4.6 — When Development Goes Wrong

About 3 to 4 percent of babies are born with a significant structural birth defect. Roughly half of all conceptions never result in a live birth, and a large share of those losses are chromosomal abnormalities so severe that development stops early.

Those numbers are worth stating at the start because parents almost always ask what they did wrong, and for the majority of birth defects the honest answer is nothing. In around 50 to 60 percent of cases the cause is never identified.

The causes, by share

Genetic — roughly 25 to 30 percent.

• Chromosomal (about 10 percent): trisomies, deletions, duplications (Chapter 2.7).
• Single-gene (about 15 to 20 percent): achondroplasia, cystic fibrosis, many skeletal dysplasias.

Environmental — roughly 5 to 10 percent.

• Maternal illness, infection, drugs, chemicals, radiation, and mechanical constraint.

Multifactorial — the largest identifiable group.

• A combination of several genetic susceptibilities with environmental factors. Cleft lip and palate, most congenital heart defects, neural tube defects and club foot are all in this category, and it is why they run in families weakly rather than following Mendelian patterns. Having one affected child typically raises the recurrence risk from around 1 in 1,000 to around 1 in 25 — a large relative increase and still a small absolute risk.

Unknown — 50 to 60 percent.

Teratogens, named specifically

Chapter 4.4 established that weeks 3 to 8 are the critical period. Here is what actually matters, with what each does.

Alcohol. The commonest preventable cause of intellectual disability in the developed world. Fetal alcohol spectrum disorder ranges from subtle learning and behavioural difficulties to full fetal alcohol syndrome — growth restriction, characteristic facial features (short palpebral fissures, smooth philtrum, thin upper lip), and permanent brain damage. No safe threshold has been established, which is why the advice in most countries is none at all. Binge drinking appears particularly damaging, and the brain is vulnerable throughout pregnancy, not only in the first trimester.

Isotretinoin (for severe acne). Extremely teratogenic — roughly 25 to 30 percent of exposed pregnancies affected, with brain, heart and ear defects. Prescribed only under pregnancy prevention programmes requiring negative tests and two forms of contraception.

Sodium valproate (for epilepsy and bipolar disorder). Around 10 percent risk of major malformation including neural tube defects, and around 30 to 40 percent risk of neurodevelopmental impairment. This one is genuinely difficult, because uncontrolled epilepsy is itself dangerous in pregnancy, and the decision requires a specialist rather than a rule. Regulatory restriction of valproate in women of childbearing age followed a long period in which the risk was known and not communicated adequately — a failure that has been the subject of public inquiries in several countries.

Warfarin. Nasal and skeletal defects in the first trimester, bleeding later. Replaced by heparin in pregnancy, which does not cross the placenta.

ACE inhibitors and angiotensin receptor blockers. Kidney damage and reduced amniotic fluid in the second and third trimesters. Stopped before or as soon as pregnancy is confirmed.

Methotrexate, thalidomide, lithium (heart), tetracyclines (tooth staining after week 14), and high-dose vitamin A.

Infections — the classic group.

• Rubella in the first trimester: deafness, cataracts, heart defects, up to 85 percent affected if infection occurs before 12 weeks. Vaccination has essentially eliminated this where coverage is high, and it returns where coverage falls.
• Cytomegalovirus: the commonest infectious cause of congenital deafness. Often the mother has no symptoms at all.
• Toxoplasmosis, from cat faeces and undercooked meat: brain calcification, eye damage.
• Zika: severe microcephaly, established during the 2015–16 South American epidemic.
• Syphilis: bone, tooth, and neurological abnormalities, and entirely preventable by treating the mother — which is why syphilis testing is part of routine antenatal care everywhere.

Maternal conditions.

• Poorly controlled diabetes before conception raises the risk of major malformation about threefold, particularly heart and neural tube defects. Good glucose control before and during early pregnancy reduces it almost to background, which is why pre-pregnancy counselling for diabetic women matters so much.
• Phenylketonuria: a mother with PKU who is not on a strict diet exposes the fetus to high phenylalanine, causing brain damage and heart defects even in a fetus who does not have PKU. The diet must be resumed before conception.
• Obesity raises the risk of neural tube defects and heart defects modestly, and also makes ultrasound detection harder.

Mechanical constraint. Reduced amniotic fluid, uterine abnormalities or amniotic bands can deform an otherwise normally formed fetus — producing club foot, joint contractures, or in the case of bands, amputations.

Deformation, disruption and malformation

These three words are used precisely in medicine and the distinction changes both prognosis and counselling.

A malformation is a structure that formed abnormally from the start. Cleft lip, ventricular septal defect. Highest recurrence risk in future pregnancies.

A deformation is a normally formed structure that was subsequently distorted by mechanical force. Club foot from cramped positioning, plagiocephaly from head moulding. Best prognosis — often corrects with time or simple treatment, and low recurrence risk.

A disruption is a normally forming structure destroyed by an external event — a vascular accident, an amniotic band. Not inherited, so recurrence risk is essentially background.

