Chapter 10

Perinatal medicine

Mithilesh Kumar Lal, Nazakat Merchant, Sunil K Sinha

With contributions by, Helen Yates, Lawrence Miall, Steve Byrne

Learning objectives

Perinatal definitions and epidemiology

Even simple definitions in perinatology can be contentious. It is traditional to calculate the baby’s due date by asking the mother about the first day of her last menstrual period and relying on this, unless there is a discrepancy with ultrasound dates of more than 10 days. However, expert opinion is divided and some would advise that when results of an ultrasound dating scan are available, the due date should be derived from ultrasound biometry alone (Perinatal Institute of Maternal and Child Health recommendations).

It follows that obtaining accurate data relating to stillbirths and mortality/survival rates in extremely preterm infants is difficult. Comparing data from different countries is even more difficult. This is due to variation in legislation, regulation, and practices of registration of stillbirth, live birth and death. There is wide variation between different countries in gestational age at which fetal deaths are registered as stillbirths, which influences the decision whether extremely preterm births are registered as live birth or miscarriage. Some definitions used in perinatal medicine are listed in Box 10.1. The main causes of perinatal deaths in the UK are listed in Table 10.1.

Box 10.1

Definitions used in perinatal medicine in the UK

• Gestational age in completed weeks is calculated from the first day of the last menstrual period (LMP) to the date of birth.

• Neonate – infant ≤28 days old.

• Preterm – gestation <37 weeks of pregnancy. Often subclassified into extreme preterm (<28 weeks’ gestation), very preterm (28–31 weeks’ gestation), moderate preterm (32–33 weeks’ gestation) or late preterm (34–36 weeks’ gestation).

• Term – 37–41 weeks of pregnancy.

• Post-term – gestation ≥42 weeks of pregnancy.

• Stillbirth – fetus delivered at or after 24⁺⁰ weeks gestational age showing no signs of life.

• Neonatal death – a live born baby (born at 20⁺⁰ weeks gestational age or later, or with a birth weight of 400 g or more where an accurate estimate of gestation is not available) who died before 28 completed days after birth.

• Perinatal mortality rate – stillbirths + deaths within the first week per 1000 live births and stillbirths.

• Neonatal mortality rate – deaths of live-born infants within the first 4 weeks after birth per 1000 live births.

• Postneonatal mortality rate is the number of deaths aged 28 days and over, but under one year per 1000 live births.

• Infant mortality rate is the number of deaths under 1 year of age per 1000 live births. This includes neonatal deaths.

• Low birth weight (LBW) – <2500 g

• Very low birth weight (VLBW) – <1500 g

• Extremely low birth weight (ELBW) – <1000 g

• Small for gestational age – birth weight <10th centile for gestational age.

• Large for gestational age – birthweight >90th centile for gestational age.

Table 10.1

Stillbirths and neonatal deaths in the UK, 2013

Stillbirths (4.2 per 1000 total births)	Neonatal deaths (1.8 per 1000 live births)
Unexplained antepartum fetal death 52%	Immaturity 44%
Intrapartum 9%	Congenital malformation 22%
Congenital malformation 6%	Intrapartum causes 6%
Infection 3%	Infection 6%
Placenta 19%	Fetal 5%
Other 11%	Other 17%

Maternal risk factors for poor fetal outcomes in the UK include coexisting medical conditions, parity, socio-economic status, age, nutrition, antenatal service provision and their utilization. The perinatal mortality rate has decreased from 13.3 in 1980 to 6.0 in 2013 in England and Wales. Improved maternal health and nutrition, socio-economic conditions, better antenatal and perinatal care, high antenatal steroid uptake and improved survival of preterm infants have contributed. Changes in neonatal, postneonatal and infant mortality rates are shown in Figure 10.1.

Fig. 10.1 Infant, neonatal and postneonatal mortality rates in England and Wales 1982–2012. (Data from Office of National Statistics).

Globally, almost 99% of neonatal deaths occur in low- and middle-income countries and the main causes are preterm birth (34%), infection (23%), and perinatal asphyxia (25%).

