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Suspected fetal anomaly
Current Obstetrics & Gynaecology (2002) 12, 161^169
c 2002 Elsevier Science Ltd doi:10.1054/cuog.2001.0253 available online at http://www.idealibrary.com on
Suspected fetal anomaly Catharine Bangham* and Timothy G.Overtonw *Associate Specialist in Fetal Medicine and wConsultant Obstetrician and Gynaecologist, Subspecialist in Maternofetal Medicine, Department of Obstetrics and Gynaecology, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK
KEYWORDS fetal anomaly; prenatal diagnosis; maternal serum screening; nuchal screening; fetal therapy
Summary Major structural abnormalities occur in 2^3% of fetuses accounting for 20^30% of perinatal mortality in the developed world. The vast majority occur in lowrisk women, are sporadic and therefore cannot be anticipated. With rapid advances in molecular diagnostic techniques and recent developments in in-utero therapy, early diagnosis of fetal problems is imperative.While tests such as ¢rst and second trimester ultrasound assessment and serum screening are becoming more e¡ective, the importance of a detailed history atthe beginning of pregnancy should not be underestimated. In addition, preconceptual counselling for ‘at risk’ families can have a major impact on pregnancy outcome.This article discusses current methods for detecting fetal anomalies and summarizes the management options.
c 2002 Elsevier Science Ltd
WHY IS DETECTIONOF A FETAL ANOMALY IMPORTANT? Initiation of fetal therapy Intrauterine transfusion (IUT) The most common cause of fetal anaemia is alloimmunization. The link between the presence of anti-RhD antibodies in the maternal circulation and erythroblastosis fetalis was ¢rst shown in 1954 by Chown when a woman gave birth to an anaemic baby with erythroblastosis and was found to have Rhesus D fetal cells in her circulation. Improved fetal surveillance techniques with ultrasound allows for the early detection of anaemic fetuses which can be transfused in utero preventing the development of fetal hydrops. Each IUT carries with it a perinatal loss rate of 1^3% although this ¢gure approaches 20% if the fetus is already hydropic. In alloimmune red cell haemolytic disease, the fetus becomes anaemic because of transplacental passage of maternal antibodies. In the early 1990s, the most common indication for intrauterine transfusions was anaemia due to anti-D antibodies. More recently, however, an increasing proportion of IUTs are required for the treatment of fetal anaemia due to other antibodies. In the case of anti-Kell, the anaemia is due to antibody suppression of fetal erythropoiesis rather
than red cell lysis. Serial middle cerebral artery (MCA) Doppler velocity measurements have recently been shown to be a useful tool for predicting fetal anaemia, whatever the aetiology. They are particularly helpful in monitoring Kell-sensitized pregnancies where serial amniocenteses for OD450 estimation are not helpful and repeated fetal blood sampling will carry a signi¢cant cumulative mortality rate and risk of worsening sensitization. Fetal infection with Parvovirus B19 can cause fetal anaemia.Features of the disease in the mother or siblings may vary from an obvious fever with distinctive erythematous rash on the cheeks (‘slapped cheek’) to being asymptomatic. If the mother has had contact with a known case and her stored pre-pregnancy serum was sero-positive, the fetus would be una¡ected by the virus. If, however, she was sero-negative, she should have weekly ultrasound scans for 12 weeks in order to look for increasing MCA Doppler velocities and non-immune hydrops. If present, the fetus should have fetal blood sampling with a view to intrauterine fetal transfusion if anaemia is con¢rmed. Unlike alloimmunization, the precipitating factor for the red cell lysis, i.e. the virus, does not persist and repeated transfusions are rarely required.
Treatment for the twin^twin transfusion syndrome Correspondence to: TGO.Tel.: +44 (0) 1603 286790; E-mail: [email protected]
Twin ^ twin transfusion syndrome (TTTS) complicates 10 ^15% of monochorionic twin pregnancies and requires
162
prompt diagnosis and urgent assessment. Untreated, TTTS has a perinatal mortality exceeding 80%. Regular ultrasound assessment throughout pregnancy at fortnightly intervals from about 16 weeks’ gestation is needed to detect early features of the disease a¡ording the opportunity for planned treatment. Presentation is usually in the second trimester, the most obvious ultrasound feature being discordant amniotic £uid volumes, with an oliguric donor (‘stuck’ twin) and a polyuric recipient with severe polyhydramnios.There are various treatment options. Amnioreduction shows a survival rate of 60 ^ 65%. Septostomy (whereby the intertwin membrane is punctured with a sterile needle under ultrasound supervision) which equilibrates the amniotic sac volumes has shown an 85% survival rate in a pilot series. Both these options are the subject of an international randomized multicentre trial. Selective feticide of one twin by cord occlusion allows the remaining twin to continue to term in less than 85% of cases. Laser ablation of communicating vessels has survival rates of 49^ 67%.
CURRENT OBSTETRICS & GYNAECOLOGY
In-utero surgery This is a rapidly developing ¢eld hampered at present by the signi¢cant risk of preterm labour once the uterus has been opened to gain access to the a¡ected fetus. There are a handful of successful case reports in the literature for the treatment of neural tube defects. Nevertheless, such aggressive treatment programmes are only carried out in a few centres worldwide in the context of research projects. Other surgical procedures such as shunting of the fetal lungs or bladder are well established. This can decrease perinatal morbidity from pulmonary hypoplasia due to pleural e¡usions or kidney damage due to bladder outlet obstruction from posterior urethral valves. Tense polyhydramnios leading to the possibility of preterm labour can be treated by amnioreduction. This condition most commonly occurs with intestinal atresias and the patient should be scanned regularly to detect the development of polyhydramnios.
Optimizing conditions for delivery Fetal medication Fetal cardiac arrhythmias can cause heart failure and hydrops. Early identi¢cation on ultrasound enables maternal administration of anti-arrhythmics, such as £ecainide or digoxin, which cross the placenta and treat the fetus. Sometimes large doses are required to achieve therapeutic levels in the fetus and maternal serum levels must be monitored in order to avoid toxicity.
Planning for the delivery of a baby with a major malformation includes consideration of the timing, the location and the provision of appropriate sta¡ both obstetric and paediatric. Patients with anomalies amenable to surgery can be reviewed by paediatric surgeons during the antenatal period, allowing parents to meet the team who will be providing care for their baby. Fetuses with major cardiac anomalies requiring intervention early in the
Figure 1 Ultrasound appearance of fetus with gastroschisis with loop of bowel herniating from the anterior abdominal wall.
