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.


2013 Print Version PDF (10 pages, 670kb)


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


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. (2013) UNSW Embryology (13th ed.). Sydney:UNSW.
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

Abnormality Links: abnormal development | abnormal genetic | abnormal environmental | Unknown | teratogens | ectopic pregnancy | cardiovascular abnormalities | coelom abnormalities | endocrine abnormalities | gastrointestinal abnormalities | genital abnormalities | head abnormalities | integumentary abnormalities | musculoskeletal abnormalities | limb abnormalities | neural abnormalities | neural crest abnormalities | placenta abnormalities | renal abnormalities | respiratory abnormalities | hearing abnormalities | vision abnormalities | twinning | Developmental Origins of Health and Disease |  ICD-11
Historic Embryology  
1915 Congenital Cardiac Disease | 1917 Frequency of Anomalies in Human Embryos | 1920 Hydatiform Degeneration Tubal Pregnancy | 1921 Anencephalic Embryo | 1921 Rat and Man | 1966 Congenital Malformations
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 (2009) cover

This recent data summarised below from Australia's mothers and babies 2009[1], 2008[2] and 2007[3]. 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.

  • 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

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).


Self-Directed Learning 2

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

300p

Teen pregnancy (USA)

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[7] 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.


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[9], 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[10] "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.[11]

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: abnormal development | abnormal genetic | abnormal environmental | Unknown | teratogens | ectopic pregnancy | cardiovascular abnormalities | coelom abnormalities | endocrine abnormalities | gastrointestinal abnormalities | genital abnormalities | head abnormalities | integumentary abnormalities | musculoskeletal abnormalities | limb abnormalities | neural abnormalities | neural crest abnormalities | placenta abnormalities | renal abnormalities | respiratory abnormalities | hearing abnormalities | vision abnormalities | twinning | Developmental Origins of Health and Disease |  ICD-11
Historic Embryology  
1915 Congenital Cardiac Disease | 1917 Frequency of Anomalies in Human Embryos | 1920 Hydatiform Degeneration Tubal Pregnancy | 1921 Anencephalic Embryo | 1921 Rat and Man | 1966 Congenital Malformations

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.

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: Introduction | low folic acid | iodine deficiency | Nutrition | Drugs | Australian Drug Categories | USA Drug Categories | thalidomide | herbal drugs | Illegal Drugs | smoking | Fetal Alcohol Syndrome | TORCH | viral infection | bacterial infection | fungal infection | zoonotic infection | toxoplasmosis | Malaria | maternal diabetes | maternal hypertension | maternal hyperthermia | Maternal Inflammation | Maternal Obesity | hypoxia | biological toxins | chemicals | heavy metals | air pollution | radiation | Prenatal Diagnosis | Neonatal Diagnosis | International Classification of Diseases | Fetal Origins Hypothesis
Bacterial Links: bacterial infection | syphilis | gonorrhea | tuberculosis | listeria | salmonella | TORCH | Environmental | Category:Bacteria
Viral Links: viral infection | TORCH | cytomegalovirus | hepatitis | HIV | parvovirus | polio | rubella virus | chickenpox | Lymphocytic Choriomeningitis Virus | Zika virus | human papillomavirus | rotavirus | West Nile virus | varicella virus | vaccination | zoonotic infection | environment
Historic Embryology - Viral 
1941 Rubella Cataracts | 1944 Rubella Defects

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-10

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

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

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