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The Biology of Prenatal Development DVD Documentation

THE EMBRYONIC PERIOD (THE FIRST 8 WEEKS)
THE FETAL PERIOD (8 WEEKS THROUGH BIRTH)
APPENDIX A − CALCULATIONS
APPENDIX B − RELATING EMBRYONIC AGE & STAGE
Bibliography
Full Names of Journals Cited
Program Index

All embryonic and fetal ages in this program refer to the time since fertilization.
Ages from 4 through 8 weeks are estimated to �3 days.
Ages from 8 through 12 weeks are estimated to �5 days.
Ages from 12 weeks through birth are generally estimated to �1 week.
To simplify age calculations, the term �month� assumes a 4-week period.
Age and stage conventions adopted during the embryonic period are listed in Appendix B.

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Chapter 1 Introduction

The dynamic process by which the single-cell human zygote (zī΄gōt)^[1] becomes a 100 trillion (10¹⁴) cell adult^[2] is perhaps the most remarkable phenomenon in all of nature.

Researchers now know that many of the routine functions performed by the adult body become established during pregnancy � often long before birth.^[3]

The developmental period before birth is increasingly understood as a time of preparation during which the developing human acquires the many structures, and practices the many skills, needed for survival after birth.

Chapter 2 Terminology

Pregnancy in humans normally lasts approximately 38 weeks^[4] as measured from the time of fertilization,^[5] or conception,^[6] until birth.

During the first 8 weeks following fertilization, the developing human is called an embryo,^[7] which means �growing within.�^[8] This time, called the embryonic period,^[9] is characterized by the formation of most major body systems.^[10]

From the completion of 8 weeks until the end of pregnancy, �the developing human is called a fetus,� which means �unborn offspring.� During this time, called the fetal period, the body grows larger and its systems begin to function.^[11]

All embryonic and fetal ages in this program refer to the time since fertilization.^[12]

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^[1] Gasser, 1975, 1.
^[2] Guyton and Hall, 2000, 2; Lodish et al., 2000, 12.
^[3] Vindla and James, 1995, 598.
^[4] Cunningham et al., 2001, 226; O�Rahilly and M�ller, 2001, 92.
^[5] O�Rahilly and M�ller, 1987, 9.
^[6] Spraycar, 1995, 377 & 637.
^[7] O�Rahilly and M�ller, 2001, 87.
^[8] Quote from Ayto, 1990, 199.
^[9] Human development�during the 8-week embryonic�period�has been divided into a series of 23 stages called Carnegie Stages. These stages are well described in O�Rahilly and M�ller, 1987. Because human growth�is unique and dependent on multiple factors, different embryos may reach a certain developmental milestone or a certain size at slightly different ages. This internationally-accepted staging system�provides a way to describe development independent of age�and size. Each of the 23 Carnegie Stages has specific structural features. As we describe various milestones of development, the Carnegie Stage at which they occur will be noted by a designation such as: [Carnegie Stage 2]. See Appendix B for additional information relating embryonic staging and age assignments.
^[10] Moore and Persaud, 2003, 3.
^[11] Quotes from Moore and Persaud, 2003, 3: �After the embryonic�period�(eight weeks), the developing human�is called a fetus.� Also see O�Rahilly and M�ller, 2001, 87.
^[12] This convention, termed �postfertilization age� by O�Rahilly, has been long preferred by embryologists. [see Mall, 1918, 400; O�Rahilly and M�ller, 1999b, 39; O�Rahilly and M�ller, 2001, 88 & 91.] Obstetricians and radiologists typically assign age�based on the time elapsed since the first day�of the last menstrual period prior to fertilization. This is correctly termed �postmenstrual age� and begins 2 weeks before fertilization occurs. To summarize: postmenstrual age = postfertilization age + 2 weeks. Therefore, postmenstrual age equals approximately 2 weeks at the time of fertilization. The commonly used term �gestational age� has been used with both age conventions and is best either avoided or carefully defined with each use.

Page 3

The Embryonic Period (The First 8 Weeks)

Embryonic Development: The First 4 Weeks

Chapter 3 Fertilization

Biologically speaking, "human development begins at fertilization,"^[13] when a woman and a man each combine 23 of their own chromosomes through the union of their reproductive cells.

A woman's reproductive cell is commonly called an "egg" but the correct term is oocyte (ō´ō-sīt).^[14]

Likewise, a man's reproductive cell is widely known as a "sperm," but the preferred term is spermatozoon (sper�mă-tō-zō�on).^[15]

Following the release of an oocyte from a woman's ovary in a process called ovulation (ov�yū-lā�shŭn),^[16] the oocyte and spermatozoon join within one of the uterine tubes,^[17] which are often referred to as Fallopian tubes.

The uterine tubes link a woman's ovaries to her uterus or womb.