The epidemiology of mortality statistics and their collection is considered in more detail in Chapter 2, Epidemiology and public health, and a global overview is considered in Chapter 33, Global child health.

Placental physiology and early embryology

Placental function

The placenta has three major functions: transport, immunity and metabolism. The placenta starts to develop as soon as the blastocyst implants in the uterine endometrium, forming the trophoblast (Fig. 10.2). A network of umbilical blood vessels then develop and branch through the chorionic plate to form villi. On the maternal side of the placenta, the blood supply is complete by 11–12 weeks. The uterine spiral arteries dilate and straighten and bathe the intervillous space with blood.

Fig. 10.2 Early embryology of the fetus.

Transport

The placenta transports nutrients from the mother to the fetus, and waste products in the other direction. This occurs in a number of ways, including simple diffusion (for small molecules) and active transport of larger molecules. The placenta is crucially also responsible for gaseous exchange of O₂ and CO₂. Oxygen diffuses from the mother (pO₂ = 10–14 KPa) to the fetus (pO₂ = 2–4 KPa), where it binds to fetal haemoglobin (Hb), which has a higher affinity for oxygen than maternal Hb for a given pO₂. This off-loading of oxygen from maternal Hb is also facilitated by a change in maternal blood pH.

Immunity

The placental trophoblast prevents the maternal immune system from reacting against ‘foreign’ fetal antigens. Rejection does not occur because the trophoblastic cells appear non-antigenic, although it is known that some fetal cells do cross into the maternal circulation where they can trigger an immune reaction (e.g. Rhesus haemolytic disease). Maternal IgG antibody, the smallest of the immunoglobulins, can cross the placenta, where it provides the newborn with innate immunity to infectious diseases. IgM immunoglobulins do not cross the placental barrier. This is of particular relevance in the diagnosis of congenital infection.

Metabolism and homeostasis

The placenta is metabolically active and produces hormones, including human chorionic gonadotrophin (HCG) and human chorionic thyrotrophin (HCT). It also detoxifies drugs and metabolites. Because of its metabolic activity, the placenta has very high energy demands and consumes over 50% of the total oxygen and glucose transported across it. The placenta is not solely responsible for fetal homeostasis – the fetal liver produces albumin, red cells and clotting factors and the fetal endocrine glands produce thyroid hormone, corticosteroids and insulin from about 12 weeks. The kidney excretes large volumes of dilute fetal urine from 10–11 weeks, which contributes to amniotic fluid volume.

Question 10.1

Advising a mother planning a pregnancy

A 32-year-old mother attends your clinic for a review of her 18-month-old child, who has gross motor delay. She tells you that she is planning another child. Current UK advice suggests she should avoid eating significant quantities of the following foods, true (T) or false (F):

A. Folate-supplemented foods

B. Honey

C. Liver

D. Tuna

E. Unpasteurized cheese

Answer 10.1

A. False; B. False; C. True; D. True; E. True.

Honey should be avoided in early childhood because of the theoretical risk of infant botulism, but avoidance in pregnancy is not currently advised. The other dietary considerations are discussed below.

Pre-pregnancy care

Advice for mothers includes:

Avoidance of smoking in pregnancy: This is because smoking reduces birth weight which becomes particularly important if there is intrauterine growth restriction. It also increases pregnancy-related risks of miscarriage and stillbirth and preterm delivery. In the infant, it increases the risk of sudden infant death syndrome and wheezing, asthma, bronchitis, pneumonia and otitis media. It has been associated with psychological problems in childhood, such as attention and hyperactivity problems.

Folic acid supplementation: This is advised for all mothers before conception and throughout the first 12 weeks of pregnancy, as it reduces the risk of neural tube defects (NTD) such as anencephaly and spina bifida. Although eating folate-rich foods may help, it is often insufficient. Higher-dose supplements are recommended for those at increased risk (previous NTD pregnancy, family history including partner and maternal diabetes). In the UK, Healthy Start provides free vitamin supplements (folic acid with vitamins C and D) for low-income pregnant women and those who have an infant less than 1 year. In the US and some other countries, folic acid is required to be added to cereals and grains.