SUSPECTED FETAL ANOMALY
neonatal period should be delivered in a unit with appropriate paediatric support.
Parental preparation Preparing parents emotionally for the birth of a child with a major malformation is an important part of fetal medicine. Unexpected (external) malformations such as facial clefts, talipes, and gastroschisis (Figures1 and 2), will cause great distress to parents at delivery. Prenatal diagnosis of these conditions allows time for the parents to meet the team involved in postnatal care, to see pictures of other infants who have been successfully treated, and to map out a provisional timetable for the postnatal plan of action. When a fetal anomaly is diagnosed a large amount of new information has to be assimilated by the parents. Making a diagnosis well before birth allows time for the parents to develop their understanding of complex problems, often with a genetic background. For example, the presence of a cystic hygroma with normal fetal karyotype can be associated with genetic syndromes which may not be diagnosed prenatally. Sometimes uncertainties exist for clinicians and these need to be shared with couples while o¡ering them maximum support. Contributions from genetics specialists at this time can be helpful to parents.They also need to be prepared for the inevitable separation when a baby has to be cared for on NICU and during paediatric surgery. Visiting the unit and meeting sta¡ prenatally will assist their understanding and also enable them to prepare other family members such as siblings and grandparents.
Acknowledging parental needs In the case of lethal conditions or malformations which will lead to severe mental or physical handicap, couples may wish to consider the option of termination of
163
pregnancy. Some couples faced with this information would not wish to end the pregnancy but would ¢nd the preparation time helpful. Of course some parents may elect not to have any prenatal screening tests at all and would rather ‘take life as it comes’.
HOW DO WE DETECT FETAL ANOMALY? Awareness of high-risk individuals Many groups of patients are at high risk of having a baby with a fetal anomaly and it is important for clinicians to be aware of these groups. Meticulous history taking and good follow-up after an a¡ected pregnancy are vital in predicting fetal anomalies. Ultrasound is one tool in the process of detection but it should not be used in isolation. Ideally, these patients should be identi¢ed before conception so that optimum conditions for pregnancy can be established.
History This should include a history of previous pregnancies and where possible a family history. Women who have had a fetal malformation or chromosomal abnormality in the past should be counselled a few weeks after an a¡ected pregnancy has ended. It is important to assemble as many results as possible prior to this consultation so that the parents can be well informed about recurrence risks. These patients should be seen early in subsequent pregnancies. A family history should include both genetic and structural anomalies, particularly cardiac malformations, facial clefts and neural tube defects in parents, siblings or grandparents. Access to a genetics counsellor should be part of a fetal medicine service and in an urgent situation, they would often be able to o¡er telephone advice with information on planning future care. The Online Mendelian Inheritance in Man, OMIM, website provides comprehensive information with constant updates.
Maternal disease
Figure 2 Immediate postnatal appearance of the gastroschisis; the need for parental preparation is well illustrated.
Cardiac malformations and neural tube defects are more common in women with insulin-dependent diabetes. The incidence can be reduced by encouraging meticulous diabetic control both preconceptually and in the early weeks of pregnancy. Thyroid disease in the mother should be diagnosed and treated preconceptually. Ninety per cent of cases of hyperthyroidism in pregnancy are due to Graves disease.The resultant fetal thyrotoxicosis is due to transplacental passage of thyroid stimulating antibodies.Untreated it has an adverse e¡ect on perinatal outcome with a preterm delivery rate of 11^25% and a stillbirth rate of 8 ^15%. Diagnosis is
164
sometimes missed because the symptoms of tachycardia, heat intolerance and systolic £ow murmurs are common in pregnancy.
Maternal medication The use of anticonvulsants in the periconceptual period increases the risk of major malformation, particularly facial clefts, neural tube defects and cardiac anomalies.The risks increase if more than one drug is used; for example, 7% with one drug, 15% with two drugs and 25% with three. Folate antagonism is a likely e¡ect of many anticonvulsants and it is recommended that these women take 5 mg of folic acid daily, both preconceptually and for the duration of the pregnancy. Preconceptual adjustment of medication by a neurologist or maternal medicine specialist is appropriate. However, it must be kept in mind that a balance should be struck when altering drug therapy so that the frequency of the ¢ts does not increase, putting the mother at risk of injury and the fetus at risk of prolonged or repeated hypoxic episodes. Lithium is associated with increased risk of cardiac malformations and preconceptual substitution with another drug, if adequately e¡ective, may be preferable. Addiction to alcohol can result in the fetal alcohol syndrome. Features seen on the ultrasound scan can include growth restriction, microcephaly, ASDs, VSDs and renal hypoplasia. There is currently a suspicion that the use of ‘recreational drugs’ in the early weeks of pregnancy may be causing an increased incidence of gastroschisis. Information on drugs in pregnancy is available from the National Teratology Information Service, telephone number +44 (0)1912321525.
Age In view of the increasing incidence of aneuploidy with advancing maternal age, many units will o¡er prenatal diagnosis with invasive testing to women over 35 years. However, this strategy alone will only detect 27% of fetuses with Trisomy 21. Some women in this age group may wish to have maternal serum screening and decide about invasive testing when a numerical risk based on both age and biochemistry is available. Others may wish for a de¢nitive test by CVS or amniocentesis but have nuchal translucency (NT) measurement ¢rst. In the event of a low-risk NT measurement she could opt for amniocentesis with its lower miscarriage risk and greater availability.
Multiple pregnancy Chorionicity should be routinely determined in all twin pregnancies before 12 weeks when 100% accuracy can be achieved. In the midtrimester, the accuracy reduces to 80 ^90% unless dicordant genitalia are seen in which
CURRENT OBSTETRICS & GYNAECOLOGY
case dizygocity and therefore dichorionicity is con¢rmed. This is important because monochorionic twins have a ¢vefold increase in late miscarriage and perinatal mortality and discussion with parents regarding risks will be based on this ¢rst trimester information. The incidence of fetal anomalies is higher in twins than in singletons, and higher in monochorionic as opposed to dichorionic twins. Major cardiac anomalies, oesophageal atresia with or without trachea-oesophageal ¢stula, and anencephaly are particularly relevant to twin pregnancies.