The resulting single-celled embryo is called a zygote,^[18] meaning "yoked or joined together."^[19]

Chapter 4 DNA, Cell Division, and Early Pregnancy Factor (EPF)

DNA

The zygote's 46 chromosomes^[20] represent the unique first edition of a new individual's complete genetic blueprint. This master plan resides in tightly coiled molecules called DNA. They contain the instructions for the development of the entire body.

DNA molecules resemble a twisted ladder known as a double helix.^[21] The rungs of the ladder are made up of paired molecules, or bases, called guanine, cytosine, adenine, and thymine.

Guanine pairs only with cytosine, and adenine with thymine.^[22] Each human cell contains approximately 3 billion (3�10⁹) of these base pairs.^[23]

The DNA of a single cell contains so much information that if it were represented in printed words, simply listing the first letter of each base would require over 1.5 million (1.5�10⁶) pages of text!^[24]

If laid end-to-end, the DNA in a single human cell measures 3⅓ feet or 1 meter.^[25]

If we could uncoil all of the DNA within an adult's 100 trillion (10¹⁴) cells, it would extend over 63 billion (6.3�10¹⁰) miles. This distance reaches from the earth to the sun and back 340 times.^[26]

Cell Division

Approximately 24 to 30 hours after fertilization, the zygote completes its first cell division.^[27] Through the process of mitosis, one cell splits into two, two into four, and so on.^[28]

Early Pregnancy Factor (EPF)

As early as 24 to 48 hours after fertilization begins, pregnancy can be confirmed by detecting a hormone called "early pregnancy factor" in the mother's blood.^[29]

^[13] Quote from Moore and Persaud, 2003, 16; From O�Rahilly and M�ller, 1987, 9: �Fertilization is the procession of events that begins when a spermatozoon�makes contact with an oocyte�or its investments and ends with the intermingling of maternal�and paternal chromosomes�at metaphase�of the first mitotic division of the zygote.� See Carlson, 2004, 3; O�Rahilly and M�ller, 2001, 8. [Carnegie Stage�1]
^[14] O�Rahilly and M�ller, 2001, 25: �The term �egg� should be discarded from human�embryology.� From O�Rahilly and M�ller, 1987, 9: �The term �egg� is best reserved for a nutritive object frequently seen on the breakfast table.�
^[15] O�Rahilly and M�ller, 2001, 23-24.
^[16] O�Rahilly and M�ller, 2001, 30.
^[17] Dorland and Bartelmez, 1922, 372; Gasser, 1975, 1; Mall, 1918, 421; O�Rahilly and M�ller, 2001, 31.
^[18] Gasser, 1975, 1; O�Rahilly and M�ller, 2001, 33.
^[19] Quote from Saunders, 1970, 1; Spraycar, 1995, 1976.
^[20] Guyton and Hall, 2000, 34.
^[21] Guyton and Hall, 2000, 24; Watson and Crick, 1953, 737.
^[22] Guyton and Hall, 2000, 24; Lodish et al., 2000, 103; Watson and Crick, 1953, 737.
^[23] Lodish et al., 2000, 456.
^[24] See Appendix A.
^[25] See Appendix A; Alberts et al., 1998, 189.
^[26] See Appendix A.
^[27] Hertig, 1968, 26; Hertig and Rock, 1973, 130; (cited by O�Rahilly and M�ller, 1987, 12); Shettles, 1958, 400.
^[28] Guyton and Hall, 2000, 34.
^[29] Moore and Persaud, 2003, 33 & 60; Morton et al., 1992, 72; Nahhas and Barnea, 1990, 105.

Page 4

Chapter 5 Early Stages (Morula and Blastocyst) and Stem Cells

By 3 to 4 days after fertilization, the dividing cells of the embryo assume a spherical shape and the embryo is called a morula (mōr�ū-lă).^[30]

By 4 to 5 days, a cavity forms within this ball of cells and the embryo is then called a blastocyst.^[31]

The cells inside the blastocyst are called the inner cell mass and give rise to the head, body, and other structures vital to the developing human.^[32]

Cells within the inner cell mass are called embryonic stem cells because they have the ability to form each of the more than 200 cell types contained in the human body.^[33]

Chapter 6 1 to 1½ Weeks: Implantation and Human Chorionic Gonadotropin (hCG)

After traveling down the uterine tube, the early embryo embeds itself into the inner wall of the mother's uterus. This process, called implantation, begins 6 days and ends 10 to 12 days after fertilization.^[34]

Cells from the growing embryo begin to produce a hormone called human chorionic gonadotropin (human kō-rē-on'ik gō'nad-ō-trō'pin), or hCG, the substance detected by most pregnancy tests.^[35]

HCG directs maternal hormones to interrupt the normal menstrual cycle, allowing pregnancy to continue.^[36]

Chapter 7 The Placenta and Umbilical Cord

Following implantation, cells on the periphery of the blastocyst give rise to part of a structure called the placenta (plă-sen'tă), which serves as an interface between the maternal and embryonic circulatory systems.