Vitamin D supplementation: Vitamin D is required for fetal bone mineralization and accumulation of infant vitamin D stores. A newborn baby’s vitamin D status is largely determined by the mother’s level of vitamin D during pregnancy. Breast milk is not a significant source of vitamin D. The main source of vitamin D is sunlight. For a significant number of months in the UK, there is little ambient ultraviolet sunlight of appropriate wavelength. Vitamin D supplements are advised for all women who are planning to breastfeed their infants and is included in the Healthy Start vitamins, available to all low-income women who are pregnant or have a child under 1 year old.

Avoid medications with teratogenic effects: In addition, all medications should be avoided unless essential.

Avoid alcohol ingestion and drug abuse (opiates, cocaine): These may damage the fetus.

Congenital rubella: Prevent by maternal immunization before pregnancy.

Toxoplasmosis: Minimize exposure by avoiding eating undercooked meat and wearing gloves when handling cat litter.

Listeria infection: Avoid eating unpasteurized dairy products, soft ripened cheeses, e.g. brie, camembert and blue-veined varieties, patés and ready-to-eat poultry.

Eating liver: Best avoided as it contains a high concentration of vitamin A.

Fish: Avoid eating swordfish, shark, marlin and limit tuna intake as they may contain high levels of mercury. Also limit oily fish as they may contain pollutants such as dioxins.

If pre-existing maternal medical conditions, e.g. diabetes and epilepsy: Optimize control.

If at increased risk of fetal abnormality: Genetic counselling should be obtained. This includes previous congenital anomaly, positive family history, parents being known carriers of genetic disorder, ethnic group with increased risk, e.g. Tay–Sachs, a neurodegenerative disorder, in Ashkenazi Jews.

Prenatal care

Routine prenatal screening includes maternal blood sampling, ultrasound scanning and attendance at an antenatal clinic.

Maternal blood

Maternal blood should be tested for blood group, antibodies for rhesus (D) and other red cell incompatibilities, hepatitis B (surface and e-antigen), syphilis serology, rubella, HIV serology, haemoglobin electrophoresis to identify thalassaemia and sickle cell traits.

Ultrasound

It is usual for mothers to have late first and mid-trimester scans. The initial scan allows gestational age estimation and can identify multiple pregnancy, the later scan structural abnormalities and amniotic fluid volume abnormalities. If fetal growth or other problems are identified, monitoring with serial scans may be performed.

Antenatal clinic attendance

Antenatal clinical attendance allows identification of pre-existing maternal medical condition (e.g. hypertension, HIV) or obstetric risk factors for complications of pregnancy or delivery (e.g. recurrent miscarriage or previous preterm delivery). It also facilitates monitoring for pregnancy complications.

Screening

Prenatal screening for disorders affecting the mother or fetus allows:

• Reassurance where disorders are not detected (though many abnormalities which are detected on ultrasound screening are not confirmed on repeat or more expert scanning, or are transient or minor but may cause considerable anxiety)

• Optimal obstetric and neonatal management to be planned and parental counselling provided when problems are detected

• Interventions for a limited number of conditions with fetal medicine or surgery (see below)

• The option of termination of pregnancy to be offered for severe disorders affecting the fetus or compromising maternal health. Parents require accurate, rapid medical advice and counselling to help them with this difficult decision.

Genetic disorders

Pregnancies at increased risk of genetic disorders may be identified on prenatal or antenatal screening. Trisomy 21 (Down’s syndrome) may be suspected on first trimester ultrasound screening of nuchal translucency measurement, which may be combined with maternal serum biochemical screening.

Non-invasive prenatal testing

Non-invasive prenatal testing (NIPT) is where cell-free fetal DNA is obtained from maternal blood. This can now be performed for identification of fetal gender (for X-linked disorders), fetal genotyping (Rhesus) and exclusion of common aneuploidy (especially trisomy 21). It is likely to become increasingly refined and available in clinical settings. It is debated if this should be offered alone or with nuchal translucency ultrasound screening to identify trisomy 21. The advantage is that it avoids the risk of miscarriage with invasive testing procedures, however there are technical, ethical and financial issues.