Screening tests Serum screening tests for Down syndrome are usually performed in the second trimester but there is increasing support for the introduction of routine ¢rst trimester screening either by nuchal translucency estimation alone or in combination with serum biochemistry.
Nuchal translucency Increased nuchal translucency (NT) is associated with aneuploidy (Figure 3), most notably Down syndrome. The largest study using 96 000 patients reported a Down detection rate of 72% while in contrast other groups in similar populations reported a rate of only 50%. The differences could be multifactorial, including di¡erences in training, de¢nition of screen positive and quality of follow-up. When comparing this method with second trimester triple screening, criticisms have been made over the value of the ¢rst trimester test which will detect some fetuses destined to miscarry due to aneuploidy, therefore diluting the numbers of a¡ected fetuses in the second trimester cohort. There is increasing evidence of an association between increased NT and some structural anomalies particularly major cardiac defects, diaphragmatic hernia, exomphalos and body stalk anomaly. If a fetus has increased NT and a normal karyotype, it is important to search for these anomalies at the 20 -week scan having ¢rst excluded infection. Other associations include some skeletal dysplasias and rare genetic syndromes. A recent report has suggested that those fetuses a¡ected by Down syndrome are more likely to have absent nasal bones on the11^14 -week scan. Mathematical modelling predicts that combining NT assessment with nasal bone visualization alone may increase the detection rate for Down syndrome to 92.4% and further combining with serum biochemistry to 97.5% for a 5% false-positive rate. Of course, a ¢rst trimester ultrasound has the additional bene¢t of accurate dating for the pregnancy, the opportunity for the detection of a number of major abnormalities and accurate determination of chorionicity in multiple pregnancies.
SUSPECTED FETAL ANOMALY
Figure 3
165
Increased nuchal translucency in fetus a¡ected by Down syndrome.
Serum screening Second trimester serum screening is widely available to patients in the UK. Success rates vary depending on the test used. Maternal age, free b-hCG and AFP will have a detection rate in the order of 63% whereas maternal age, free b-hCG, AFP, uE3 and inhibin A will have a detection rate of nearer 72%. The debate between the relative advantages of ¢rst versus second trimester screening continues. Two large trials comparing the two are currently underway. The SURUSS trial (Serum Urine and Ultrasound Screening Study) is UK based and funded by the MRC.The FASTER trial (First and Second Trimester Evalation of risk for aneuploidy) is USA based, is enrolling 60 000 patients for ¢rst and second trimester screening and patients will be followed up until pregnancy completion. Until these large prospective trials report it will be di⁄cult to compare the e⁄cacy of these di¡erent screening programmes.
and a 19-week anomaly scan coupled with invasive testing indicated that the overall detection rate was 68%.
Look at the clinical picture Despite signi¢cant technological advances over the last decade, it is important not to ignore the clinical picture. Hyperemesis requiring hospital admission in the ¢rst trimester should raise the suspicion of molar or multiple pregnancy. Illness in the mother suggestive of cytomegalovirus, toxoplasmosis, Parvovirus B19, should be con¢rmed by serology. Ultrasound should be used to look for intracerebral features (such as microcephaly, ventriculomegaly, periventricular calci¢cation), cardiomegaly, hydrops and growth restriction. Anomalies may have gone undetected in the ¢rst and second trimesters. Presentation in the third trimester as large for gestational age would raise the possibility of polyhydramnios associated with fetal anomaly or macrosomia due to diabetes.
Twenty-week anomaly scan
CONCLUSION
The value of this scan performed routinely in an unselected population has been the subject of great debate (RADIUS study). A high detection rate of major malformation is dependent on the availability of well-trained sta¡, good-quality machines and rigorous audit. Regular joint meetings with feedback on anomalies, detected and missed, form an essential part of improving quality. In a recent study, where the detection of Down syndrome relied on the o¡er of invasive testing to women over 35
Suspected fetal abnormality is not merely the detection of problems by ultrasound. Complicated pregnancies should be anticipated prenatally in order to optimize conditions for pregnancy, counsel appropriately and plan for the pregnancy itself. If an unexpected anomaly is detected in pregnancy referral to a specialist unit should be arranged for discussion regarding de¢nitive diagnosis, therapy where necessary, and careful preparation for the delivery. Cases such as these require sensitive
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management with adequate protected time and the opportunity for follow-up visits for further discussion.
Case 1: Fetal anomaly in a high-risk pregnancy A 36 -year-old patient, Para 2, with previously uncomplicated pregnancies presented at 10 weeks’ gestation for a dating scan. The patient had had a cleft lip and palate repaired in infancy but otherwise had no relevant history. A dichorionic, diamniotic twin pregnancy was diagnosed and nuchal translucency screening gave a low risk of Down syndrome for both fetuses. The 20 -week fetal anomaly scan demonstrated that both twins were female, discordant for growth and the smaller twin appeared to have an absent stomach, a two-vessel cord and marginal polyhydramnios. No facial clefting was demonstrated in either twin. A tentative diagnosis of oesophageal atresia was made and amniocentesis was discussed because of the association of these markers with aneuploidy. The parents declined amniocentesis at this stage, although the option of karyotyping in the third trimester was left open. At 34 weeks, after repeated monitoring had shown discordant growth, the polyhydramnios had become signi¢cant, resulting in anxiety over potential preterm labour with the possible need for amnioreduction. However, the abdomen remained soft, there were no contractions and the cervical length measured by transvaginal ultrasound was 31mm with no funnelling at the internal os. At all times, the parents wished to do everything possible to maximize the chances of a good outcome for both fetuses but they appreciated that knowing the karyotype of the a¡ected fetus would make management easier. At 36 weeks an amniocentesis was performed for the a¡ected fetus and the PCR result available after 48 h was negative for Trisomy 21, 18 and 13. She was induced at 37 weeks and 3 days because of reduced fetal growth in Twin 2. The labour was complicated by fetal distress in Twin 2 at 8 cm dilatation and an emergency Caesarean section was performed. The infants weighed 2.83 and 1.92 kg and the diagnosis of oesophageal atresia was con¢rmed in the smaller twin.
CURRENT OBSTETRICS & GYNAECOLOGY
considered. Early testing may have precipitated miscarriage or preterm labour thus jeopardizing the chances for the una¡ected twin. Third trimester testing causing preterm labour would give the una¡ected twin a better chance. However, an abnormal karyotype at that stage would have raised issues of management, for example selective feticide or non-intervention in the event of severe IUGR antenatally or fetal distress in labour. If karyotyping is delayed, the patient may deliver before a result is available. Ten per cent of dichorionic twins will be monozygous and genetically identical. Aneuploidy if present would a¡ect both. In this case, if the karyotype of the a¡ected twin had been abnormal, testing of the apparently normal co-twin would have been necessary.
