Clinical review

Fetal medicine

David James, professor of fetomaternal medicine. 

Queen's Medical Centre, Nottingham NG7 2UH

	Introduction

Top Introduction Methods Conclusions References

In the 13 years since the first annual symposium of "The Fetus as a Patient," diagnostic skills with fetal disease have improved enormously, but therapeutic approaches remain limited. Periconceptual folate, maternal steroids, and fetal blood transfusion are the best examples of preventive, transplacental, and invasive treatments, respectively, and all three were developed more than a decade ago.

Arguably, the most significant advance is that most professionals and parents consider the fetus as a separate individual and a potential patient in his or her own right. Indeed, once the fetus is recognised to be at risk the perinatal outcome is better than in an apparently low risk pregnancy.¹ Antepartum "unexplained" fetal death is by far the commonest cause of death between 20 weeks' gestation and the age of one year, comprising nearly 40% of deaths in this period.² The main challenge in pregnancy care is to improve fetal surveillance in low risk pregnancies so that potentially compromised fetuses can be identified.

	Methods

Top Introduction Methods Conclusions References

In most sections of this review, the references were chosen after a systematic review of the literature of the past eight years. My Medline search (with Ovid) used the keywords fetal assessment, fetal monitoring, twin pregnancy, amnioinfusion, fetal therapy, and fetal awareness. For the sections on fetal assessment and amnioinfusion I also used the Cochrane Library. The references (except on fetal pain, for which there were few references) were chosen to reflect all management options and include, where possible, randomised controlled trials.

	Fetal assessment

Though advances in fetal treatment are limited, progress in fetal evaluation has been considerable. The use of umbilical artery Doppler ultrasonography in the assessment of high risk pregnancies approximately halves the perinatal death rate in normally formed babies.³ Antepartum monitoring of fetal heart rate, though the most widely used method of fetal assessment in late pregnancy, by itself is a poor predictor of fetal health; indeed, it is associated with a threefold increase in perinatal death.⁴ If it has a place in management, it is as part of a comprehensive surveillance package.⁵ It remains to be seen whether the addition to the package of documentation of regional blood flow within the fetusfor example, to the brain⁶ or through the ductus venosus⁷will further improve outcome. Furthermore, the emphasis in fetal care is now no longer exclusively on survival but on the quality of that survival.⁸

Advances in ultrasound technology have contributed greatly to these improvements in outcome in normally formed fetuses (fig 1). Such developments have also resulted in improved diagnosis and evaluation of fetal abnormality. The overall approach to pregnancies with fetal abnormalities has changed: the emphasis is no longer on termination of pregnancy. Further evaluation with rapid karyotyping and tertiary referral to fetal medicine centres are commonplace. Extensive discussion and parental counselling, often interdisciplinary, is the norm, and careful consideration is given to timing, method, and place of delivery.⁹

View larger version (37K): [in this window] [in a new window]   Fig 1.   Use of Doppler ultrasonography has led to improved outcomes of high risk pregnancies. Adapted from Alfirevic and Neilson3

	Problems in twin pregnancies

The twin-twin transfusion syndrome is associated with high mortality and morbidity. It is usually found in monochorionic pregnancies: placental vascular anastamoses have been reported in about 80% of cases compared with less than 1% in dichorionic pregnancies.⁷ The diagnostic ultrasound features of the syndrome are a single placental mass and absence of the lamda sign at the end of the first trimester, and oligohydramnios or anhydramnios in the donor twin (often with apparent absence of a bladder) and hydramnios and a large bladder in the recipient in the second trimester.⁷ There may also be discordant growth between the fetuses or hydrops in one or both.