Invasive prenatal testing

Invasive prenatal testing (see Fig. 10.3) requires an invasive test in pregnancy with the aim of collecting fetal cells. These can be used for:

• Cytogenetic analysis to look for chromosomal abnormalities.

• Molecular analysis in the case of a known genetic mutation.

• Biochemical analysis in the case of a defined disorder with a suitable prenatal biochemical test.

In families already affected by a genetic condition, a prenatal test is only possible where the genetic mutation in the family is known. In a small number of disorders, mainly metabolic, prenatal biochemical or enzyme testing may be possible if the diagnosis has been confirmed in an affected family member.

Fetal medicine

The techniques involved in fetal medicine and their indications are shown in Figure 10.3. Examples of fetal therapy include:

• Glucocorticoid therapy before preterm delivery to accelerate lung maturity and surfactant production

• Digoxin or flecainide given to the mother to treat fetal supraventricular tachycardia

• Rhesus or other isoimmunization causing severe anaemia and hydrops fetalis (oedema and ascites) can be monitored with fetal middle cerebral artery Doppler ultrasound and managed with fetal blood transfusion via the umbilical vein

• Perinatal isoimmune thrombocytopenia, due to antiplatelet antibodies crossing the placenta. Severe thrombocytopenia can be treated with intrauterine intravenous immunoglobulin or platelet transfusion. This is to prevent intracranial haemorrhage, which occurs in up to 25%.

Fig. 10.3 Techniques in fetal medicine and their indications. (Adapted from Neonatology at a Glance. Tom Lissauer, Av Fanaroff, Lawrence Miall, Jonathan Fanaroff (eds). Wiley-Blackwell. 3^rd Edn. 2015.)

Fetal surgery

This is performed in a few specialist perinatal centres, although outcomes have been highly variable. Some examples include:

• Catheter shunts inserted under ultrasound guidance to drain fetal pleural effusions (pleuro–amniotic shunts), often from a chylothorax (lymphatic fluid) or congenital cystic adenomatous malformation of the lung. One end of a looped catheter lies in the chest, the other end in the amniotic cavity. The aim is to reduce the risk of fetal death from hydrops and pulmonary hypoplasia.

• Fetoscopic laser therapy to ablate placental anastomoses which lead to the twin–twin transfusion syndrome (TTTS).

• Intrauterine shunting for urinary outflow obstruction as with posterior urethral valves. Results have been disappointing in reducing morbidity or death because of pre-existing renal damage.

• Fetal endoscopic tracheal occlusion (FETO) for congenital diaphragmatic hernia. As fetal tracheal obstruction promotes lung growth, this is replicated in utero by inflating a balloon in the fetal trachea. This is not recommended outside research trials.

• Spina bifida surgical correction by hysterotomy at 22–24 weeks’ gestation has been performed in a few specialist centres but may precipitate preterm delivery and its benefit remains uncertain. Hydrocephalus requiring shunting may be reduced. Such interventions still remain experimental and without proven long-term benefit.

• Surgery for sacrococcygeal teratoma to remove a growing tumour has been done with mixed results.

Intrauterine growth restriction

An infant’s gestation and birth weight influence the nature of the medical problems likely to be encountered in the neonatal period. In the UK, 7% of babies are of low birth weight (<2.5 kg). However, they account for about 70% of neonatal deaths.

Babies with a birth weight below the 10th centile for their gestational age are called small for gestational age (SGA) or small-for-dates (SFD). The majority of these infants are normal, but constitutionally small. An infant’s birth weight may also be low because of preterm birth, or because the infant is both preterm and small for gestational age. SGA infants may have grown normally but are small, or they may have experienced intrauterine growth restriction (IUGR), i.e. they have failed to reach their full genetically determined growth potential and appear thin and malnourished. Babies with a birth weight above the 10th centile may also be growth restricted, e.g. a fetus growing along the 80^th centile who develops growth failure and whose weight falls to the 20th centile.