The placenta delivers maternal oxygen, nutrients, hormones, and medications to the developing human; removes all waste products; and prevents maternal blood from mixing with the blood of the embryo and fetus.^[37]

The placenta also produces hormones and maintains embryonic and fetal body temperature slightly above that of the mother's.^[38]

The placenta communicates with the developing human through the vessels of the umbilical (ŭm-bil'i-kăl) cord.^[39]

The life support capabilities of the placenta rival those of intensive care units found in modern hospitals.

^[30] Gasser, 1975, 1; O�Rahilly and M�ller, 2001, 37; Spraycar, 1995, 1130: �Morula� is derived from the Latin word morus meaning �mulberry.� [Carnegie Stage�2]
^[31] O�Rahilly and M�ller, 2001, 39. [Carnegie Stage�3]
^[32] Gasser, 1975, 1; O�Rahilly and M�ller, 2001, 39; Sadler, 2005, 6.
^[33] Alberts et al., 1998, 32. For a discussion and definition of embryonic�stem cells�see the website of the National Institutes of Health: http://stemcells.nih.gov/infoCenter/stemCellBasics.asp#3
^[34] O�Rahilly and M�ller, 2001, 40; Implantation begins with attachment of the blastocyst�at about 6 days�after fertilization. [Attachment of the blastocyst to the inner wall of the uterus�is a transient event and is the hallmark of Carnegie Stage�4.] See also Adams, 1960, 13-14; Cunningham et al., 2001, 20; Hamilton, 1949, 285-286; Hertig, 1968, 41; Hertig and Rock, 1944, 182; Hertig and Rock, 1945, 81 & 83; Hertig and Rock, 1949, 183; Hertig et al., 1956, 444. [Carnegie Stage 5]
^[35] Chartier et al., 1979, 134; Cunningham et al., 2001, 27; O�Rahilly and M�ller, 2001, 43.
^[36] Cunningham et al., 2001, 20 & 26-27; O�Rahilly and M�ller, 2001, 31.
^[37] Hertig, 1968, 16; Cunningham et al., 2001, 86 & 136; For a detailed description of the placenta�see Hamilton and Boyd, 1960. For a detailed description of the placenta vasculature see Harris and Ramsey, 1966. This separation of maternal�and fetal�blood�is almost but not quite perfect as a small number of fetal cells�may be found in the maternal circulation and vice-versa. See Cunningham et al., 2001, 96 & 136.
^[38] Liley, 1972, 101; O�Rahilly and M�ller, 2001, 78-79.
^[39] For a detailed description of umbilical cord�formation�see Florian, 1930.

Page 5

Chapter 8 Nutrition and Protection

By 1 week, cells of the inner cell mass form two layers called the hypoblast and epiblast.^[40]

The hypoblast gives rise to the yolk sac,^[41] which is one of the structures through which the mother supplies nutrients to the early embryo.^[42]

Cells from the epiblast form a membrane called the amnion (am-nē-on),^[43] within which the embryo and later the fetus develop until birth.

Chapter 9 2 to 4 Weeks: Germ Layers and Organ Formation

By approximately 2½ weeks, the epiblast has formed 3 specialized tissues, or germ layers, called ectoderm, endoderm, and mesoderm.^[44]

Ectoderm gives rise to numerous structures including the brain, spinal cord, nerves, skin, nails, and hair.

Endoderm produces the lining of the respiratory system and digestive tract and generates portions of major organs such as the liver and pancreas.

Mesoderm forms the heart, kidneys, bones, cartilage, muscles, blood cells, and other structures.^[45]

By 3 weeks the brain is dividing into 3 primary sections called the forebrain, midbrain, and hindbrain.^[46]

Development of the respiratory and digestive systems is also underway.^[47]

As the first blood cells appear in the yolk sac,^[48] blood vessels form throughout the embryo, and the tubular heart emerges.^[49]

Almost immediately, the rapidly growing heart folds in upon itself as separate chambers begin to develop.^[50]

The heart begins beating 3 weeks and 1 day following fertilization.^[51]

The circulatory system is the first body system, or group of related organs, to achieve a functional state.^[52]

Chapter 10 3 to 4 Weeks: The Folding of the Embryo

Between 3 and 4 weeks, the body plan emerges as the brain, spinal cord, and heart of the embryo are easily identified alongside the yolk sac.

Rapid growth causes folding of the relatively flat embryo.^[53] This process incorporates part of the yolk sac into the lining of the digestive system and forms the chest and abdominal cavities of the developing human.^[54]

