BGD Tutorial - Applied Embryology and Teratology

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Introduction

Chris.jpg
This Medicine Phase 2 tutorial introduces the topics of Applied Embryology and Teratology. This one and a half hour presentation uses your existing knowledge of normal human development in an applied clinical manner in relation to our existing knowledge of teratogens. In addition, you should begin considering the variables that will not change and those that will in future medical practice. Due to time limitations, only a brief coverage can be given of any one topic.


Self-Directed Learning boxes on this page will not be discussed within the tutorial. You should also return here and later work through the linked online resources for more detailed descriptions and an understanding of these issues. This current page appears in the lefthand menu under Medicine as BGD 2 Tutorial.


2014 Print Version PDF (10 pages, 670kb)


Similar content was covered in the previous online tutorials in 2012 | 2012 PDF | 2011 PDF and 2010.

Whats in the News?
Embryo Epigenetics
Epigenetics cartoon.jpg
Embryos Reprogram their Epigenetics

Two recent studies show that after fertilisation human embryos loose DNA methylation from most of the genome. This implies that there is an early "reprogramming" or "resetting" of the embryo's epigenetic status.

  • The DNA methylation landscape of human early embryos PMID 25079557 "We show that the major wave of genome-wide demethylation is complete at the 2-cell stage, contrary to previous observations in mice. Moreover, the demethylation of the paternal genome is much faster than that of the maternal genome, and by the end of the zygotic stage the genome-wide methylation level in male pronuclei is already lower than that in female pronuclei."
  • DNA methylation dynamics of the human preimplantation embryo PMID 25079558 "our data confirm that paternal genome demethylation is a general attribute of early mammalian development that is characterized by distinct modes of epigenetic regulation."
(More? Epigenetics | Nature. 2014 Jul PMID 25079558 PMID 25079557)

Older News Articles


Objectives

Human Embryonic Development (week 1 to 8)

Applied Embryology: birth statistics, unintended pregnancies, ART, abnormalities statistics, timeline of development, trophoblastic disease, embryonic development, placenta, fetal development, maternal diet, multiple pregnancies.

Teratology: definitions, critical periods, medications, chromosomal abnormalities, environmental factors and infections.

Textbooks

Logo.png Hill, M.A. (2014). UNSW Embryology (14th ed.) Retrieved September 2, 2014, from http://php.med.unsw.edu.au/embryology
Diagnosis Links: Prenatal Diagnosis | Pregnancy Test | Amniocentesis | Chorionic villus sampling | Ultrasound | Alpha-Fetoprotein | Pregnancy-associated plasma protein-A | Fetal Blood Sampling | Magnetic Resonance Imaging | Computed Tomography | Non-Invasive Prenatal Testing | Fetal Cells in Maternal Blood | Preimplantation Genetic Screening | Comparative Genomic Hybridization | Genome Sequencing | Neonatal Diagnosis | Category:Prenatal Diagnosis | Fetal Surgery | Classification of Diseases | Category:Neonatal Diagnosis
Neonatal Diagnosis: APGAR test | Guthrie test | Hearing test | Electrocardiogram (ECG/EKG) | X-ray | Tandem mass spectrometry | Classification of Diseases
Abnormality Links: Introduction | Genetic | Environmental | Unknown | Teratogens | Cardiovascular | Coelomic Cavity | Endocrine | Gastrointestinal Tract | Genital | Head | Integumentary | Musculoskeletal | Limb | Neural | Neural Crest | Renal | Respiratory | Placenta | Sensory | Twinning | Developmental Origins of Health and Disease | ICD-10
The Developing Human, 9th edn.jpg Citation: The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (chapter links only work with a UNSW connection)
Larsen's human embryology 4th edn.jpg Citation: Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (chapter links only work with a UNSW connection)

Applied Embryology

Australia’s mothers and babies (2011) cover

This recent data summarised below from Australia's mothers and babies 2011[1], 2009[2], 2008[3] and 2007[4]. This data should help you as a clinician and researcher to understand the current trends in reproductive medicine within Australia. Also see recent general population data in Australian Statistics.

  • 2011 - 301,810 live births and 2,220 fetal deaths
  • 2009 - 296,791 live births and 2,341 fetal deaths
  • 2008 - 294,737 live births and 2,188 fetal deaths
  • 2007 - 292,027 live births and 2,177 fetal deaths
Australian-births 2011.jpg
Mothers

Mothers

  • Average maternal age in 2011 was 30.0 years, the same as 2009 but still more than the earlier years (2000, 29.0 years; 2002, 29.4 years).
  • Approximately 43.0% (2009, 41.6%) of women were having their first baby.
    • Average age for first time mothers was 28.3 (2009, 27.9 years).
    • Of all first-time mothers, 14.2 were aged 35 years or older (2009, 13.7%; 2000, 10.3%).
  • ART was used by 3.8% (2009, 3.6%) of women who gave birth. (see also below Assisted Reproduction Technology)
  • 0.4% (1,267) of all women who gave planned home birth (2009, 0.3%, 863).