Case 2: Fetal anomaly suspected following serum screening A 33-year-old patient, Para1, presented for a dating scan at 10 weeks and the gestation was con¢rmed. This was her ¢rst pregnancy in a new relationship and her partner had no children. She was o¡ered maternal serum screening and this was performed at 17 weeks and 3 days. The serum AFP (0.62 mom), unconjugated oestriol (0.41mom) and HCG (0.19 mom) were all low, raising the suspicion of Trisomy 18. She was seen at 18 weeks to discuss this result and a fetal anomaly scan was performed to look for markers of aneuploidy. The fetus was slightly small for dates, had bilateral 4 mm choroid plexus cysts (Figure 4), abnormal hands with the ¢fth and second ¢ngers overlapping the second and third (Figure 5), a VSD, and echogenic bowel. The fetal pro¢le appeared normal. These ¢ndings were discussed with the parents and they opted for amniocentesis. Amniotic £uid was sent for culture and also for polymerase chain reaction (PCR) assay for the detection of Trisomy 21, 18, 13, and DF508, the common mutation of cystic ¢brosis. PCR was positive for Trisomy 18 and also demonstrated that the fetus was homozygous for the cystic ¢brosis mutation.Termination of pregnancy was o¡ered and performed. The ultrasound ¢ndings were con¢rmed at autopsy.
Comments This woman had a detailed scan because of the 4 ^7% recurrence risk of a cleft. Having suspected oesophageal atresia, information about the possible outcomes and therapies was given. The risk of polyhydramnios and resultant preterm labour were discussed. Oesophageal atresia is associated with aneuploidy, particularly Trisomy 18 in 10% of cases in some series, therefore the possibility of karyotyping needed to be addressed. In addition, the timing of an invasive test needed to be
Comments Genetic counselling for this couple will be extremely important.The chances of recurrence of the Trisomy18 are small. However, they are both carriers of the cystic ¢brosis mutation and therefore there is a 25% chance that future pregnancies will also be a¡ected. Chorionic villus sampling between 11 and 14 weeks will be o¡ered in any future pregnancies to check the karyotype and cystic ¢brosis status of the fetus.
SUSPECTED FETAL ANOMALY
Figures 4 and 5
167
Choroid plexus cyst and abnormal hand in fetus a¡ected with Edwards syndrome.
Case 3: Unexpected fetal anomaly in a low-risk patient A 23-year-old primigravid patient had a routine anomaly scan at 21 weeks. A 6.5 cm cystic sacrococcygeal teratoma Type I was diagnosed (Figure 6). No associated anomalies were detected although these can occur in 18% of cases. She was assessed every 2 weeks in order to detect polyhydramnios with its risks of preterm labour, hydrops due to high output cardiac failure and fetal anaemia (with MCA velocity Doppler), due to chronic
haemorrhage into the tumour (Figure 7). The pregnancy was uneventful until 37 weeks when the patient was admitted with prelabour rupture of membranes and a breech presentation.The tumour measured 20 cm in diameter. A Caesarean section under spinal anaesthetic was organized and 400 ml of slightly blood-stained £uid was aspirated from the tumour under ultrasound guidance in theatre immediately prior to Caesarean section. The fetus was delivered to the paediatric team in good condition (Figure 8) and successful surgical repair took place the next day.The baby was discharged12 days later.
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CURRENT OBSTETRICS & GYNAECOLOGY
Figure 6
Cystic sacrococcygeal teratoma.
Figure 7
Vascular nature of sacrococcygeal teratoma demonstrated by power Doppler.
Comments Detection of this rare anomaly on the 20 -week scan had many advantages. The couple had time to adjust to the diagnosis, had the opportunity of meeting the paediatric team, surgeons and neonatal unit and were fully prepared for the likely postnatal outcome. In addition, monitoring in pregnancy was planned in the knowledge that
antenatal intervention would be possible should the above complications occur. Towards the end of the pregnancy, it was clear that delivery would be complicated by the large tumour. Arrangements were made for aspiration of the cystic component of the teratoma prior to Caesarean section which, despite prelabour rupture of the membranes, proceeded smoothly with a subsequent straightforward delivery.
SUSPECTED FETAL ANOMALY
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FURTHER READING Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides K. Absence of nasal bone in fetuses with trisomy 21at11^14 weeks of gestation: an observation study. Lancet 2001; 358:1665. Cuckle H. Time for total shift to ¢rst-trimester screening for Down’s syndrome. Lancet 2001; 35: 1658. Ewigman BG, Crane JP, Frigoletto FD, LeFevre ML, Bain RP, McNellis D. E¡ect of prenatal ultrasound screening on perinatal outcome. RADIUS Study Group. N Engl J Med 1993; 329: 821^ 827. Howe DT, Gornall R, Wellesley D, BoyleT, Barber J. Six year survey of screening for Down syndrome by maternal age and mid-trimester ultrasound scans. BMJ 2000; 320: 606^ 610. Malone FD, Berkowitz RL, Canick JA, D’Alton ME. First trimester screening for aneuploidy: research or standard of care? Am J Obstet Gynecol 2000; 182:490 ^ 496. OMIM. On line Mendelian Inheritance in Man. www.ncbi.nlm.nih.gov/ Omim/mimhelp.html. Souka AP, Snijders RJ, Novakov A, Soares W, Nicolaides KH. Defects and syndromes in chromosomally normal fetuses with increased nuchal translucency thickness at 10 ^14 weeks of gestation. Ultrasound Obstet Gynaecol 1998; 11: 391^ 400. Twining P, McHugo JM, Pilling DW (eds). Texbook of Fetal Abnormalities. London: Churchill Livingstone, 2000. Taylor MJO, Fisk NM. Multiple pregnancy. Obstet Gynaecol 2000; 2: 4 ^10. Wald NJ, Cuckle HS. Maternal serum screening for Down syndrome. BMJ1988; 297: 883^ 887.
Figure 8 surgery.