^[40] O�Rahilly and M�ller, 2001, 39.
^[41] Moore and Persaud, 2003, 50; O�Rahilly and M�ller, 2001, 82. [Carnegie Stages�5 & 6]; In humans, the term �yolk sac� has fallen out of favor among some embryologists (including O�Rahilly and M�ller) because it is not a nutrient reservoir and does not contain yolk. The technically preferred term is umbilical vesicle. This structure�plays a vital role in the transfer of nutrients from mother to embryo�before placental circulation becomes fully functional.
^[42] Campbell et al., 1993, 756; Kurjak et al., 1994, 437; O�Rahilly and M�ller, 2001, 82.
^[43] O�Rahilly and M�ller, 1987, 29; O�Rahilly and M�ller, 2001, 43. [Carnegie Stages�4-5]
^[44] O�Rahilly and M�ller, 2001, 14 & 135. [Carnegie Stage�7]; It should be noted there are many examples of organs derived from multiple germ layers. For instance, the liver�is largely derived from endoderm�but contains blood�vessels�and blood cells�derived from mesoderm�and nerves�of ectodermal origin.
^[45] Moore and Persaud, 2003, 80 & 83; Sadler, 2005, 9.
^[46] Bartelmez, 1923, 236; M�ller and O�Rahilly, 1983, 419-420 & 429; O�Rahilly and Gardner, 1979, 123 & 129; O�Rahilly and M�ller, 1984, 422; O�Rahilly and M�ller, 1987, 90; O�Rahilly and M�ller, 1999a, 47 & 52. [Carnegie Stage 9]
^[47] DiFiore and Wilson, 1994, 221; Fowler et al., 1988, 793; Grand et al., 1976, 793-794 & 796 & 798; O�Rahilly, 1978, 125; O�Rahilly and Boyden, 1973, 238-239; O�Rahilly and M�ller, 1984, 421; O�Rahilly and Tucker, 1973, 6 & 8 & 23; Streeter, 1942, 232 & 235.
^[48] Carlson, 2004, 117.
^[49] Gilmour, 1941, 28; O�Rahilly and M�ller, 1987, 86. [Carnegie Stage�9]
^[50] Campbell, 2004, 14; Carlson, 2004, 116 & 446; Navaratnam, 1991, 147-148; O�Rahilly and M�ller, 1987, 99. [Carnegie Stage�10]
^[51] Campbell, 2004, 14; Carlson, 2004, 430; De Vries and Saunders, 1962, 96; Gardner and O�Rahilly, 1976, 583; Gilbert-Barness and Debich-Spicer, 1997, 650; Gittenger-de Groot et al., 2000, 17; van Heeswijk et al., 1990, 151; Kurjak and Chervenak, 1994, 439; Navaratnam, 1991, 147-148; O�Rahilly and M�ller, 1987, 99; Wisser and Dirschedl, 1994, 108. [Carnegie Stage�10, possibly late Stage 9]
^[52] Moore and Persaud, 2003, 70: �The cardiovascular�system�is the first organ system to reach a functional state.�
^[53] Moore and Persaud, 2003, 78.
^[54] Gasser, 1975, 26; Moore and Persaud, 2003, 78.

Page 6

Embryonic Development: 4 to 6 Weeks

Chapter 11 4 Weeks: Amniotic Fluid

By 4 weeks the clear amnion surrounds the embryo in a fluid-filled sac.^[55] This sterile liquid, called amniotic (am-nē-ot'ik) fluid, provides the embryo with protection from injury.^[56]

Chapter 12 The Heart in Action

The heart typically beats about 113 times per minute.^[57]

Note how the heart changes color as blood enters and leaves its chambers with each beat.

The heart will beat approximately 54 million (5.4�10⁷) times before birth and over 3.2 billion (3.2�10⁹) times over the course of an 80-year lifespan.^[58]

Chapter 13 Brain Growth

Rapid brain growth is evidenced by the changing appearance of the forebrain, midbrain, and hindbrain.

Chapter 14 Limb Buds

Upper and lower limb development begins with the appearance of the limb buds by 4 weeks.^[59]

The skin is transparent at this point because it is only one cell thick.

As the skin thickens, it will lose this transparency, which means that we will only be able to watch internal organs develop for about another month.^[60]

Chapter 15 5 Weeks: Cerebral Hemispheres

Between 4 and 5 weeks, the brain continues its rapid growth and divides into five distinct sections.^[61]

The head comprises about one-third of the embryo's total size.^[62]

The cerebral (ser'ĕ-brăl) hemispheres appear,^[63] gradually becoming the largest parts of the brain.^[64]

Functions eventually controlled by the cerebral hemispheres include thought, learning, memory, speech, vision, hearing, voluntary movement, and problem-solving.^[65]

^[55] Gasser, 1975, 30; O�Rahilly and M�ller, 2001, 80.
^[56] O�Rahilly and M�ller, 2001, 81.
^[57] van Heeswijk et al., 1990, 153.
^[58] See Appendix A.
^[59] Gasser, 1975, 49 & 59; O�Rahilly and Gardner, 1975, 11; O�Rahilly and M�ller, 1985, 148 & 151; O�Rahilly and M�ller, 1987, 143; Streeter, 1945, 30; Uhthoff, 1990, 7 & 141. [upper and lower limb buds: Carnegie Stages 12 & 13]
^[60] Moore and Persaud, 2003, 486; O�Rahilly, 1957, 459; O�Rahilly and M�ller, 2001, 165. For information about the first-trimester direct- imaging technique used in this program (called embryoscopy), see Cullen et al., 1990.
^[61] O�Rahilly and M�ller, 1999a, 134; Sadler, 2005, 106. [Carnegie Stage�15]
^[62] Laffont, 1982, 5.
^[63] Bartelmez and Dekaban, 1962, 25; Campbell, 2004, 17; O�Rahilly and Gardner, 1979, 130; O�Rahilly et al., 1984, 249; O�Rahilly and M�ller, 1999a, 115; van Dongen and Goudie, 1980, 193. [Carnegie Stage�14]
^[64] Moore, 1980, 938.
^[65] Guyton and Hall, 2000, 663-677.