As the incidence of congenital abnormalities and neonatal problems is higher in those whose birth weight falls below the second centile (two standard deviations (SD) below the mean), some restrict the term SGA to this group of babies.

In obstetric care, fetal centiles may be customized for maternal characteristics (weight, height, parity, and ethnicity) as well as gestation and gender; this is more predictive of morbidity and mortality.

Patterns of growth restriction

Intrauterine growth restriction implies a pathological restriction of genetic growth potential; this may be identified or monitored by evidence of fetal compromise, such as reduced liquor volume and abnormal Doppler waveforms. It has traditionally been classified as symmetrical or asymmetrical. In the more common asymmetrical growth restriction, the weight or abdominal circumference lies on a lower centile than that of the head. This occurs when the placenta fails to provide adequate nutrition late in pregnancy but brain growth is relatively spared at the expense of liver glycogen and skin fat. This form of growth restriction is associated with uteroplacental dysfunction secondary to maternal pre-eclampsia, multiple pregnancy, maternal smoking or may be idiopathic. These infants rapidly put on weight after birth.

In symmetrical growth restriction, the head circumference is equally reduced. It suggests a prolonged period of poor intrauterine growth starting in early pregnancy. It is usually due to a small but normal fetus, but may be due to a fetal chromosomal disorder or syndrome, a congenital infection, maternal drug and alcohol abuse or a chronic medical condition or malnutrition. These infants are more likely to remain small permanently. In practice, distinction between symmetrical and symmetrical growth restriction often cannot be made.

Monitoring the growth-restricted fetus

The fetus with IUGR is at risk from intrauterine hypoxia/intrauterine death and asphyxia during labour and delivery. The growth-restricted fetus should be monitored closely to determine the optimal time for delivery. Progressive uteroplacental failure results in:

• Reduced growth in femur length and abdominal circumference (<10th centile)

• Reduced amniotic fluid volume

• Abnormal umbilical artery Doppler waveforms due to increased placental impedance – absent and then reversed end-diastolic flow velocity

• Redistribution of blood flow in the fetus – increased to the brain, reduced to the gastrointestinal tract, liver, skin and kidneys

• Abnormal ductus venosus Doppler waveform denoting diastolic cardiac dysfunction

• Reduced fetal movements

• Abnormal CTG (cardiotocography)

• Intrauterine death or hypoxic damage to the fetus.

Risks and complications after birth include:

• Hypothermia because of their relatively large surface area

• Hypoglycaemia from poor fat and glycogen stores

• Hypocalcaemia

• Polycythaemia (venous haematocrit >0.65).

Umbilical artery Doppler

In the healthy fetus, there is forward flow in the umbilical artery throughout systole and diastole. In IUGR due to placental disease, the resistance in the placenta increases (e.g. due to loss of placental villi or pre-eclampsia) resulting in reduced, then absent or even reversed flow during diastole (Fig. 10.4). If end-diastolic flow is absent, detailed Doppler studies of the middle cerebral artery (MCA) and ductus venosus are indicated.

Middle cerebral artery Doppler

As IUGR becomes increasingly severe, there is redistribution of fetal blood flow, with an increase in flow to the brain, and increased end-diastolic velocity. Evidence of cerebral redistribution should trigger intensive regular monitoring.

Ductus venosus Doppler

This reflects the physiological state of the right heart. In the second trimester growth-restricted fetus, reversed flow during atrial contraction represents cardiac decompensation. It is a better predictor of stillbirth than umbilical artery Doppler alone. Timing of delivery will be based on Doppler findings, gestation and estimated fetal weight.

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Jun 15, 2016 | Posted by admin in PEDIATRICS | Comments Off

Screening

Genetic disorders

Non-invasive prenatal testing

Invasive prenatal testing

Fetal medicine

Fetal surgery

Monitoring the growth-restricted fetus

Umbilical artery Doppler

Middle cerebral artery Doppler

Ductus venosus Doppler

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Perinatal medicine

Perinatal medicine

Perinatal definitions and epidemiology