When the syndrome is untreated, survival ranges from 4% to 75%.^10-12 This wide range probably reflects a variation in severity and diagnostic criteria in the different studies. In the survivors there is a high incidence of neurodevelopmental disability, which is due to a combination of the effects of intrauterine hypoxia or to preterm delivery, or both. In addition, when one of the fetuses dies there is a further increased risk of brain injury (see below).¹³

Serial amniodrainage and laser coagulation of the communicating placental vessels are the most studied treatments for twin-twin transfusion syndrome. Medical methods (indomethacin) and selective fetocide have been used on fewer than 20 fetuses and no conclusions can be drawn from such anecdotal data.¹³

Serial amniodrainage has produced fetal survival rates of 30-80%, and at least one fetus survives in 45-100% of pregnancies.^10-14 In these reports the survival rates were better than those of a conservatively managed group either derived from historical data¹⁰ or from cases concurrently collected but deemed to have less severe disease. ^{10 13-14} The non-randomised, uncontrolled nature of the serial amniodrainage data is unsatisfactory. Furthermore, despite apparently better survival rates, survivors of serial amniodrainage have high morbidity (36-53%), including cerebral palsy. ^{10 13}

Laser coagulation of the communicating vessels has been considered as an alternative. ^{13 15} Overall fetal survival rates of about 50% have been reported, with at least one fetus surviving in 60-72% of pregnancies. Survivors of the procedure are at risk of neurodevelopmental problems; though the incidence of those problems seems lower than in the serial amniodrainage studies, the heterogeneity and non-randomised nature of the case selection makes comparisons difficult.¹⁶

Both serial amniodrainage and laser coagulation seem to have some benefits in twin-twin transfusion syndrome. But published studies of both procedures are non-randomised and uncontrolled. It is time for a multicentre randomised controlled comparison; only 80 patients in each arm of such a trial would be needed to show a significant difference in perinatal mortality and morbidity.¹⁶ Fetal death in a twin can result in death or central nervous system hypoxia or ischaemia in the survivor, though the degree of this risk is disputed.^17-19 It is thought that this event is an extreme outcome of the twin-twin transfusion syndrome in monochorionic twins; the underlying pathophysiological mechanism of death or neurodevelopmental problems in the survivor has been widely debated. The two main hypotheses are disseminated intravascular coagulation resulting from the release of thromboplastins from the dead twin¹³ and hypovolaemia due to haemorrhage from the survivor into the placenta of the dead fetus.²⁰ The latter, a vascular basis for the process, is now more generally accepted.²¹

Options for management are prompt elective preterm delivery of the survivor (with steroids to enhance surfactant production) or a conservative approach.²² The risks of the former strategy are the consequences of prematurity and the risks of the latter are intrauterine death and neurodevelopmental injury. Here too a multicentre randomised trial would be justified.

	Amnioinfusion

Antepartum amnioinfusion has been advocated as a means of improving ultrasound imaging when there is oligohydramnios, ^{23 24} but there have been no randomised trials of the benefits and risks of this approach. Antepartum amnioinfusion has also been studied as a therapeutic approach in oligohydramnios to prevent pulmonary hypoplasia.²⁴

Amnioinfusion (usually with warmed isotonic saline) during labour for potential or suspected umbilical cord compression due to oligohydramnios has been suggested as a preventive or therapeutic strategy. The main finding of the meta-analysis of the several small randomised trials is that the procedure had no effect on Apgar scores or umbilical artery blood gas values (fig 2).²⁵ The incidence of fetal heart rate abnormalities was reduced, as were caesarean section rates, but this benefit seemed to occur when caesarean sections were undertaken on the basis of fetal heart rate abnormalities alone rather than when the suspicion of fetal hypoxia was confirmed by sampling scalp blood before abdominal delivery.²⁶

View larger version (33K): [in this window] [in a new window]   Fig 2.   Meta-analysis of randomised controlled trials of amnioinfusion for potential or suspected (diagnosed by fetal heart rate monitor) umbilical cord compression. Adapted from Hofmeyer25

Another role for intrapartum amnioinfusion has been to "dilute" thick meconium and hence reduce the risk of meconium aspiration syndrome. Meta-analysis has shown some benefit from this approach; caesarean section rates were lower in the treated groups.²⁷ Furthermore, meconium was less common below the vocal cords of the newborn and meconium aspiration syndrome occurred less frequently. The caesarean section rates might have been influenced by the use of fetal heart rate monitoring rather than scalp blood sampling as the principal indicator of fetal wellbeing. The only proved side effects of amnioinfusion in labour are uterine hyperstimulation. ^{26 28}