Smoking during pregnancy

  • Smoking while pregnant was reported by 13.2% of all mothers (2009, 14.5%).
    • down from 16.6% over the previous five years.
  • Smoking by 35.8% of teenage mothers (2009, 37.0%)


Preterm Birth

Probably the most significant ongoing issue related to development, with both known and unknown contributors. Importantly, preterm infants also occupy the majority of special care units.
  • Australia - 8.3% of babies were born preterm (less than 37 weeks gestation) (2009, 8.2%; 2008, 7.4%).
    • NSW preterm birth was 7.5% (2010, 7.4%).
  • 0.7% post-term (42 weeks gestation or more) (2009, 0.9%).
  • Born Too Soon: The Global Action Report on Preterm Birth (2012) The first-ever country-by-country estimate of premature births finds that 15 million babies a year are born preterm - more than one in 10 live births. The report on preterm birth provides the first-ever national, regional and global estimates of preterm birth. The report shows the extent to which preterm birth is on the rise in most countries, and is now the second leading cause of death globally for children under five, after pneumonia. Preterm Birth
Links: Nursery beds
Preterm birth screening.jpg

Multiple pregnancy

Australian multiple birth data
  • The number of multiple births has increased in the last two decades.
  • 4,595 multiple pregnancies (1.6% of all mothers) (2009, 4,605; 2008, 4,634)
    • 4,520 twin pregnancies (2009, 4,521; 2008, 4,558)
    • 75 triplet pregnancies and other higher-order(2009, 84; 2008, 76)

Presentation at birth

Breech presentation (Galletti, 1770)

2009 data

  • Cephalic (any part (vertex, face or brow) 94.4% (2008, 94.6%)
  • Vertex (crown (vertex) of the fetal head is the presenting part) (2009, 94.2%)
  • Breech presentation (buttocks or feet in labour) (2009, 3.9%; 2008, 4.0%)
    • 11,565 women with a breech presentation - 92.2% were singleton and 7.8% were multiple pregnancies.

Method of birth

2009 data

  • vaginal birth 201,631 women
  • 56.8% had a non-instrumental vaginal birth.
  • instrumental vaginal delivery 11.7%
  • caesarean sections 32.3% (2009, 92,687)
  • 31.5% nationally (2000 - 23.3%)
Birth caesarean.jpg

Birth caesarean

Australian caesarean and instrumental birth 2009.jpg

Caesarean and Instrument Delivery

Pre-existing and pregnancy-related medical conditions

  • The following conditions were also reported: epilepsy, diabetes mellitus and hypertension, antepartum haemorrhage, gestational diabetes, cord prolapse and retained placenta, pregnancy-induced hypertension, fetal distress in labour and post-partum haemorrhage rates
    • Note data is not standard across jurisdictions.


ICD Links: XVII Congenital Malformations | XVI Perinatal Period | Chapter XV Pregnancy Childbirth | Abnormal Development | Reports

Postnatal length of stay

2009 data

  • median postnatal hospital stay for mothers was 3.0 days
  • 2.0 days non-instrumental vaginal birth
  • 3.0 days vacuum extraction delivery
  • 4.0 days caesarean section or forceps delivery
    • 5.4% caesarean section had a postnatal length of stay of 7+ days
Babies

Babies

2009 data

  • 296,791 live births and 2,341 fetal deaths (2008 - 292,027 live births and 2,177 fetal deaths)
    • stillbirth rate of 7.5 per 1,000 births
  • most births occurred in October, September and July
  • 106 sex ratio, number of male per 100 female liveborn babies. (2008 - 105.6)

Gestational age

Special educational need by gestational age (UK data)[5]

2009 data

  • 90.8% term, 37–41 weeks gestation. (2008 - 90.9%)
  • 8.2% were preterm and 33.1 weeks was the mean gestational age for all preterm births
    • Preterm births were classified groups of 20–27 weeks, 28–31 weeks and 32–36 weeks

Birthweight

Apgar.jpg

2009 data

  • 92% of liveborn babies had a birthweight in the range 2,500–4,499 grams
    • average birthweight was 3,374 grams
  • 18,347 (6.2%) low birthweight (weighing less than 2,500 grams) (2008 - 6.1%)
  • 3,017 (1.0%) very low birthweight (weighing less than 1,500 grams)
  • 1,357 (0.5%) extremely low birthweight (weighing less than 1,000 grams)

Apgar scores - 1.5% of liveborn babies had a low Apgar score (between 0 and 6) at 5 minutes (More? Apgar test)

Special care nurseries (SCN) or neonatal intensive care units (NICU) - 14.2% of liveborn babies admitted (2008 - 14.5%)

Perinatal mortality

Perinatal mortality rate NSW 1992-2002
  • Different definitions in Australia for reporting and registering perinatal deaths.
    • NPDC definition of perinatal deaths to include all fetal and neonatal deaths of at least 400 grams birthweight or at least 20 weeks gestation.
    • ABS definition of a perinatal death includes birthweight of at least 400 grams or, where birthweight is unknown, a gestational age of at least 20 weeks.
  • 2,341 fetal deaths, 7.8 per 1,000 births (2008 - 2,177)
  • 667 neonatal deaths (3.0 per 1,000 live births) (2008 - 846)
    • neonatal deaths are those occurring in live births up to 28 completed days after birth
  • 2,221 Australian perinatal deaths, 70.0% were fetal deaths (2008 - 3,024)
    • perinatal death includes birthweight of at least 400 grams or, where birthweight is unknown, a gestational age of at least 20 weeks
  • 31.2% congenital abnormalities (anomalies) (2008 - 23.5%)
  • 18.9% spontaneous preterm birth
Self-Directed Learning 1
2013 National core maternity indicators
National core maternity indicators 2013.jpg

2013 National core maternity indicators[6]

This report provides a baseline for monitoring changes in the quality of maternity services across Australia using 10 national core maternity indicators.