Page 7

Chapter 16 Major Airways

In the respiratory system, the right and left main stem bronchi (brong'kī) are present^[66] and will eventually connect the trachea (trā�kē-ă), or windpipe, with the lungs.

Chapter 17 Liver and Kidneys

Note the massive liver filling the abdomen adjacent to the beating heart.

The permanent kidneys appear by 5 weeks.^[67]

Chapter 18 Yolk Sac and Germ Cells

The yolk sac contains early reproductive cells called germ cells. By 5 weeks these germ cells migrate to the reproductive organs adjacent to the kidneys.^[68]

Chapter 19 Hand Plates and Cartilage

Also by 5 weeks, the embryo develops hand plates,^[69] and cartilage formation begins by 5½ weeks.^[70]

Here we see the left hand plate and wrist at 5 weeks and 6 days.

^[66] Moore and Persaud, 2003, 245; O�Rahilly and Boyden, 1973, 239; O�Rahilly and M�ller, 2001, 291; Sparrow et al., 1999, 550.
^[67] Angtuaco et al., 1999, 13; Lipschutz, 1998, 384; Moore and Persaud, 2003, 288; O�Rahilly and M�ller, 1987, 167 & 182; O�Rahilly and M�ller, 2001, 301; Sadler, 2005, 72. [Carnegie Stage�14]
^[68] O�Rahilly and M�ller, 2001, 23; Waters and Trainer, 1996, 16; Witschi, 1948, 70, 77 & 79.
^[69] O�Rahilly and M�ller, 1987, 175; Streeter, 1948, 139. [Carnegie Stage�15 ]
^[70] O�Rahilly and Gardner, 1975, 4. [Carnegie Stages�16 and 17 ]

Page 8

Embryonic Development: 6 to 8 Weeks

Chapter 20 6 Weeks: Motion and Sensation

By 6 weeks the cerebral hemispheres are growing disproportionately faster than other sections of the brain.

The embryo begins to make spontaneous and reflexive movements.^[71] Such movement is necessary to promote normal neuromuscular development.

A touch to the mouth area causes the embryo to reflexively withdraw its head.^[72]

Chapter 21 The External Ear and Blood Cell Formation

The external ear is beginning to take shape.^[73]

By 6 weeks, blood cell formation is underway in the liver where lymphocytes are now present.^[74] This type of white blood cell is a key part of the developing immune system.

Chapter 22 The Diaphragm and Intestines

The diaphragm (dī'ă-fram), the primary muscle used in breathing, is largely formed by 6 weeks.^[75]

A portion of the intestine now protrudes temporarily into the umbilical cord. This normal process, called physiologic herniation (fiz-ē-ō-loj'ik her-nē-ā'shŭn), makes room for other developing organs in the abdomen.^[76]

Chapter 23 Hand Plates and Brainwaves

At 6 weeks the hand plates develop a subtle flattening.^[77]

Primitive brainwaves have been recorded as early as 6 weeks and 2 days.^[78]

^[71] Birnholz et al., 1978, 539; de Vries et al., 1982, 301 & 304: �The first movements�were observed at 7.5 weeks postmenstrual age.� [or 5� weeks postfertilization age]; Humphrey, 1964, 99: earliest reflex�5� weeks; Humphrey, 1970, 12; Humphrey and Hooker, 1959, 76; Humphrey and Hooker, 1961, 147; Kurjak and Chervenak, 1994, 48; Visser et al., 1992, 175-176: �Endogenously generated fetal�movements can first be observed after 7 weeks postmenstrual age�(i.e. 5 weeks after conception);� Natsuyama, 1991, 13; O�Rahilly and M�ller, 1999a, 336: 5� weeks postfertilization; Sorokin and Dierker, 1982, 723 & 726; Visser et al., 1992, 175-176; Natsuyama, 1991, 13: Spontaneous movement observed by �Carnegie stage 15� (about 33 days�postfertilization); Hogg, 1941, 373: Reflex activity�begins at 6� weeks [adjusted to postfertilization age].
^[72] Goodlin, 1979, D-128.
^[73] Karmody and Annino, 1995, 251; O�Rahilly and M�ller, 2001, 480; Streeter, 1948, 190.
^[74] Kurjak and Chervenak, 1994, 19.
^[75] de Vries et al., 1982, 320.
^[76] Gilbert-Barness and Debich-Spicer, 1997, 774; Grand et al., 1976, 798; O�Rahilly and M�ller, 1987, 213; Sadler, 2005, 66; Spencer, 1960, 9; Timor-Tritsch et al., 1990, 287.
^[77] O�Rahilly and M�ller, 1987, 202-203.
^[78] Borkowski and Bernstine, 1955, 363 (cited by Bernstine, 1961, 63 & 66; O�Rahilly and M�ller, 1999a, 195; van Dongen and Goudie, 1980, 193.); Hamlin, 1964, 113. For a summary of in utero fetal�encephalography�(measuring brainwaves) in the near- term fetus�using abdominal�and vaginal electrodes�see Bernstine et al., 1955.