Appearance of the teratoma prior to postnatal
PRACTICE POINTS K
K
K K
Fetal anomalies are not just suspected or diagnosed by ultrasound Prenatal planning is essential where there is either a relevant family or past obstetric history Seek genetic advice early RememberFkeep up to date; advice given in a pregnancy 1 year ago may not be applicable now
c 2002 Elsevier Science Ltd doi:10.1054/cuog.2001.0253 available online at http://www.idealibrary.com on
Suspected fetal anomaly Catharine Bangham* and Timothy G.Overtonw *Associate Specialist in Fetal Medicine and wConsultant Obstetrician and Gynaecologist, Subspecialist in Maternofetal Medicine, Department of Obstetrics and Gynaecology, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK
KEYWORDS fetal anomaly; prenatal diagnosis; maternal serum screening; nuchal screening; fetal therapy
Summary Major structural abnormalities occur in 2^3% of fetuses accounting for 20^30% of perinatal mortality in the developed world. The vast majority occur in lowrisk women, are sporadic and therefore cannot be anticipated. With rapid advances in molecular diagnostic techniques and recent developments in in-utero therapy, early diagnosis of fetal problems is imperative.While tests such as ¢rst and second trimester ultrasound assessment and serum screening are becoming more e¡ective, the importance of a detailed history atthe beginning of pregnancy should not be underestimated. In addition, preconceptual counselling for ‘at risk’ families can have a major impact on pregnancy outcome.This article discusses current methods for detecting fetal anomalies and summarizes the management options.
c 2002 Elsevier Science Ltd
WHY IS DETECTIONOF A FETAL ANOMALY IMPORTANT? Initiation of fetal therapy Intrauterine transfusion (IUT) The most common cause of fetal anaemia is alloimmunization. The link between the presence of anti-RhD antibodies in the maternal circulation and erythroblastosis fetalis was ¢rst shown in 1954 by Chown when a woman gave birth to an anaemic baby with erythroblastosis and was found to have Rhesus D fetal cells in her circulation. Improved fetal surveillance techniques with ultrasound allows for the early detection of anaemic fetuses which can be transfused in utero preventing the development of fetal hydrops. Each IUT carries with it a perinatal loss rate of 1^3% although this ¢gure approaches 20% if the fetus is already hydropic. In alloimmune red cell haemolytic disease, the fetus becomes anaemic because of transplacental passage of maternal antibodies. In the early 1990s, the most common indication for intrauterine transfusions was anaemia due to anti-D antibodies. More recently, however, an increasing proportion of IUTs are required for the treatment of fetal anaemia due to other antibodies. In the case of anti-Kell, the anaemia is due to antibody suppression of fetal erythropoiesis rather
than red cell lysis. Serial middle cerebral artery (MCA) Doppler velocity measurements have recently been shown to be a useful tool for predicting fetal anaemia, whatever the aetiology. They are particularly helpful in monitoring Kell-sensitized pregnancies where serial amniocenteses for OD450 estimation are not helpful and repeated fetal blood sampling will carry a signi¢cant cumulative mortality rate and risk of worsening sensitization. Fetal infection with Parvovirus B19 can cause fetal anaemia.Features of the disease in the mother or siblings may vary from an obvious fever with distinctive erythematous rash on the cheeks (‘slapped cheek’) to being asymptomatic. If the mother has had contact with a known case and her stored pre-pregnancy serum was sero-positive, the fetus would be una¡ected by the virus. If, however, she was sero-negative, she should have weekly ultrasound scans for 12 weeks in order to look for increasing MCA Doppler velocities and non-immune hydrops. If present, the fetus should have fetal blood sampling with a view to intrauterine fetal transfusion if anaemia is con¢rmed. Unlike alloimmunization, the precipitating factor for the red cell lysis, i.e. the virus, does not persist and repeated transfusions are rarely required.
Treatment for the twin^twin transfusion syndrome Correspondence to: TGO.Tel.: +44 (0) 1603 286790; E-mail: [email protected]
Twin ^ twin transfusion syndrome (TTTS) complicates 10 ^15% of monochorionic twin pregnancies and requires
162
prompt diagnosis and urgent assessment. Untreated, TTTS has a perinatal mortality exceeding 80%. Regular ultrasound assessment throughout pregnancy at fortnightly intervals from about 16 weeks’ gestation is needed to detect early features of the disease a¡ording the opportunity for planned treatment. Presentation is usually in the second trimester, the most obvious ultrasound feature being discordant amniotic £uid volumes, with an oliguric donor (‘stuck’ twin) and a polyuric recipient with severe polyhydramnios.There are various treatment options. Amnioreduction shows a survival rate of 60 ^ 65%. Septostomy (whereby the intertwin membrane is punctured with a sterile needle under ultrasound supervision) which equilibrates the amniotic sac volumes has shown an 85% survival rate in a pilot series. Both these options are the subject of an international randomized multicentre trial. Selective feticide of one twin by cord occlusion allows the remaining twin to continue to term in less than 85% of cases. Laser ablation of communicating vessels has survival rates of 49^ 67%.
CURRENT OBSTETRICS & GYNAECOLOGY
In-utero surgery This is a rapidly developing ¢eld hampered at present by the signi¢cant risk of preterm labour once the uterus has been opened to gain access to the a¡ected fetus. There are a handful of successful case reports in the literature for the treatment of neural tube defects. Nevertheless, such aggressive treatment programmes are only carried out in a few centres worldwide in the context of research projects. Other surgical procedures such as shunting of the fetal lungs or bladder are well established. This can decrease perinatal morbidity from pulmonary hypoplasia due to pleural e¡usions or kidney damage due to bladder outlet obstruction from posterior urethral valves. Tense polyhydramnios leading to the possibility of preterm labour can be treated by amnioreduction. This condition most commonly occurs with intestinal atresias and the patient should be scanned regularly to detect the development of polyhydramnios.
Optimizing conditions for delivery Fetal medication Fetal cardiac arrhythmias can cause heart failure and hydrops. Early identi¢cation on ultrasound enables maternal administration of anti-arrhythmics, such as £ecainide or digoxin, which cross the placenta and treat the fetus. Sometimes large doses are required to achieve therapeutic levels in the fetus and maternal serum levels must be monitored in order to avoid toxicity.
Planning for the delivery of a baby with a major malformation includes consideration of the timing, the location and the provision of appropriate sta¡ both obstetric and paediatric. Patients with anomalies amenable to surgery can be reviewed by paediatric surgeons during the antenatal period, allowing parents to meet the team who will be providing care for their baby. Fetuses with major cardiac anomalies requiring intervention early in the
Figure 1 Ultrasound appearance of fetus with gastroschisis with loop of bowel herniating from the anterior abdominal wall.