  1. Smoking in pregnancy for all women giving birth
  2. Antenatal care in the first trimester for all women giving birth
  3. Episiotomy for women having their first baby and giving birth vaginally
  4. Apgar score of less than 7 at 5 minutes for births at or after term
  5. Induction of labour for selected women giving birth for the first time
  6. Caesarean section for selected women giving birth for the first time
  7. Normal (non-instrumental) vaginal birth for selected women giving birth for the first time
  8. Instrumental vaginal birth for selected women giving birth for the first time
  9. General anaesthetic for women giving birth by caesarean section
  10. Small babies among births at or after 40 weeks gestation
  • National rates have decreased for smoking in pregnancy, episiotomy among women having their first baby and giving birth vaginally and the proportion of babies born weighing less than 2,750 grams at or after 40 weeks.
  • However for some indicators, including induction of labour, caesarean section and instrumental vaginal birth, rates have increased and point to areas for possible further attention.

Unintended Pregnancy

Approximately one-half of pregnancies in the United States (2001) were unintended (Finer 2006, Perspectives on Sexual and Reproductive Health).

An earlier 1995 USA National Survey of Family Growth (NSFG) found:

  • 49% of pregnancies in the USA (excluding miscarriages)
  • 31% of pregnancies resulting in a live birth are unintended

Unintended pregnancy is either mistimed (woman wanted to be pregnant later) or unwanted (did not want to ever be pregnant).

Teen pregnancy USA.png

Teen pregnancy (USA)

Teen Pregnancy
A recent Canadian retrospective study[7] of half a million births comparing pregnant women < 20 years of age (adolescent) were compared with those of women 20 to 35 years old.
  • Adolescents had a higher rate of smoking and substance use than adult women and were within the lowest education and family income quintiles.
  • Adolescents had a significantly lower risk of gestational hypertension, gestational diabetes, placental abruption, and placenta previa, but their risk of preterm premature rupture of membranes was significantly higher.
  • Neonates with an adolescent mother had significantly higher risks of admission to NICU and very preterm birth.
  • There was no significant difference between the two groups in rates of small for gestational age babies, low birth weight, preterm birth, and fetal death.
Self-Directed Learning 2

Links: CDC Unintended Pregnancy Prevention | Pregnancy Risk Assessment Monitoring System USA | The Measurement and Meaning of Unintended Pregnancy

Assisted Reproduction Technology

Assisted reproductive technology in Australia and New Zealand 2010

Assisted Reproduction Technology (ART) is also sometimes also used to identify In vitro fertilization (IVF) but now includes many new techniques.

Assisted reproductive technology in Australia and New Zealand 2010[8] 26 Oct 2012

2010 ART treatment cycles

  • 61,774 assisted reproductive technology (ART) treatment cycles performed in Australia and New Zealand.
  • 23.9% resulted in a clinical pregnancy
  • 18.1% in a live delivery (the birth of at least one liveborn baby).
  • 12,056 liveborn babies following ART treatments in 2010.

Trends in ART procedures

  • In the last 5 years there has been a shift from day 2-3 embryo (cleavage stage) transfers to day 5-6 embryo (blastocyst) transfers.
  • The proportion of blastocyst transfers has increased from 27.1% in 2006 to 52.1% in 2010.
  • Increase in the transfer of vitrified (ultra-rapid frozen) embryos. Compared with 2009, the proportion has more than doubled from 18.3% to 38.2%.
  • reduction in the rate of multiple birth deliveries, with a decrease from 12% in 2006 to 7.9% in 2010.
  • shifting to single embryo transfer, the proportion of which increased from 56.9% in 2006 to almost 70% in 2009 and 2010.
  • decrease in the multiple delivery rate was achieved while clinical pregnancy rates remained stable at about 23% per cycle.
2009 Data
Assisted reproductive technology in Australia and New Zealand 2009.jpg

The following data from Assisted reproductive technology in Australia and New Zealand 2009.[9] 9 Nov 2011

2009 ART treatment cycles

  • 70,541 treatment cycles (2005 - 51,017)
  • 13,114 live born babies
    • 17.2% of cycles a live delivery (birth of at least one liveborn baby).

single embryo transfer

  • increase of single embryo transfer, from 48.3% in 2005 to 69.7% in 2009.
    • reduction of multiple delivery rate from 14.1% in 2005 to 8.2% in 2009.
  • average age of women undergoing autologous cycles was 35.8 years

cryopreserved embryos

  • 22,472 frozen/thawed embryo transfer cycles.
  • 18.3% embryos had been cryopreserved using ultra-rapid method (vitrification).
  • 33% blastocyst (day 5–6 embryo) was transferred used vitrified blastocysts.
  • 1.7% cleavage embryo (day 2–3 embryo) was transferred.Media:Example.ogg


Links: Assisted Reproductive Technology | In Vitro Fertilization
Self-Directed Learning 3

Early Development Issues

Abnormal Implantation

Ectopic Implantation (Pregnancy)
Ectopic tubal pregnancy
Abnormal implantation sites or Ectopic Pregnancy occurs if implantation is in uterine tube or outside the uterus.
  • sites - external surface of uterus, ovary, bowel, gastrointestinal tract, mesentry, peritoneal wall
  • If not spontaneous then, embryo has to be removed surgically

Tubal pregnancy - 94% of ectopic pregnancies

  • if uterine epithelium is damaged (scarring, pelvic inflammatory disease)
  • if zona pellucida is lost too early, allows premature tubal implantation
  • embryo may develop through early stages, can erode through the uterine horn and reattach within the peritoneal cavity
Ectopic 01.jpg
 ‎‎Ectopic Pregnancy
Page | Play

This is also the most common cause of pregnancy-related deaths in the first trimester. A United Kingdom enquiry into maternal deaths[10], identified ectopic pregnancy as the fourth most common cause of maternal death (73% of early pregnancy deaths).

