The World Health Organization (WHO)’s Global Strategy for Women’s, Children’s and Adolescents’ Health is to promote equality in access to care by providing adapted screening, diagnosis and care strategies based on the rights to physical and mental health and well-being. Even in the fetal period, prenatal diagnosis and recent fetal therapies aim to investigate and treat the fetus as it would be in postnatal life, and face issues of equitable access and feasibility, particularly in low-income countries.

Supraventricular tachycardia (SVT) belongs to the common cardiac causes of fetal heart failure and perinatal death [1]. With the arrival of ultrasound imaging to non-invasively detect cardiac anomalies before birth, the fetus has increasingly become the target of intended prenatal treatment. This includes the off-label administration of pharmaceutical agents via the maternal circulation or directly into the fetus to treat SVT. As anti-arrhythmic drugs act on one or several ion channels, the autonomous system, or both, we will start with an overview of the normal and abnormal electro-mechanical activation of the heart before discussing indications, modes of action, and effects of anti-arrhythmic therapy for fetal SVT.

Gene therapy uses a vector to deliver a gene to its required site, where expression of the protein can produce a therapeutic effect. In the last decade there have been significant therapeutic breakthroughs, with clinical trials of postnatal gene therapy showing efficacy for a variety of diseases, such as hemophilia, congenital blindness, congenital immunodeficiency and neuromuscular disorders, and the first gene therapy for familial hyperlipidemia was approved in the European Union (EU) in 2012.

Fetal growth restriction (FGR) can be defined as the failure of the fetus to meet its genetically predetermined growth potential [1] and is associated with significant fetal and perinatal morbidity and mortality. In addition, there is evidence to suggest a longer-term impact of FGR on childhood neurodevelopmental outcomes [2] and cardiovascular and metabolic diseases that manifest in adulthood [3]. However, predicting FGR is not straightforward and methods for screening and diagnosis are imprecise. In the UK and USA, ultrasound scans in the second half of pregnancy are not performed routinely but targeted at women considered to be at risk for FGR, where high risk is identified by maternal characteristics (including anthropometry and pre-existing disease), the development of complications, or clinical suspicion based on being ‘small for dates’ on physical examination. For practical purposes, FGR may be suspected if biometric measurements are below a given threshold of the distribution in the population, typically <10th, 5th or 3rd centile for gestational age, or if there is a reduction in growth velocity (‘crossing centiles’) from previous scans [4]. The difficulty with using biometry alone is that it does not differentiate between the growth-restricted fetus affected by placental insufficiency, and the healthy, constitutionally small fetus. Therefore, additional measures may be employed to diagnose placental dysfunction, such as Doppler studies of the fetal and uteroplacental circulation, and analysis of maternal serum biomarkers. At present, the only treatment available for FGR is to expedite delivery, but at preterm gestations this can also can cause harm. However, new genomics-based research could help us better understand the etiology of growth restriction and identify more accurate diagnostic biomarkers or potential therapeutic targets. This chapter will focus on current practice in screening for and intervention in FGR and will also consider new developments and the future of the field.

Preterm birth, defined as delivery <37 weeks’ gestation, is a major public health issue worldwide. An estimated 15 million babies are born preterm every year [1]. Preterm birth and the associated complications are now the leading cause of mortality in children under the age of 5 worldwide, accounting for 1 million deaths per year [2]. In the US, 11–12% of deliveries occur preterm, and worldwide, this figure is increasing. Babies born at ‘term’ – conventionally designated as 37–42 weeks’ gestation – have consistently better morbidity and mortality outcomes than those born before 37 weeks. In the short term, organ immaturity predisposes the preterm neonate to complications such as intraventricular hemorrhage and periventricular leukomalacia, necrotizing enterocolitis, and respiratory distress syndrome. Immaturity of the immune system increases the risk of neonatal sepsis, meningitis, and pneumonia. In the longer term, preterm babies have an increased prevalence of neurodevelopmental delay and chronic lung disease, and later in life, higher rates of adult-onset disease, from diabetes to hypertension and obesity [3]. Whilst extremely preterm (<28 weeks) and very preterm (28–32 weeks) neonates are at the highest risk of complications, studies have demonstrated that even late preterm birth (34 – 36 + 6 weeks) confers an increased risk of morbidity and mortality [4]. These effects appear to be pervasive, and as such premature infants have been shown to have lower educational attainment and employment than those born at term [5, 6].

Twin, triplet or higher order pregnancies are referred to as multiple pregnancies. The prevalence of multiple pregnancies is around 1 per 80 live births [1]. Twins can be either dizygotic, resulting from the fertilization of two separate ova during a single ovulatory cycle, or monozygotic, resulting from a single fertilized ovum that subsequently divides into two separate individuals. Dizygotic twins are more prevalent than monozygotic twins. Higher order multiples can result from either or both processes. Monozygotic twins can either be dichorionic (1/3), monochorionic (2/3), or mono-amniotic (1/3). Which type of monozygotic twin eventually develops depends on the moment of splitting of the fertilized ovum. If the ovum splits within the first 3 days dichorionic twins develop, if the ovum splits between 4 and 8 days monochorionic/diamniotic twins develop, between 8 and 12 days mono-amniotic twins develop, and if the ovum splits after 12 days this gives rise to conjoined twins.