A syndrome is a recognised pattern of multiple anomalies from a single cause. A sequence is a cascade in which one primary defect causes all the rest — Potter sequence from absent kidneys (Chapter 4.5) is the standard example, where one problem produces a whole picture. An association is a group of anomalies that occur together more often than chance without a known unifying cause.

Antenatal screening: what it actually tells you

This section is written carefully because misunderstanding screening results causes real distress and occasionally real harm.

First trimester, 11 to 14 weeks: the combined test.

• Nuchal translucency — an ultrasound measurement of fluid at the back of the fetal neck. Increased thickness is associated with chromosomal abnormality and with heart defects.
• Blood markers — PAPP-A and free beta-hCG.
• Combined with maternal age, these produce a risk figure, not a diagnosis. Detection rate for Down syndrome is around 85 to 90 percent with a false positive rate of about 5 percent.

Non-invasive prenatal testing (NIPT), from 10 weeks. Analyses fragments of placental DNA circulating in maternal blood. Detection for trisomy 21 exceeds 99 percent with a very low false positive rate.

And here is the point that must be understood. A test with 99 percent sensitivity and 99.9 percent specificity still produces a substantial proportion of false positives when the condition is rare in the population being tested. In a 25-year-old, where the background risk of trisomy 21 is around 1 in 1,250, a meaningful minority of positive NIPT results are false. In a 40-year-old, where background risk is around 1 in 100, the great majority of positives are true.

The test's accuracy has not changed. The interpretation has, and it depends entirely on the prior probability. This is Bayes' theorem (Volume II, Chapter 7), and it is the most clinically important piece of statistics in this volume.

So NIPT is a screening test. A positive result must be confirmed by an invasive diagnostic test before any irreversible decision. Failing to make that clear has led to terminations of normal pregnancies, which is a documented harm and an avoidable one.

The 18 to 22 week anomaly scan is a detailed structural ultrasound. Detection rates vary sharply by organ: over 95 percent for anencephaly and abdominal wall defects, but only around 50 to 60 percent for congenital heart disease and lower still for some defects. A normal scan reduces the probability of a serious abnormality; it does not exclude one.

Diagnostic tests — these give a definite answer and carry a procedure risk.

• Chorionic villus sampling, from 11 weeks, samples placental tissue. Miscarriage risk about 0.2 percent above background in experienced hands.
• Amniocentesis, from 15 weeks, samples amniotic fluid containing fetal cells. Similar risk.

Both give a karyotype or microarray, and both can test for specific known familial mutations.

Newborn screening happens after birth — the heel-prick blood spot taken at around day 5. The exact panel varies by country, but typically includes congenital hypothyroidism, phenylketonuria, cystic fibrosis, sickle cell disease and several metabolic disorders.

The principle behind which conditions are screened is worth stating, because it is not "everything detectable". A condition is screened if it is serious, if it is detectable before symptoms, and — critically — if early treatment changes the outcome. PKU qualifies perfectly: undetected it causes severe permanent disability; detected on day 5 and treated with diet, development is normal (Chapter 2.6). Screening for an untreatable condition offers no benefit to the child and is generally not done.

Prevention: what actually works

Folic acid, 400 micrograms daily from before conception, or 5 mg for higher-risk women. Reduces neural tube defects by around 70 percent. Must be started before conception (Chapter 4.4).

Rubella vaccination before pregnancy.

Diabetes control before conception, not after the pregnancy is discovered.

No alcohol. No smoking — which causes growth restriction, prematurity and raises stillbirth risk, and is associated with cleft lip and palate.

Medication review before conception for any woman on long-term treatment, particularly for epilepsy, autoimmune disease, and psychiatric conditions. The correct time to review is before pregnancy, not at the first antenatal visit, by which time organogenesis is well advanced.

Avoid cat litter and undercooked meat during pregnancy, for toxoplasmosis.

Genetic counselling where there is a family history, consanguinity, or a previous affected child.

What to say when it happens

A note on communication, because this is where medicine most often fails families.

Most birth defects are not anyone's fault, and the reflex assumption that something the mother did caused it is usually wrong and always harmful. Even for the environmentally caused minority, the exposure often occurred before the pregnancy was known.

Recurrence risk is a real question with a real answer, and it varies enormously — from essentially background for a disruption, to 25 percent for an autosomal recessive condition, to 50 percent for a dominant one. Genetic counselling exists to give the actual number rather than a guess.

And many conditions detected antenatally have far better outcomes than parents fear, because the information available to a frightened person searching the internet is dominated by the worst cases. A ventricular septal defect that closes by itself, a cleft lip repaired at three months, a club foot corrected by casting — these are common outcomes and they do not generate memorable content.

What the next page fixes

The body is now built. What holds it together for eighty years is a set of control systems that keep every internal condition inside a narrow band while the outside world does whatever it likes. Chapter 4.7 covers homeostasis: the anatomy of a control loop, the difference between negative and positive feedback, why almost every disease in this book is a control loop failing, and why the normal ranges on a blood test are what they are.