Hydatidiform Mole

Hydatidiform Mole

Another type of abnormality is when only the conceptus trophoblast layers proliferates and not the embryoblast, no embryo develops, this is called a "hydatidiform mole", which is due to the continuing presence of the trophoblastic layer, this abnormal conceptus can also implant in the uterus. The trophoblast cells will secrete human chorionic gonadotropin (hCG), as in a normal pregnancy, and may appear maternally and by pregnancy test to be "normal". Prenatal diagnosis by ultrasound analysis demonstrates the absence of a embryo.

There are several forms of hydatidiform mole: partial mole, complete mole and persistent gestational trophoblastic tumor. Many of these tumours arise from a haploid sperm fertilizing an egg without a female pronucleus (the alternative form, an embryo without sperm contribution, is called parthenogenesis). The tumour has a "grape-like" placental appearance without enclosed embryo formation. Following a first molar pregnancy, there is approximately a 1% risk of a second molar pregnancy.

This topic is also covered in Placenta - Abnormalities

Twinning

  • Twin deliveries and place of birth in NSW 2001-2005[11] "Both infant and maternal morbidity increase from 39 weeks gestation. Delivery of twins before 36 weeks at smaller hospitals (< 500 deliveries per annum) should be avoided. A twin pregnancy where there is a greater or equal to 20% difference in estimated fetal weights should be considered for referral to a tertiary obstetric unit."

Dizygotic Twinning

Dizygotic twins (fraternal, non-identical) arise from separate fertilization events involving two separate oocyte (egg, ova) and spermatozoa (sperm). Dizygotic twinning can be increased by Assisted Reproductive Technologies (ART) that use double embryo transfer techniques.

Monoygotic Twinning

Monoygotic twins (identical) produced from a single fertilization event (one fertilised egg and a single spermatazoa, form a single zygote), these twins therefore share the same genetic makeup. Occurs in approximately 3-5 per 1000 pregnancies, more commonly with aged mothers. The later the twinning event, the less common are initially separate placental membranes and finally resulting in conjoined twins.

Week Week 1 Week 2
Day 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Cell Number 1 1 2 16 32 128 bilaminar
Event Ovulation fertilization First cell division Morula Early blastocyst Late blastocyst

Hatching

Implantation starts X inactivation
Follicle 001 icon.jpg Early zygote.jpg Human embryo day 2.jpg Human embryo day 3.jpg Human embryo day 5.jpg CSt3.jpg Week2 001 icon.jpg
Monoygotic

Twin Type

Diamniotic

Dichorionic

Diamniotic

Monochorionic

Monoamniotic

Monochorionic

Conjoined

Table based upon recent Twinning Review.[12]

Links: Twinning


Self-Directed Learning 4

Abnormal Development

Australian abnormalities by System
Australian abnormalities by System

Embryological development is a robust biological system able to cope with many stresses without long-term consequences. When development does go wrong there are generally 3 major types groups: Genetic (inherited), Environmental (maternal) derived and Unknown (not determined or known) abnormalities. Also often not considered, is that pregnancy itself can also expose abnormalities in the mother (congenital heart disease, diabetes, reproductive disorders) that until the pregnancy had gone undetected.

Genetic abnormalities in medicine are still mainly about determining a family history and good prenatal/neonatal diagnosis. Realise that there exists in all of us genetic variations and some variations which eventually expand be expressed as a genetic disorder (CAG expansions).

Abnormality Links
Abnormality Links: Introduction | Genetic | Environmental | Unknown | Teratogens | Cardiovascular | Coelomic Cavity | Endocrine | Gastrointestinal Tract | Genital | Head | Integumentary | Musculoskeletal | Limb | Neural | Neural Crest | Renal | Respiratory | Placenta | Sensory | Twinning | Developmental Origins of Health and Disease | ICD-10

Prenatal diagnosis are the clinical tools used to determine both normal and abnormal development. There are a growing number of new diagnostic techniques that are being applied to human embryonic development.

Prenatal Diagnosis Links
Diagnosis Links: Prenatal Diagnosis | Pregnancy Test | Amniocentesis | Chorionic villus sampling | Ultrasound | Alpha-Fetoprotein | Pregnancy-associated plasma protein-A | Fetal Blood Sampling | Magnetic Resonance Imaging | Computed Tomography | Non-Invasive Prenatal Testing | Fetal Cells in Maternal Blood | Preimplantation Genetic Screening | Comparative Genomic Hybridization | Genome Sequencing | Neonatal Diagnosis | Category:Prenatal Diagnosis | Fetal Surgery | Classification of Diseases | Category:Neonatal Diagnosis

While genetic abnormalities will have well-defined impacts upon development, environmentally derived effects can be harder to define and often variable depending on many different factors (timing, exposure level, and the combination effects with other factors). This combination effect can also be seen between genetic and environmental interacting to give an even broader spectrum of both major and minor abnormalities.

Environmental Links
Environmental Links: Introduction | Low Folic Acid | Iodine Deficiency | Nutrition | Drugs | Australian Drug Categories | USA Drug Categories | Thalidomide | Herbal Drugs | Illegal Drugs | Smoking | Fetal Alcohol Syndrome | TORCH Infections | Viral Infection | Bacterial Infection | Zoonotic Infection | Toxoplasmosis | Malaria | Iodine Deficiency | Maternal Diabetes | Maternal Hyperthermia | Maternal Inflammation | Hypoxia | Biological Toxins | Chemicals | Heavy Metals | Radiation | Prenatal Diagnosis | Neonatal Diagnosis | International Classification of Diseases | Fetal Origins Hypothesis


Bacterial Links: Syphilis | Gonorrhea | Tuberculosis | Listeria | TORCH Infections | Environmental | Category:Bacteria
Viral Links: TORCH Infections | Cytomegalovirus | Hepatitis Virus | HIV | Measles Virus | Parvovirus | Polio Virus | Rubella Virus | Chickenpox | Lymphocytic Choriomeningitis Virus | Vaccination | Environmental

International Classification of Diseases

The International Classification of Diseases (ICD) World Health Organization's classification used worldwide as the standard diagnostic tool for epidemiology, health management and clinical purposes. This includes the analysis of the general health situation of population groups. It is used to monitor the incidence and prevalence of diseases and other health problems. Within this classification "congenital malformations, deformations and chromosomal abnormalities" are (Q00-Q99) but excludes "inborn errors of metabolism" (E70-E90).