The fetal membranes (FM) are comprised of the amniotic membrane (AM), chorionic membrane (CM), and underlying maternal decidua. Together they provide a barrier towards ascending infection and enable amniotic fluid (AF) homeostasis. Preterm premature rupture of the membranes (PPROM) can occur spontaneously and complicates around 2% of all pregnancies, leading to preterm birth, chorioamnionitis, neonatal sepsis, limb position defects, respiratory distress syndrome, pulmonary hypoplasia, and chronic lung disease. Membrane separation is a common finding after open fetal surgery that leads to iatrogenic PPROM (iPPROM) and intrauterine infection, complicating over 30% of fetal surgeries. The subsequent associated preterm birth compromises the outcome of treatment, reducing the clinical effectiveness of fetal surgery [1]. Spontaneous healing of the membranes does not occur after fetoscopic surgery, leaving a visible defect in the FM (Figure 50.1) that is prone to AF leakage and subsequent iPPROM [2]. To date, there are no clinical solutions to improve healing of the FM after they rupture.

Significant advances in prenatal imaging have allowed us to diagnose tumors in utero more accurately. These prenatal diagnostic capabilities have significantly increased the benefits for parents, the fetal patient, and the perinatal team who take care of these delicate patients. For the parents of a fetus diagnosed with a neoplastic tissue growth, it affords them more comprehensive prenatal counseling so that they are aware of what to expect for the duration of the pregnancy, and to help them prepare for the challenges the baby will face at the perinatal stage and beyond. For the fetus, prenatal diagnosis has enabled us to identify a subset of these babies who have historically faced a very poor prognosis and may benefit from an in utero intervention that could potentially salvage the pregnancy. Lastly, for the perinatal team prenatal diagnosis helps identify those high-risk patients who will endure significant perinatal challenges and thus empower them to ensure that the baby is delivered in the appropriate setting, at an optimal gestational age, and when indicated with advanced delivery techniques, such as the ex utero intrapartum treatment (EXIT) procedure, to afford the best possible outcome for the most critical patients.

Although not all small babies are truly growth restricted, the fetus that struggles to reach its full growth potential is at substantial risk of fetal and neonatal complications, even more so if not identified antenatally as a faltering fetus. As with most pregnancy complications, the risk of fetal growth restriction (FGR) is increased in twin pregnancies, and more so in monochorionic twin pregnancies. Around 19.7% of monochorionic twin pregnancies are complicated by FGR, compared with only 10.5% of dichorionic twin pregnancies [1]. They also experience a higher incidence of perinatal mortality associated with growth restriction – 75.1/1000 compared with 33.0/1000 [2].

Structural fetal anomalies complicate up to 5% of pregnancies and an underlying chromosomal or genetic etiology underlies up to half of cases. Understanding the fetal genome is increasingly key in attempting to make a prenatal diagnosis and in delineating a prognosis for the baby. Over the past decades, the field of prenatal genomics has advanced exponentially, beginning with the conventional ‘full’ karyotype available in the 1960s and going up to the present day and beyond with the application of next-generation sequencing (NGS) (Figure 4.1). Current and potential future advances in prenatal diagnostics will allow couples to make more informed decisions prospectively about their pregnancies in addition to aiding decisions on and the development of fetal therapies [1]. In the wake of advancing technologies and large prospective studies such as the United Kingdom’s ‘proof of principle’ 100 000 Genomes Project [2] and the Prenatal Assessment of Genomes and Exomes (PAGE) study [3], the degree of information obtained and turnaround time of results with the development of more sophisticated bioinformatic analytical pathways is likely to improve rapidly. Fetal medicine subspecialists, obstetricians, pediatricians, geneticists, genomic scientists and genetic counselors have a responsibility to stay up to date with this wealth of advances so that couples can be informed accordingly.

Despite advances in neonatal intensive care, prematurity remains an unsolved clinical challenge and a leading cause of infant morbidity and mortality [1]. Approximately 6% of all live births in the USA are considered extremely preterm (delivery at less than 28 weeks’ gestation), and the incidence of prematurity has slowly risen over the past decade [2]. Prematurity is thought to account for one-third of infant mortality [3], one-half of cerebral palsy, and 80% of survivors born at 22–28 weeks’ gestation will suffer at least one major co-morbidity [4].

The volume of amniotic fluid, for which nomograms exist [1], is the result of a balance between its production and removal. Amniotic fluid production largely reflects fetal urine production, but includes respiratory tract and oral secretions. Amniotic fluid removal relies on fetal swallowing. Fluid dynamics across the membranes are the third component of this balance. In current clinical practice a surrogate estimate for amniotic volume is made by 2-dimensional ultrasound-derived measurements of vertical cord-free liquor pools, either by amniotic fluid index (AFI) – a cumulative measurement of vertical pools made within 4 quadrants of the uterus – or by the measurement of the single deepest vertical pocket (DVP) within the uterus. Increased production or decreased removal will result in the development of polyhydramnios. The converse will result in development of oligohydramnios. The importance of these abnormalities of amniotic fluid volume is that they are a marker for fetal pathology. Their significance in isolation is limited, as are indications for their manipulation.