Page 9

Chapter 24 Nipple Formation

Nipples appear along the sides of the trunk shortly before reaching their final location on the front of the chest.^[79]

Chapter 25 Limb Development

By 6½ weeks, the elbows are distinct, the fingers are beginning to separate,^[80] and hand movement can be seen.

Bone formation, called ossification (os'i-fi-kā'shŭn), begins within the clavicle, or collar bone, and the bones of the upper and lower jaw.^[81]

Chapter 26 7 Weeks: Hiccups and Startle Response

Hiccups have been observed by 7 weeks.^[82]

Leg movements can now be seen, along with a startle response.^[83]

Chapter 27 The Maturing Heart

The four-chambered heart is largely complete.^[84] On average, the heart now beats 167 times per minute.^[85]

Electrical activity of the heart recorded at 7½ weeks reveals a wave pattern similar to the adult's.^[86]

Chapter 28 Ovaries and Eyes

In females, the ovaries are identifiable by 7 weeks.^[87]

By 7½ weeks, the pigmented retina of the eye is easily seen and the eyelids are beginning a period of rapid growth.^[88]

Chapter 29 Fingers and Toes

Fingers are separate and toes are joined only at the bases.

The hands can now come together, as can the feet.^[89]

Knee joints are also present.^[90]

^[79] O�Rahilly and M�ller, 1985, 155: �The nipple�appears at stages 17 and 18.� [41-44 days�postfertilization]; Wells, 1954, 126.
^[80] O�Rahilly and M�ller, 2001, 221; Streeter, 1948, 187.
^[81] Carlson, 2004, 189; O�Rahilly and Gardner, 1972, 293; O�Rahilly and Gardner, 1975, 19; O�Rahilly and M�ller, 2001, 385; Sperber, 1989, 122 & 147. [Carnegie Stage�19]
^[82] de Vries et al., 1982, 305 & 311; Visser et al., 1992, 176.
^[83] de Vries et al., 1988, 96; Visser et al., 1992, 176.
^[84] Cooper and O�Rahilly, 1971, 292; James, 1970, 214; Jordaan, 1979, 214; Streeter, 1948, 192; Vernall, 1962, 23: �The four chambers�of the heart�and the associated major vessels are externally apparent in a close�approximation to their adult�positions.� [Carnegie Stage�18]
^[85] van Heeswijk et al., 1990, 153.
^[86] Straus et al., 1961, 446 (cited by Gardner and O�Rahilly, 1976, 571.): ��an electrocardiogram�with the classical P, QRS, and T configuration has been obtained from a 23mm human�embryo�(Straus, Walker, and Cohen, 1961).�
^[87] O�Rahilly and M�ller, 2001, 320. [Carnegie Stage�20]
^[88] Andersen et al., 1965, 646; O�Rahilly, 1966, 35; O�Rahilly and M�ller, 1987, 259; Pearson, 1980, 39; Streeter, 1951, 193. [Carnegie Stage 22] Pigment within the retina�is present from about 37 days�postfertilization per O�Rahilly, 1966, 25. [Carnegie Stage�16]
^[89] Streeter, 1951, 191; reiterated by O�Rahilly and Muller, 1987, 257.
^[90] O�Rahilly and Gardner, 1975, 11; O�Rahilly and M�ller, 1987, 262.

Page 10

The 8-Week Embryo

Chapter 30 8 Weeks: Brain Development

At 8 weeks the brain is highly complex^[91] and constitutes almost half of the embryo's total body weight.^[92]

Growth continues at an extraordinary rate.

Chapter 31 Right- and Left-Handedness

By 8 weeks, 75 percent of embryos exhibit right-hand dominance. The remainder is equally divided between left-handed dominance and no preference. This is the earliest evidence of right- or left-handed behavior.^[93]

Chapter 32 Rolling Over

Pediatric textbooks describe the ability to "roll over" as appearing 10 to 20 weeks after birth.^[94] However, this impressive coordination is displayed much earlier in the low-gravity environment of the fluid-filled amniotic sac.^[95] Only the lack of strength required to overcome the higher gravitational force outside the uterus prevents newborns from rolling over.^[96]

The embryo is becoming more physically active during this time.

Motions may be slow or rapid, single or repetitive, spontaneous or reflexive.