ICD Links: XVII Congenital Malformations | XVI Perinatal Period | Chapter XV Pregnancy Childbirth | Abnormal Development | Reports

Australian Birth Anomalies System

"The national collation and reporting of birth anomalies data has been suspended in recent years due to concerns about data quality and comparability."
  • Variability among states and territories in scope of birth anomalies data collections: sources of birth anomalies notifications and definitions and classifications used; method of data collection and available resources.
  • Variability among the states and territories in the timing and method of the provision of birth anomalies data to the AIHW National Perinatal Statistics Unit (NPSU) for national collation and reporting.
  • New Australian Birth Anomalies System should be data for birth anomalies detected up to 1 year of age
    • including data on terminations of pregnancies with birth anomalies and regardless of gestational age (i.e. including less than 20 weeks gestation)
  • System will initially be based on data from the states able to detect birth anomalies at least up to 1 year of age (NSW, VIC, WA and SA), further extending the period of detection in the future.
  • Congenital anomalies are coded using the British Paediatric Association Classification of Diseases (ICD-9-BPA), based on the International Classification of Diseases, 9th Revision (ICD-9).
The Australian Congenital Anomalies Monitoring System (ACAMS) supersedes the National Congenital Malformations and Birth Defects Data Collection (NCM&BD).

Links: Australian Congenital Anomalies Monitoring System | Congenital Anomalies in Australia 2002-2003

NSW Data

Congenital Conditions Register

Scheduled congenital conditions (section 2) detected during pregnancy or in infants up to one year of age in NSW are required to be reported under the NSW Public Health Act 1991.

Scheduled congenital conditions include:

  1. All structural malformations. Examples include spina bifida, microcephaly, transposition of the great vessels, ventricular septal defects, pulmonary agenesis, polycystic lungs, duodenal atresia, exomphalos, hypospadias, cleft lip/palate, microphthalmia, limb reductions, polydactyly, birthmarks greater than 4 cms diameter, cystic hygroma and multisystem syndromes including at least one structural malformation.
  2. Chromosomal abnormalities. Examples include Down syndrome and unbalanced translocations.
  3. Four medical conditions: cystic fibrosis, phenylketonuria, congenital hypothyroidism and thalassaemia major.

Congenital conditions that are not notifiable include:

  1. Minor anomalies occurring in isolation (Examples of minor anomalies include skin tags, deviated nasal septum, tongue tie, benign heart murmurs, clicky non-dislocating hips, sacral dimples, positional talipes, abnormal palmar creases, dysmorphic features).
  2. Birth injuries.
  3. Congenital infections which do not result in a structural malformation.
  4. Tumours and cysts.
  5. Conditions arising from prematurity or asphyxiation.


Links: NSW Health - Congenital Conditions Register - Reporting Requirements 2012 | PDF

Mothers and Babies Report 2010

  • preterm birth (less than 37 weeks gestation) was 7.4%.
  • rate of low birth weight (less than 2,500 grams) was 6.1%
    • in Aboriginal or Torres Strait Islander babies was 11.2%.
  • About 2% of infants are born with congenital conditions each year in NSW.
  • In 2004–2010, anomalies of the cardiovascular system were most commonly reported, followed by anomalies of the musculoskeletal system and the genito-urinary system.
  • Congenital conditions were more common among premature infants compared to full term infants, and among male infants compared to female infants.
  • rate of congenital conditions increases with increasing maternal age, especially after age 35.
    • However, as most babies are born to mothers aged less than 35 years, the majority of babies with congenital conditions were born to younger mothers.
  • perinatal deaths 755, 134 (17.7%) of these deaths were unexplained stillbirths.
  • neonatal death was extreme prematurity (41.3%), followed by congenital abnormalities (21.5%).

Data<refCentre for Epidemiology and Evidence. New South Wales Mothers and Babies 2010. Sydney: NSW Ministry of Health, 2012.</ref>

Links: New South Wales Mothers and Babies Report 2010

Victoria - 10 most reported birth anomalies
Based upon statistics from the Victorian Perinatal Data Collection Unit in Victoria between 2003-2004.
Hypospadia Hypospadias (More? Development Animation - Genital Male External | Genital Abnormalities - Hypospadia)
Obstructive Defect of the Renal Pelvis Obstructive Defects of the Renal Pelvis (obstructive defects of the renal pelvis, uteropelvic junction obstruction, pelvo-uterero junction obstruction) Term describing a developmental renal abnormality due to partial or complete blockage of the drainage of the kidney pelvis requiring surgical correction. The blockage can also have several causes including: unusual ureter twisting or bending, ureter compression by a blood vessel, malformations of the muscular wall. The blockage leads to an accumulation of urine in the affected region, with several potential effects: nephron damage from compression (hydronephrosis); decreased urine output leading to lack of amniotic fluid (oligohydramnios); respiratory development effects due to the lack of amniotic fluid.
  • The most common type of obstruction is at the uteropelvic junction (UPJ), between the junction of the ureter and the kidney.
  • Blockage lower as the ureter enters the bladder, the ureterovesicular junction (UVJ), usually involves only one kidney and the back flow enlarges the affected ureter (megaureter).

