Mendelian. D gene is the most significant cause of isoimmunization, because ~16% of white mothers are rhesus D −ve (d/d). Incidence lower in Afro-Caribbean and Asian populations. Other significant antigens include c, E, and atypical Kell antibody. Because of success of anti-D prophylaxis, these account for up to 1/2 of cases.

▶ Amniocentesis or fetal blood sampling based on antibody levels or history alone is now obsolete.

The risk of fetal loss, or need for urgent delivery if >26wks, is 1–3% per transfusion in skilled hands.

Antibodies may persist for weeks, causing continued haemolysis in the neonate; this requires careful monitoring with haematocrit measurements.

Amniotic fluid after 20wks largely consists of fetal urine. The volume depends on urine production, fetal swallowing, and absorption. Normal volume varies with gestation, and is highest between 24 and 36wks. The volume is measured by ultrasound, either by measuring the deepest vertical pool, or by adding up the deepest pools in the four quadrants of the uterus (AFI).

In oligohydramnios, the amniotic fluid volume is reduced. Normograms of both measures are available, but, as a general rule, a deepest pool of <2cm or an AFI of <8cm is considered low.

The amniotic fluid is increased. In general a deepest pool of >8cm or an AFI >22 is abnormal.

The fetus is believed to have an inherent growth potential which under ideal conditions should produce a healthy baby of the appropriate size. Attaining this potential relies on such factors as a healthy mother, well-functioning placenta, and the absence of pathology. If the in utero circumstances are less than ideal, the fetus will fail to achieve its full potential growth and fetal well-being may be compromised. This problem is analogous to ‘failure to thrive’ in children and is termed intrauterine growth restriction (IUGR).

▶ The term IUGR implies a fetus that is pathologically small.

Most epidemiological studies use small for gestational age (SGA) as a surrogate marker. The most commonly used method of identification of SGA is where the estimated weight of the fetus is below the 10th percentile for its gestational age.

This method is not perfect as it includes small, but healthy babies, and average-sized unhealthy babies that should have been born big.

To identify actual pathology and to improve detection of IUGR it is important to try to define the inherent growth potential of each individual fetus. Physiological factors known to affect growth and birth weight include:

Some of these factors have been used to generate customized growth charts which aim to identify the optimal growth curve for an individual fetus. These are freely available at  www.gestation.net. They appear to reduce the rate of constitutionally small babies being classed as IUGR (false +ve rate) while helping to increase detection of pathologically small babies.

Defining expected growth also requires accurate dating of pregnancy, ideally by USS in the 1st trimester between 8 and 13wks gestation.

Causes of growth restriction may be grouped into maternal, utero-placental, and fetal.

By far the most common cause is utero-placental insufficiency.

IUGR is often classified into symmetric and asymmetric, although the two groups overlap substantially

Early identification and intensive fetal monitoring are the key to managing IUGR. The aim is to continue the pregnancy safely for as long as possible, thereby decreasing the problems associated with prematurity, but deliver before the fetus becomes excessively compromised. This is covered in depth in Antenatal fetal surveillance, p. 146.

Most congenitally normal IUGR babies will go on to grow normally in infancy and childhood, but there may be more subtle long-term consequences, including up to 1/3 of children not reaching their predicted adult height, and having childhood attention and performance deficits.

The effects appear to last into adulthood, with a stimulus or insult at a critical, sensitive period of early life having permanent effects on structure, physiology, and metabolism. People who were small or disproportionate (thin or short) at birth have been found to have higher rates of coronary heart disease, high blood pressure, high cholesterol concentrations, and abnormal glucose-insulin metabolism (Barker hypothesis).

The fetus is vulnerable to any strain in the uteroplacental unit—its supply line for nutrition and gas exchange. Nearly 1/100 babies in developed countries are stillborn and 1/3 of all stillbirths occur in babies that are small for dates.

Any uteroplacental shortfall becomes more critical as the fetus gets bigger, and there is an extraordinary rate of growth during the last weeks of pregnancy. The stillbirth risk rises at the same stage.

▶ There are no treatments to reverse uteroplacental insufficiency but, potentially, delivering the baby at the right time can prevent death and disability.

The only intervention is delivery so monitoring is not useful if the fetus could not survive if it were delivered, i.e. if it is <24wks or <500g.

Antepartum fetal monitoring is done in two stages.

In the future, screening for placental function using serum markers, history, and ultrasound could establish itself as a routine test, in the same way as screening for Down’s syndrome.

Accurate knowledge of the age of the fetus is required. The fetal head circumference (HC) and abdominal circumference (AC) are measured together with the deepest pool of amniotic fluid using ultrasound and the results are charted against gestational age. Serial measurements are useful to assess the pattern of the fetal growth.

Late ultrasound aims to detect:

It should be used only where growth abnormality is suspected (SFH outside the normal range) or the patient is at high risk of uteroplacental insufficiency, because its usage has not been proven to improve outcome in unselected patients.

Auscultation of the fetal heart merely confirms the fetus is alive. It provides no predictive information done (with hand-held Doppler or a Pinard stethoscope) as part of a standard antenatal examination.

Doppler ultrasound uses sound waves to study blood circulation in the baby, uterus, and placenta.

This is most used for identification of risk pregnancy.

▶ The most useful features in assessing the fetus’s health are the variability and presence or absence of accelerations.

Caused by a failure of autonomic regulation of the heart rate, this is an end-stage event, so the lead-time between uteroplacental insufficiency causing an abnormal CTG and fetal death or long-term damage is short, and this limits its usefulness in antenatal screening.

Routine antenatal CTG has not been found to be useful in low-risk populations.

CTG is used to exclude current compromise:

Because the CTG only becomes abnormal at a very late stage in IUGR, less frequent than daily CTGs should not be relied upon as a method of monitoring.