Head rotation, neck extension, and hand-to-face contact occur more often.^[97]

Touching the embryo elicits squinting, jaw movement, grasping motions, and toe pointing.^[98]

Chapter 33 Eyelid Fusion

Between 7 and 8 weeks, the upper and lower eyelids rapidly grow over the eyes and partially fuse together.^[99]

Chapter 34 "Breathing" Motion and Urination

Although there is no air in the uterus, the embryo displays intermittent breathing motions by 8 weeks.^[100]

By this time, kidneys produce urine which is released into the amniotic fluid.^[101]

In male embryos, the developing testes begin to produce and release testosterone (tes-tos�tĕ-rōn).^[102]

Chapter 35 The Limbs and Skin

The bones, joints, muscles, nerves, and blood vessels of the limbs closely resemble those in adults.^[103]

By 8 weeks the epidermis, or outer skin, becomes a multi-layered membrane,^[104] losing much of its transparency.

Eyebrows grow as hair appears around the mouth.^[105]

Chapter 36 Summary of the First 8 Weeks

Eight weeks marks the end of the embryonic period.

During this time, the human embryo has grown from a single cell into the nearly 1 billion (10⁹) cells^[106] which form over 4,000 (4�10³) distinct anatomic structures.

The embryo now possesses more than 90 percent of the structures found in adults.^[107]

^[91] O�Rahilly and M�ller, 1999a, 288: �The brain�at [Carnegie] Stage 23 is far more advanced morphologically than is generally appreciated, to such an extent that functional considerations are imperative.�
^[92] Jordaan, 1979, 149.
^[93] Hepper et al., 1998, 531; McCartney and Hepper, 1999, 86.
^[94] Bates, 1987, 534.
^[95] de Vries et al., 1982, 320; Goodlin and Lowe, 1974, 348; Humphrey, 1970, 8.
^[96] Liley, 1972, 101.
^[97] de Vries et al., 1982, 311.
^[98] Humphrey, 1964, 102; Humphrey, 1970, 19.
^[99] Process described by Andersen et al., 1965, 648-649; O�Rahilly, 1966, 36-37; O�Rahilly and M�ller, 1987, 261.�[Carnegie Stage�23]
^[100] Connors et al., 1989, 932; de Vries et al., 1982, 311; McCray, 1993, 579; Visser et al.,1992, 177.
^[101] O�Rahilly and M�ller, 2001, 304; Windle, 1940, 118; (Windle reports urine�formation�begins at nine weeks.)
^[102] Moore and Persaud, 2003, 307; Waters and Trainer, 1996, 16-17.
^[103] O�Rahilly and Gardner, 1975, 15: �By the end of the embryonic�proper (Stage 23, 8 postovulatory weeks), all of the major skeletal, articular, muscular, neural, and vascular�elements of the limbs�are present in a form and arrangement closely resembling those of the adult.� See O�Rahilly, 1957, for a summary of joint types and a description of limb joint development during the embryonic period. See Gray et al., 1957, for a detailed examination of the bones and joints of the hand throughout the embryonic and fetal periods.
^[104] Hogg, 1941, 407; Pringle, 1988, 178.
^[105] Hogg, 1941, 387; O�Rahilly and M�ller, 2001, 169.
^[106] Pringle, 1988, 176.
^[107] O�Rahilly and M�ller, 2001, 87: �It has been estimated that more than 90% of the more than 4500 named structures�of the adult�body�become apparent during the embryonic�period�(O�Rahilly).�

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The Fetal Period (8 Weeks through Birth)

Chapter 37 9 Weeks: Swallows, Sighs, and Stretches

The fetal period continues until birth.

By 9 weeks, thumb sucking begins^[108] and the fetus can swallow amniotic fluid.^[109]

The fetus can also grasp an object,^[110] move the head forward and back, open and close the jaw, move the tongue, sigh,^[111] and stretch.^[112]

Nerve receptors in the face, the palms of the hands, and the soles of the feet can sense light touch.^[113]

"In response to a light touch on the sole of the foot," the fetus will bend the hip and knee and may curl the toes.^[114]

The eyelids are now completely closed.^[115]

In the larynx, the appearance of vocal ligaments signals the onset of vocal cord development.^[116]

In female fetuses, the uterus is identifiable^[117] and immature reproductive cells called oogonia (ō-ō-gō′nē-ă) are replicating within the ovary.^[118]

External genitalia begin to distinguish themselves as either male or female.^[119]

Chapter 38 10 Weeks: Rolls Eyes and Yawns, Fingernails & Fingerprints

A burst of growth between 9 and 10 weeks increases body weight by over 75 percent.^[120]

By 10 weeks, stimulation of the upper eyelid causes a downward rolling of the eye.^[121]

The fetus yawns and often opens and closes the mouth.^[122]

Most fetuses suck the right thumb.^[123]

Sections of intestine within the umbilical cord are returning to the abdominal cavity.^[124]

Ossification is underway in most bones.^[125]

Fingernails and toenails begin to develop.^[126]

Unique fingerprints appear 10 weeks after fertilization. These patterns can be used for identification throughout life.^[127]

Chapter 39 11 Weeks: Absorbs Glucose and Water

By 11 weeks the nose and lips are completely formed.^[128] As with every other body part, their appearance will change at each stage of the human life cycle.