(More? Renal System - Abnormalities | Renal System Development)

Ventricular Septal Defect Ventricular Septal Defect (More? Cardiovascular Abnormalities - Ventricular Septal Defect)

Basic Heart Development Timeline.jpg

Heart Development Timeline (see Basic Cardiac Embryology)

Congenital dislocation hip Congenital Dislocated Hip (More? Musculoskelal Abnormalities - Congenital Dislocation of the Hip (CDH))

(DHH, congenital dislocated hip, congenital hip dislocation, congenital hip dysplasia) Term describes a spectrum of musculoskeletal disorders of hip instability due either to the femoral head being able to move outside the acetabulum (luxation or dislocation), or abnormally within the acetabulum (subluxation or partial dislocation). This includes presentation following a normal examination of the hips in the newborn period (Ortolani and Barlow tests). When detected can be managed with splinting (Denis-Browne splint) allows the hip joint to develop normally and does not require surgery. If undetected and left untreated, the hip joint develops abnormally and surgical reduction is required. (More? Musculoskeletal System Development)

Trisomy 21 male Trisomy 21 or Down syndrome - (More? Trisomy 21)
Hydrocephalus Hydrocephalus (More? Neural Abnormalities - Hydrocephalus | NINDS - Hydrocephalus Fact Sheet | Hydrocephalus Support Association | USA National Hydrocephalus Foundation)
Cleft palate Cleft Palate (More? Development Animation - Palate 1 | Development Animation - Palate 2 | Cleft Palate)
Trisomy 18 male Trisomy 18 or Edward Syndrome - multiple abnormalities of the heart, diaphragm, lungs, kidneys, ureters and palate 86% discontinued (More? Trisomy 18)
Renal Agenesis/Dysgenesis - reduction in neonatal death and stillbirth since 1993 may be due to the more severe cases being identified in utero and being represented amongst the increased proportion of terminations (approximately 31%). (More? Renal Abnormalities - Renal Agenesis)
Bilateral cleft palate Cleft Lip and Palate - occur with another defect in 33.7% of cases. (More? Cleft Lip)
USA Statistics

USA Selected - CDC National estimates for 21 selected major birth defects (2004–2006).

Birth Defects Cases per Births (1 in ...) Estimated Annual Number of Cases
Anencephaly 4,859 859
Spina bifida without anencephaly 2,858 1,460
Encephalocele 12,235 341
Anophthalmia/microphthalmia 5,349 780
Common truncus 13,876 301
Transposition of great arteries 3,333 1,252
Tetralogy of Fallot 2,518 1,657
Atrioventricular septal defect 2,122 1,966
Hypoplastic left heart syndrome 4,344 960
Cleft palate without cleft lip 1,574 2,651
Cleft lip with and without cleft palate 940 4,437
Esophageal atresia/tracheoesophageal fistula 4,608 905
Rectal and large intestinal atresia/stenosis 2,138 1,952
Reduction deformity, upper limbs 2,869 1,454
Reduction deformity, lower limbs 5,949 701
Gastroschisis 2,229 1,871
Omphalocele 5,386 775
Diaphragmatic hernia 3,836 1,088
Trisomy 13 7,906 528
Trisomy 21 (Down syndrome) 691 6,037
Trisomy 18 3,762 1,109
Links: Human Abnormal Development | CDC Birth Defects - Data & Statistics


Genetic

Links: Abnormal Development - Genetic
Self-Directed Learning 5

Teratology

Prenatal Screening

Amniocentesis

How and why do things go wrong in development?

These notes cover abnormalities that can occur during development often described as congenital defects or birth defects. There are many different ways that developmental abnormalities can occur the 3 major types are Genetic (inherited), Environmental (maternal) and Unknown (not determined) derived abnormalities. The environmental factors that cause or lead to any of these abnormalities are described as Teratogens.

Diagnosis Links: Prenatal Diagnosis | Pregnancy Test | Amniocentesis | Chorionic villus sampling | Ultrasound | Alpha-Fetoprotein | Pregnancy-associated plasma protein-A | Fetal Blood Sampling | Magnetic Resonance Imaging | Computed Tomography | Non-Invasive Prenatal Testing | Fetal Cells in Maternal Blood | Preimplantation Genetic Screening | Comparative Genomic Hybridization | Genome Sequencing | Neonatal Diagnosis | Category:Prenatal Diagnosis | Fetal Surgery | Classification of Diseases | Category:Neonatal Diagnosis
Ultrasound
Ultrasound
Ectopic 01.jpg
 ‎‎Ectopic Pregnancy
Page | Play
Cleft lip 01.jpg
 ‎‎Cleft Lip 18 Week
Page | Play
Cleft lip 02.jpg
 ‎‎Cleft Lip 15 Week
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Gastroschisis 01.jpg
 ‎‎Gastroschisis
Page | Play

Now consider the terms used to describe the different environmental effects that can occur during pregnancy that may influence outcomes.