SUSPECTED FETAL ANOMALY
neonatal period should be delivered in a unit with appropriate paediatric support.
Parental preparation Preparing parents emotionally for the birth of a child with a major malformation is an important part of fetal medicine. Unexpected (external) malformations such as facial clefts, talipes, and gastroschisis (Figures1 and 2), will cause great distress to parents at delivery. Prenatal diagnosis of these conditions allows time for the parents to meet the team involved in postnatal care, to see pictures of other infants who have been successfully treated, and to map out a provisional timetable for the postnatal plan of action. When a fetal anomaly is diagnosed a large amount of new information has to be assimilated by the parents. Making a diagnosis well before birth allows time for the parents to develop their understanding of complex problems, often with a genetic background. For example, the presence of a cystic hygroma with normal fetal karyotype can be associated with genetic syndromes which may not be diagnosed prenatally. Sometimes uncertainties exist for clinicians and these need to be shared with couples while o¡ering them maximum support. Contributions from genetics specialists at this time can be helpful to parents.They also need to be prepared for the inevitable separation when a baby has to be cared for on NICU and during paediatric surgery. Visiting the unit and meeting sta¡ prenatally will assist their understanding and also enable them to prepare other family members such as siblings and grandparents.
Acknowledging parental needs In the case of lethal conditions or malformations which will lead to severe mental or physical handicap, couples may wish to consider the option of termination of
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pregnancy. Some couples faced with this information would not wish to end the pregnancy but would ¢nd the preparation time helpful. Of course some parents may elect not to have any prenatal screening tests at all and would rather ‘take life as it comes’.
HOW DO WE DETECT FETAL ANOMALY? Awareness of high-risk individuals Many groups of patients are at high risk of having a baby with a fetal anomaly and it is important for clinicians to be aware of these groups. Meticulous history taking and good follow-up after an a¡ected pregnancy are vital in predicting fetal anomalies. Ultrasound is one tool in the process of detection but it should not be used in isolation. Ideally, these patients should be identi¢ed before conception so that optimum conditions for pregnancy can be established.
History This should include a history of previous pregnancies and where possible a family history. Women who have had a fetal malformation or chromosomal abnormality in the past should be counselled a few weeks after an a¡ected pregnancy has ended. It is important to assemble as many results as possible prior to this consultation so that the parents can be well informed about recurrence risks. These patients should be seen early in subsequent pregnancies. A family history should include both genetic and structural anomalies, particularly cardiac malformations, facial clefts and neural tube defects in parents, siblings or grandparents. Access to a genetics counsellor should be part of a fetal medicine service and in an urgent situation, they would often be able to o¡er telephone advice with information on planning future care. The Online Mendelian Inheritance in Man, OMIM, website provides comprehensive information with constant updates.
Maternal disease
Figure 2 Immediate postnatal appearance of the gastroschisis; the need for parental preparation is well illustrated.
Cardiac malformations and neural tube defects are more common in women with insulin-dependent diabetes. The incidence can be reduced by encouraging meticulous diabetic control both preconceptually and in the early weeks of pregnancy. Thyroid disease in the mother should be diagnosed and treated preconceptually. Ninety per cent of cases of hyperthyroidism in pregnancy are due to Graves disease.The resultant fetal thyrotoxicosis is due to transplacental passage of thyroid stimulating antibodies.Untreated it has an adverse e¡ect on perinatal outcome with a preterm delivery rate of 11^25% and a stillbirth rate of 8 ^15%. Diagnosis is
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sometimes missed because the symptoms of tachycardia, heat intolerance and systolic £ow murmurs are common in pregnancy.
Maternal medication The use of anticonvulsants in the periconceptual period increases the risk of major malformation, particularly facial clefts, neural tube defects and cardiac anomalies.The risks increase if more than one drug is used; for example, 7% with one drug, 15% with two drugs and 25% with three. Folate antagonism is a likely e¡ect of many anticonvulsants and it is recommended that these women take 5 mg of folic acid daily, both preconceptually and for the duration of the pregnancy. Preconceptual adjustment of medication by a neurologist or maternal medicine specialist is appropriate. However, it must be kept in mind that a balance should be struck when altering drug therapy so that the frequency of the ¢ts does not increase, putting the mother at risk of injury and the fetus at risk of prolonged or repeated hypoxic episodes. Lithium is associated with increased risk of cardiac malformations and preconceptual substitution with another drug, if adequately e¡ective, may be preferable. Addiction to alcohol can result in the fetal alcohol syndrome. Features seen on the ultrasound scan can include growth restriction, microcephaly, ASDs, VSDs and renal hypoplasia. There is currently a suspicion that the use of ‘recreational drugs’ in the early weeks of pregnancy may be causing an increased incidence of gastroschisis. Information on drugs in pregnancy is available from the National Teratology Information Service, telephone number +44 (0)1912321525.
Age In view of the increasing incidence of aneuploidy with advancing maternal age, many units will o¡er prenatal diagnosis with invasive testing to women over 35 years. However, this strategy alone will only detect 27% of fetuses with Trisomy 21. Some women in this age group may wish to have maternal serum screening and decide about invasive testing when a numerical risk based on both age and biochemistry is available. Others may wish for a de¢nitive test by CVS or amniocentesis but have nuchal translucency (NT) measurement ¢rst. In the event of a low-risk NT measurement she could opt for amniocentesis with its lower miscarriage risk and greater availability.
Multiple pregnancy Chorionicity should be routinely determined in all twin pregnancies before 12 weeks when 100% accuracy can be achieved. In the midtrimester, the accuracy reduces to 80 ^90% unless dicordant genitalia are seen in which
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case dizygocity and therefore dichorionicity is con¢rmed. This is important because monochorionic twins have a ¢vefold increase in late miscarriage and perinatal mortality and discussion with parents regarding risks will be based on this ¢rst trimester information. The incidence of fetal anomalies is higher in twins than in singletons, and higher in monochorionic as opposed to dichorionic twins. Major cardiac anomalies, oesophageal atresia with or without trachea-oesophageal ¢stula, and anencephaly are particularly relevant to twin pregnancies.