	Fetal surgery

In many centres, closed surgical procedures on the fetus have been undertaken for conditions such as lower urinary tract obstruction and hydrothorax.²⁹ The benefits of these procedures have been difficult to prove, and there have been no randomised controlled trials.³⁰ Complications, including fetal loss, are well documented. ^{30 31} Indeed, it is now well established that for fetal hydrocephalus such procedures have no benefit.³²

Open fetal surgery has been performed in a small number of centres over the past decade and has attracted much publicity. The main conditions that have been treated are lower urinary tract obstruction, cystic adenomatous malformation of the lung, congenital diaphragmatic hernia, and large sacrococcygeal teratomas.³³ The perinatal loss rates are as high as 50% in some series.³⁴ Part of this mortality is related to the intraoperative risk and some is due to the high rates of prematurity from the almost inevitable associated preterm labour, which can be difficult to control. ^{33 34} Maternal morbidity, especially from thromboembolism, is also high.^33-35 The mother has to have a classic caesarean section for the fetal surgery to be performed and another caesarean section to deliver the baby later in pregnancy.³¹

The benefits of open fetal surgery over no intervention or alternative closed procedures performed under ultrasound control are difficult to assess. The numbers involved are very small and, not surprisingly, there are no data from randomised controlled trials. The high maternal morbidity and high fetal mortality and morbidity, which includes not only the consequences of prematurity but also an apparently independent risk of neurodevelopmental disability in as much as one fifth of long term survivors,³⁶ has led most observers to conclude that the case for open fetal surgery has not been proved.³¹ The hope for the future lies with endoscopic techniques, which are at the research and development phase.³¹

	Fetal pain

The question of whether fetuses feel pain has recently become the focus of much debate.³⁷ It is of practical relevance in the context of late abortions and invasive fetal procedures and, not surprisingly, has been brought into the public debate over abortion in general. The arguments are of several types.

The physiological arguments centre on the view that although the fetus can show responses to a variety of stimuli, that property does not imply "pain," which requires a degree of consciousness and awareness of "self."³⁸ In 1995 Fitzgerald produced a paper for the Department of Health claiming that the fetus before 26 weeks manifests reflexes to stimuli but these are not dependent on conscious appreciation since the cortex is not functional.³⁸ Fitzgerald was not as definitive about fetuses after 26 weeks since thalamocortical fibres penetrate the cortical plate between 26 and 34 weeks. Others have argued that pain is a multidimensional event involving sensory, emotional, and cognitive factors and that there is no evidence for the emotional and cognitive functions being developed in the fetus even after 26 weeks.³³

Another approach to the debate is that although pain cannot be measured directly in the fetus, fetal hormonal stress responses to various stimuli can be, and these have been used as an indirect measure by some workers. This endocrinological approach to diagnosing pain has been used to justify the use of analgesic strategies in newborns. Such endocrine responses in the fetus have been documented from as early as 23 weeks. ^{37 39} Another indicator of acute fetal stress is redistribution of blood flow to the fetal brain (recorded with Doppler techniques) in response to invasive procedures performed as early as 18 weeks.³⁷

All these issues have been considered by a recent working party on fetal awareness.⁴⁰ The working party recommended that:

• Practitioners who undertake procedures directly on the fetus at or after 24 weeks should consider the requirements for fetal analgesia and sedation;
• Practitioners who undertake termination of pregnancy at 24 weeks or later should consider the requirements for fetal analgesia or sedation prior to fetocide;
• Further research into the issues of fetal pain and its treatment should be undertaken.

	Conclusions

Top Introduction Methods Conclusions References

In its early days, fetal medicine focused on the question, "What can we do?" but it should now be asking, "What ought we to do?" The ways in which a variety of fetal diseases might be treated are increasing rapidly. However, fetal medicine now needs to move into the phase of evidence based management, including randomised controlled trials. Given the relative rarity of fetal disorders, this will inevitably mean multicentre collaboration. This is the challenge for the next decade of fetal medicine.

	Acknowledgments

Funding: None.

Conflict of interest: None.

	References

Top Introduction Methods Conclusions References

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