  • Teratogen (Greek, teraton = monster) any agent that causes a structural abnormality (congenital abnormalities) following fetal exposure during pregnancy. The overall effect depends on dosage and time of exposure.
  • Absolute risk the rate of occurrence of an abnormal phenotype among individuals exposed to the agent. (e.g. fetal alcohol syndrome)
  • Relative risk the ratio of the rate of the condition among the exposed and the nonexposed. (e.g. smokers risk of having a low birth weight baby compared to non-smokers) A high relative risk may indicate a low absolute risk if the condition is rare.
  • Mutagen a chemical or agent that can cause permanent damage to the deoxyribonucleic acid (DNA) in a cell. DNA damage in the human egg or sperm may lead to reduced fertility, spontaneous abortion (miscarriage), birth defects and heritable diseases.
  • Fetotoxicant is a chemical that adversely affects the developing fetus, resulting in low birth weight, symptoms of poisoning at birth or stillbirth (fetus dies before it is born).
  • Synergism when the combined effect of exposure to more than one chemical at one time, or to a chemical in combination with other hazards (heat, radiation, infection) results in effects of such exposure to be greater than the sum of the individual effects of each hazard by itself.
  • Toxicogenomics the interaction between the genome, chemicals in the environment, and disease. Cells exposed to a stress, drug or toxicant respond by altering the pattern of expression of genes within their chromosomes. Based on new genetic and microarray technologies.

Teratogens

  • Infections, collectively grouped under the acronym TORCH for Toxoplasmosis, Other organisms (parvovirus, HIV, Epstein-Barr, herpes 6 and 8, varicella, syphilis, enterovirus) , Rubella, Cytomegalovirus and Hepatitis. See also the related topics on maternal hyperthermia and bacterial infections. (More? Postnatal Immunisation)
  • Maternal diet the best characterised is the role of low folic acid and Neural Tube Defects (NTDs) see also abnormal neural development and Neural Tube Defects (NTDs). More recently the focus has been on dietary iodine levels and the role they also play on neural development.
  • Maternal drugs effects either prescription drugs (therapeutic chemicals/agents, thalidomide limb development), non-prescription drugs (smoking), and illegal drugs (Cannabis/Marijuana, Methamphetamine/Amphetamine, Cocaine, Heroin, Lysergic Acid Diethylamide)
  • Environment (smoking, chemicals, heavy metals, radiation) and maternal endocrine function (maternal diabetes, thyroid development) and maternal stress.
  • Teratogen synergism, different environmental effects can act individually or in combination on the same developing system. For example, neural development can be impacted upon by alcohol (fetal alcohol syndrome), viral infection (rubella) and/or inadequate dietry folate intake (neural tube defects). These effects may also not be seen as a direct effect on a system or systems but result in a reduced birth weight and the potential postnatal developmental effects. Consider also this in relation to the increasing support to the fetal origins hypothesis.

Links:

Abnormality Links: Introduction | Genetic | Environmental | Unknown | Teratogens | Cardiovascular | Coelomic Cavity | Endocrine | Gastrointestinal Tract | Genital | Head | Integumentary | Musculoskeletal | Limb | Neural | Neural Crest | Renal | Respiratory | Placenta | Sensory | Twinning | Developmental Origins of Health and Disease | ICD-10
Environmental Links: Introduction | Low Folic Acid | Iodine Deficiency | Nutrition | Drugs | Australian Drug Categories | USA Drug Categories | Thalidomide | Herbal Drugs | Illegal Drugs | Smoking | Fetal Alcohol Syndrome | TORCH Infections | Viral Infection | Bacterial Infection | Zoonotic Infection | Toxoplasmosis | Malaria | Iodine Deficiency | Maternal Diabetes | Maternal Hyperthermia | Maternal Inflammation | Hypoxia | Biological Toxins | Chemicals | Heavy Metals | Radiation | Prenatal Diagnosis | Neonatal Diagnosis | International Classification of Diseases | Fetal Origins Hypothesis
Genetic Links: Introduction | Genetic risk maternal age | Trisomy 21 | Trisomy 18 | Trisomy X | Fragile X | Williams | Philadelphia chromosome | Hydatidiform Mole | Prenatal Diagnosis | Neonatal Diagnosis | International Classification of Diseases | Molecular Development - Genetics

Critical Periods of Development

Human critical periods of development
  • Finally, when studying this topic remember the concept of critical periods of development that will affect the overall impact of the above listed factors. This can be extended to the potential differences between prenatal and postnatal effects, for example with infections and outcomes.
Conceptus Embryonic development (weeks) Fetal period (weeks)
1
2
3
4
5
6
7
8
9
16
20-36
38
Early zygote.jpg Week2 001 icon.jpg Stage9 sem4c.jpg Stage13 sem1c.jpg Stage15 bf1c.jpg Stage17 bf1c.jpg Stage19 bf1c.jpg Stage23 bf1c.jpg
Neural
Stage2.jpg Heart
Upper limbs
Lower limbs
Ear
Eye
CSt3.jpg Palate
Teeth
Week2 001 icon.jpg External genitalia
Loss Major abnormalities Functional and Minor abnormalities
Self-Directed Learning 6

Links: Embryonic Development | Timeline human development | Movie - Human Development annotated cartoon | Human - critical periods

Australian Drug Categories

Legal drugs are classified, usually by each country's appropriate regulatory body, on the safety of drugs during pregnancy. In Australia, the Therapeutic Goods Authority has classes (A, B1, B2, B3, C, D and X) to define their safety. In the USA, drugs are classified by the Food and Drug Administration (FDA) into classes (A, B, C, D, and X) to define their safety. (More? Australian Drug Categories)

  • Pregnancy Category A - Have been taken by a large number of pregnant women and women of childbearing age without an increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.
  • Pregnancy Category B1 - Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.
  • Pregnancy Category B2 - Have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.
  • Pregnancy Category B3 - Have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
  • Pregnancy Category C - Have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible.
  • Pregnancy Category D - Have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
  • Pregnancy Category X - Have such a high risk of causing permanent damage to the fetus that they should NOT be used in pregnancy or when there is a possibility of pregnancy.