Screening tests Serum screening tests for Down syndrome are usually performed in the second trimester but there is increasing support for the introduction of routine ¢rst trimester screening either by nuchal translucency estimation alone or in combination with serum biochemistry.
Nuchal translucency Increased nuchal translucency (NT) is associated with aneuploidy (Figure 3), most notably Down syndrome. The largest study using 96 000 patients reported a Down detection rate of 72% while in contrast other groups in similar populations reported a rate of only 50%. The differences could be multifactorial, including di¡erences in training, de¢nition of screen positive and quality of follow-up. When comparing this method with second trimester triple screening, criticisms have been made over the value of the ¢rst trimester test which will detect some fetuses destined to miscarry due to aneuploidy, therefore diluting the numbers of a¡ected fetuses in the second trimester cohort. There is increasing evidence of an association between increased NT and some structural anomalies particularly major cardiac defects, diaphragmatic hernia, exomphalos and body stalk anomaly. If a fetus has increased NT and a normal karyotype, it is important to search for these anomalies at the 20 -week scan having ¢rst excluded infection. Other associations include some skeletal dysplasias and rare genetic syndromes. A recent report has suggested that those fetuses a¡ected by Down syndrome are more likely to have absent nasal bones on the11^14 -week scan. Mathematical modelling predicts that combining NT assessment with nasal bone visualization alone may increase the detection rate for Down syndrome to 92.4% and further combining with serum biochemistry to 97.5% for a 5% false-positive rate. Of course, a ¢rst trimester ultrasound has the additional bene¢t of accurate dating for the pregnancy, the opportunity for the detection of a number of major abnormalities and accurate determination of chorionicity in multiple pregnancies.
SUSPECTED FETAL ANOMALY
Figure 3
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Increased nuchal translucency in fetus a¡ected by Down syndrome.
Serum screening Second trimester serum screening is widely available to patients in the UK. Success rates vary depending on the test used. Maternal age, free b-hCG and AFP will have a detection rate in the order of 63% whereas maternal age, free b-hCG, AFP, uE3 and inhibin A will have a detection rate of nearer 72%. The debate between the relative advantages of ¢rst versus second trimester screening continues. Two large trials comparing the two are currently underway. The SURUSS trial (Serum Urine and Ultrasound Screening Study) is UK based and funded by the MRC.The FASTER trial (First and Second Trimester Evalation of risk for aneuploidy) is USA based, is enrolling 60 000 patients for ¢rst and second trimester screening and patients will be followed up until pregnancy completion. Until these large prospective trials report it will be di⁄cult to compare the e⁄cacy of these di¡erent screening programmes.
and a 19-week anomaly scan coupled with invasive testing indicated that the overall detection rate was 68%.
Look at the clinical picture Despite signi¢cant technological advances over the last decade, it is important not to ignore the clinical picture. Hyperemesis requiring hospital admission in the ¢rst trimester should raise the suspicion of molar or multiple pregnancy. Illness in the mother suggestive of cytomegalovirus, toxoplasmosis, Parvovirus B19, should be con¢rmed by serology. Ultrasound should be used to look for intracerebral features (such as microcephaly, ventriculomegaly, periventricular calci¢cation), cardiomegaly, hydrops and growth restriction. Anomalies may have gone undetected in the ¢rst and second trimesters. Presentation in the third trimester as large for gestational age would raise the possibility of polyhydramnios associated with fetal anomaly or macrosomia due to diabetes.
Twenty-week anomaly scan
CONCLUSION
The value of this scan performed routinely in an unselected population has been the subject of great debate (RADIUS study). A high detection rate of major malformation is dependent on the availability of well-trained sta¡, good-quality machines and rigorous audit. Regular joint meetings with feedback on anomalies, detected and missed, form an essential part of improving quality. In a recent study, where the detection of Down syndrome relied on the o¡er of invasive testing to women over 35
Suspected fetal abnormality is not merely the detection of problems by ultrasound. Complicated pregnancies should be anticipated prenatally in order to optimize conditions for pregnancy, counsel appropriately and plan for the pregnancy itself. If an unexpected anomaly is detected in pregnancy referral to a specialist unit should be arranged for discussion regarding de¢nitive diagnosis, therapy where necessary, and careful preparation for the delivery. Cases such as these require sensitive
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management with adequate protected time and the opportunity for follow-up visits for further discussion.
Case 1: Fetal anomaly in a high-risk pregnancy A 36 -year-old patient, Para 2, with previously uncomplicated pregnancies presented at 10 weeks’ gestation for a dating scan. The patient had had a cleft lip and palate repaired in infancy but otherwise had no relevant history. A dichorionic, diamniotic twin pregnancy was diagnosed and nuchal translucency screening gave a low risk of Down syndrome for both fetuses. The 20 -week fetal anomaly scan demonstrated that both twins were female, discordant for growth and the smaller twin appeared to have an absent stomach, a two-vessel cord and marginal polyhydramnios. No facial clefting was demonstrated in either twin. A tentative diagnosis of oesophageal atresia was made and amniocentesis was discussed because of the association of these markers with aneuploidy. The parents declined amniocentesis at this stage, although the option of karyotyping in the third trimester was left open. At 34 weeks, after repeated monitoring had shown discordant growth, the polyhydramnios had become signi¢cant, resulting in anxiety over potential preterm labour with the possible need for amnioreduction. However, the abdomen remained soft, there were no contractions and the cervical length measured by transvaginal ultrasound was 31mm with no funnelling at the internal os. At all times, the parents wished to do everything possible to maximize the chances of a good outcome for both fetuses but they appreciated that knowing the karyotype of the a¡ected fetus would make management easier. At 36 weeks an amniocentesis was performed for the a¡ected fetus and the PCR result available after 48 h was negative for Trisomy 21, 18 and 13. She was induced at 37 weeks and 3 days because of reduced fetal growth in Twin 2. The labour was complicated by fetal distress in Twin 2 at 8 cm dilatation and an emergency Caesarean section was performed. The infants weighed 2.83 and 1.92 kg and the diagnosis of oesophageal atresia was con¢rmed in the smaller twin.
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considered. Early testing may have precipitated miscarriage or preterm labour thus jeopardizing the chances for the una¡ected twin. Third trimester testing causing preterm labour would give the una¡ected twin a better chance. However, an abnormal karyotype at that stage would have raised issues of management, for example selective feticide or non-intervention in the event of severe IUGR antenatally or fetal distress in labour. If karyotyping is delayed, the patient may deliver before a result is available. Ten per cent of dichorionic twins will be monozygous and genetically identical. Aneuploidy if present would a¡ect both. In this case, if the karyotype of the a¡ected twin had been abnormal, testing of the apparently normal co-twin would have been necessary.