Infant Drug Clearance

Drug clearance rates

The drug clearance data below are only approximate calculated rates for the fetus and infant from NZ Drug Safety in Lactation

Post-conceptual Age (weeks) Clearance of Drug (percentage of adults)
24-28 5%
28-34 10%
34-40 33%
40-44 50%
44-68 66%
> 68 100%


Links: Abnormal Development - Drugs | Australian Fetal Risk Categories | USA FDA Fetal Risk Categories | Therapeutic Goods Authority | Australian Drug Evaluation Committee (ADEC) | TGA - Medicines Pregnancy Database | Appendix A: Therapeutic goods exempted from pregnancy classification | NSW Poisons Information Centre


Self-Directed Learning 7

References

  1. Li Z, Zeki R, Hilder L & Sullivan EA 2013. Australia’s mothers and babies 2011. Perinatal statistics series no. 28. Cat. no. PER 59. Canberra: AIHW.
  2. Li Z, McNally L, Hilder L & Sullivan EA 2011. Australia's mothers and babies 2009 AIHW Perinatal statistics series no. 25 Cat. no. PER 52. Sydney: AIHW National Perinatal Epidemiology and Statistics Unit.
  3. Laws P & Sullivan EA 2010 Australia's mothers and babies 2008 AIHW Perinatal statistics series no. 24 Cat. no. PER 48. Sydney: AIHW National Perinatal Statistics Unit.
  4. Laws P & Sullivan EA 2009. Australia's mothers and babies 2007 AIHW Perinatal statistics series no. 23 Cat. no. PER 48. Sydney: AIHW National Perinatal Statistics Unit.
  5. | PLoS Medicine
  6. AIHW National Perinatal Epidemiology and Statistics Unit and AIHW 2013. National core maternity indicators. Cat. no. PER 58. Canberra: AIHW.
  7. Nathalie Fleming, Natalia Ng, Christine Osborne, Shawna Biederman, Abdool Shafaaz Yasseen, Jessica Dy, Ruth Rennicks White, Mark Walker Adolescent pregnancy outcomes in the province of ontario: a cohort study. J Obstet Gynaecol Can: 2013, 35(3);234-45 PMID:23470111
  8. AIHW, Macaldowie A, Wang YA, Chambers GM & Sullivan EA 2012. Assisted reproductive technology in Australia and New Zealand 2010. Assisted reproduction technology series. Cat. no. PER 55. Canberra: AIHW. Online Summary | PDF
  9. Wang YA, Macaldowie A, Hayward I, Chambers GM, & Sullivan EA 2011. Assisted reproductive technology in Australia and New Zealand 2009. Assisted reproduction technology series no. 15. Cat. no. PER 51. Canberra: AIHW. Online Summary | PDF
  10. Confidential Enquiry into Maternal Deaths (CEMD) Why Mothers Die 2000–2002 PDFPDF2

Links

The following are links to relevant notes pages that cover the key embryology concepts in this tutorial. These pages and their links will provide further detailed information.

Applied Embryology

Timeline human development | Fetal Development | Birth | Apgar test | Neonatal Development | Week 2 Abnormalities - Trophoblastic Disease | Placenta Development | Neural Abnormalities | Abnormal Development - Folic Acid and Neural Tube Defects | Week 3 | Cardiovascular Abnormalities | Twinning | Blastocyst | Molecular Development

Teratology Links

Human Abnormal Development | Genetic Abnormalities | Environmental Factors | Drugs | Trisomy 21 (Down Syndrome) | Fetal Alcohol Syndrome | Viral Infection | Rubella Virus | Hyperthermia

Self-Directed Learning

Self-Directed Learning 1 - Australian Statistics
Once you have thought about the Australian statistics, now look at the latest report summary Australia’s mothers and babies 2010 and Australian Statistics.
  • What are the current trends in Australia?
  • What factors may be contributing to these changes?
  • Are there any long-term trends in birth statistics?
  • What does this mean for future health care provision?


Self-Directed Learning 2 - Pregnancy
  • What indications would prompt a woman to take a pregnancy test?
  • What test are available and where is test information provided?
  • How much do these tests cost?
  • When does a doctor become involved and what issues should be discussed?


Self-Directed Learning 3 - Assisted Reproductive Technologies
  • Why is this more than "in vitro fertilization"?
  • How many different Assisted Reproductive Technologies are available in Australia?
  • How has the change from DET to SET impacted on reproductive outcomes?
  • What other clinical issues should be considered when discussing ART?
  • What preimplantation genetic tests are currently available?


Self-Directed Learning 4 - The First Few Weeks
  • After fertilization, when does initial implantation occur?
  • Which hormone maintains the initial pregnacy, where is it from and how does it act?
  • How would an ectopic pregnancy differ at this stage?
  • What additional maternal issues should be considered for multiple pregnancies?


Self-Directed Learning 5 - Abnormal Development
  • What are the 3 major forms of abnormal development?
  • What are the main chromosomal abnormalities and how do they occur?
  • How are congenital abnormalities reported and classified within Australia?


Self-Directed Learning 6 - Prenatal Diagnosis
  • What maternal lifestyle issues should be considered for a pregnancy?
  • What diagnostic techniques are currently available and in development?
  • What can ultrasound normally identify?


Self-Directed Learning 7 - Medications in Pregnancy
  • How does drug classification differ between countries?
  • Do european and asian countries apply the same drug classification system(s)?
  • How are teratogens identified?
  • Why does fetal drug clearance differ from maternal clearance?

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name.


Glossary Links

A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers | Symbols


Cite this page: Hill, M.A. (2014) Embryology BGD Tutorial - Applied Embryology and Teratology. Retrieved September 2, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=BGD_Tutorial_-_Applied_Embryology_and_Teratology

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© Dr Mark Hill 2014, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G