Case 2: Fetal anomaly suspected following serum screening A 33-year-old patient, Para1, presented for a dating scan at 10 weeks and the gestation was con¢rmed. This was her ¢rst pregnancy in a new relationship and her partner had no children. She was o¡ered maternal serum screening and this was performed at 17 weeks and 3 days. The serum AFP (0.62 mom), unconjugated oestriol (0.41mom) and HCG (0.19 mom) were all low, raising the suspicion of Trisomy 18. She was seen at 18 weeks to discuss this result and a fetal anomaly scan was performed to look for markers of aneuploidy. The fetus was slightly small for dates, had bilateral 4 mm choroid plexus cysts (Figure 4), abnormal hands with the ¢fth and second ¢ngers overlapping the second and third (Figure 5), a VSD, and echogenic bowel. The fetal pro¢le appeared normal. These ¢ndings were discussed with the parents and they opted for amniocentesis. Amniotic £uid was sent for culture and also for polymerase chain reaction (PCR) assay for the detection of Trisomy 21, 18, 13, and DF508, the common mutation of cystic ¢brosis. PCR was positive for Trisomy 18 and also demonstrated that the fetus was homozygous for the cystic ¢brosis mutation.Termination of pregnancy was o¡ered and performed. The ultrasound ¢ndings were con¢rmed at autopsy.
Comments This woman had a detailed scan because of the 4 ^7% recurrence risk of a cleft. Having suspected oesophageal atresia, information about the possible outcomes and therapies was given. The risk of polyhydramnios and resultant preterm labour were discussed. Oesophageal atresia is associated with aneuploidy, particularly Trisomy 18 in 10% of cases in some series, therefore the possibility of karyotyping needed to be addressed. In addition, the timing of an invasive test needed to be
Comments Genetic counselling for this couple will be extremely important.The chances of recurrence of the Trisomy18 are small. However, they are both carriers of the cystic ¢brosis mutation and therefore there is a 25% chance that future pregnancies will also be a¡ected. Chorionic villus sampling between 11 and 14 weeks will be o¡ered in any future pregnancies to check the karyotype and cystic ¢brosis status of the fetus.
SUSPECTED FETAL ANOMALY
Figures 4 and 5
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Choroid plexus cyst and abnormal hand in fetus a¡ected with Edwards syndrome.
Case 3: Unexpected fetal anomaly in a low-risk patient A 23-year-old primigravid patient had a routine anomaly scan at 21 weeks. A 6.5 cm cystic sacrococcygeal teratoma Type I was diagnosed (Figure 6). No associated anomalies were detected although these can occur in 18% of cases. She was assessed every 2 weeks in order to detect polyhydramnios with its risks of preterm labour, hydrops due to high output cardiac failure and fetal anaemia (with MCA velocity Doppler), due to chronic
haemorrhage into the tumour (Figure 7). The pregnancy was uneventful until 37 weeks when the patient was admitted with prelabour rupture of membranes and a breech presentation.The tumour measured 20 cm in diameter. A Caesarean section under spinal anaesthetic was organized and 400 ml of slightly blood-stained £uid was aspirated from the tumour under ultrasound guidance in theatre immediately prior to Caesarean section. The fetus was delivered to the paediatric team in good condition (Figure 8) and successful surgical repair took place the next day.The baby was discharged12 days later.
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Figure 6
Cystic sacrococcygeal teratoma.
Figure 7
Vascular nature of sacrococcygeal teratoma demonstrated by power Doppler.
Comments Detection of this rare anomaly on the 20 -week scan had many advantages. The couple had time to adjust to the diagnosis, had the opportunity of meeting the paediatric team, surgeons and neonatal unit and were fully prepared for the likely postnatal outcome. In addition, monitoring in pregnancy was planned in the knowledge that
antenatal intervention would be possible should the above complications occur. Towards the end of the pregnancy, it was clear that delivery would be complicated by the large tumour. Arrangements were made for aspiration of the cystic component of the teratoma prior to Caesarean section which, despite prelabour rupture of the membranes, proceeded smoothly with a subsequent straightforward delivery.
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FURTHER READING Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides K. Absence of nasal bone in fetuses with trisomy 21at11^14 weeks of gestation: an observation study. Lancet 2001; 358:1665. Cuckle H. Time for total shift to ¢rst-trimester screening for Down’s syndrome. Lancet 2001; 35: 1658. Ewigman BG, Crane JP, Frigoletto FD, LeFevre ML, Bain RP, McNellis D. E¡ect of prenatal ultrasound screening on perinatal outcome. RADIUS Study Group. N Engl J Med 1993; 329: 821^ 827. Howe DT, Gornall R, Wellesley D, BoyleT, Barber J. Six year survey of screening for Down syndrome by maternal age and mid-trimester ultrasound scans. BMJ 2000; 320: 606^ 610. Malone FD, Berkowitz RL, Canick JA, D’Alton ME. First trimester screening for aneuploidy: research or standard of care? Am J Obstet Gynecol 2000; 182:490 ^ 496. OMIM. On line Mendelian Inheritance in Man. www.ncbi.nlm.nih.gov/ Omim/mimhelp.html. Souka AP, Snijders RJ, Novakov A, Soares W, Nicolaides KH. Defects and syndromes in chromosomally normal fetuses with increased nuchal translucency thickness at 10 ^14 weeks of gestation. Ultrasound Obstet Gynaecol 1998; 11: 391^ 400. Twining P, McHugo JM, Pilling DW (eds). Texbook of Fetal Abnormalities. London: Churchill Livingstone, 2000. Taylor MJO, Fisk NM. Multiple pregnancy. Obstet Gynaecol 2000; 2: 4 ^10. Wald NJ, Cuckle HS. Maternal serum screening for Down syndrome. BMJ1988; 297: 883^ 887.
Figure 8 surgery.
Appearance of the teratoma prior to postnatal
PRACTICE POINTS K
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Fetal anomalies are not just suspected or diagnosed by ultrasound Prenatal planning is essential where there is either a relevant family or past obstetric history Seek genetic advice early RememberFkeep up to date; advice given in a pregnancy 1 year ago may not be applicable now