The intestine starts to absorb glucose and water swallowed by the fetus.^[129]

Though sex is determined at fertilization, external genitalia can now be distinguished as male or female.^[130]

^[108] Liley, 1972, 103.
^[109] Campbell, 2004, 24; de Vries, 1982, 311; Petrikovsky et al., 1995, 605.
^[110] Robinson and Tizard, 1966, 52; Valman and Pearson, 1980, 234.
^[111] de Vries et al., 1982, 305-307.
^[112] de Vries et al., 1982, 311.
^[113] Humphrey, 1964, 96; Humphrey, 1970, 16-17 (cited by Reinis and Goldman, 1980, 232); Humphrey and Hooker, 1959, 77-78.
^[114] Robinson and Tizard, 1966, 52; Quote from Valman and Pearson, 1980, 234.
^[115] Andersen et al., 1965, 648-649; O�Rahilly and M�ller, 2001, 465; Pearson, 1980, 39-41.
^[116] O�Rahilly and M�ller, 1984, 425. See also Campbell, 2004, 29.
^[117] O�Rahilly, 1977a, 128; O�Rahilly, 1977b, 53; O�Rahilly and M�ller, 2001, 327.
^[118] O�Rahilly and M�ller, 2001, 25 & 322.
^[119] Campbell, 2004, 28 & 35; O�Rahilly and M�ller, 2001, 336.
^[120] Brenner et al., 1976, 561.
^[121] Goodlin, 1979, D-128; Humphrey, 1964, 102.
^[122] de Vries et al., 1982, 309.
^[123] Hepper et al., 1991, 1109.
^[124] Grand et al., 1976, 798; Pringle, 1988, 178; Sadler, 2005, 66; Spencer, 1960, 9. [Pringle reports the bowel�returns during the ninth or tenth week.]
^[125] Cunningham et al., 2001, 133.
^[126] O�Rahilly and M�ller, 2001, 170-171.
^[127] Babler, 1991, 95; Penrose and Ohara, 1973, 201; For an overview of ridge formation�in the skin of the hands see Cummins, 1929.
^[128] Timor-Tritsch et al., 1990, 291.
^[129] Koldovsk� et al., 1965, 186.
^[130] O�Rahilly and M�ller, 2001, 336; Wilson, 1926, 29.

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Chapter 40 3 to 4 Months (12 to 16 Weeks): Taste Buds, Jaw Motion, Rooting Reflex, Quickening

Between 11 and 12 weeks, fetal weight increases nearly 60 percent.^[131]

Twelve weeks marks the end of the first third, or trimester, of pregnancy.

Distinct taste buds now cover the inside of the mouth. By birth, taste buds will remain only on the tongue and roof of the mouth.^[132]

Bowel movements begin as early as 12 weeks and continue for about 6 weeks.^[133]

The material first expelled from the fetal and newborn colon is called meconium (mĭ-kō'nē-ŭm).^[134] It is composed of digestive enzymes, proteins, and dead cells shed by the digestive tract.^[135]

By 12 weeks, upper limb length has nearly reached its final proportion to body size. The lower limbs take longer to attain their ultimate proportions.^[136]

With the exception of the back and the top of the head, the body of the entire fetus now responds to light touch.^[137]

Sex-dependent developmental differences appear for the first time. For instance, female fetuses exhibit jaw movement more frequently than males.^[138]

In contrast to the withdrawal response seen earlier, stimulation near the mouth now evokes a turning toward the stimulus and an opening of the mouth.^[139] This response is called the "rooting reflex" and it persists after birth, helping the newborn find his or her mother's nipple during breastfeeding.^[140]

The face continues to mature as fat deposits begin to fill out the cheeks^[141] and tooth development begins.^[142]

By 15 weeks, blood-forming stem cells arrive and multiply in the bone marrow. Most blood cell formation will occur here.^[143]

Although movement begins in the 6-week embryo, a pregnant woman first senses fetal movement between 14 and 18 weeks.^[144] Traditionally, this event has been called quickening.^[145]

^[131] Brenner, 1976, 561.
^[132] Lecanuet and Schaal, 1996, 3; Miller, 1982, 169; Mistretta and Bradley, 1975, 80.
^[133] Abramovich and Gray, 1982, 296; Ram�n y Cajal and Martinez, 2003, 154-155, report visualizing defecation (bowel movements) with ultrasound in utero in all 240 fetuses studied between 15 and 41 weeks [postmenstrual age].
^[134] O�Rahilly and M�ller, 2001, 257; For a description of meconium�by Aristotle see Grand et al., 1976, 791.
^[135] Grand et al., 1976, 806.
^[136] Moore and Persaud, 2003, 105.
^[137] Lecanuet and Schaal, 1996, 2; Reinis and Goldman, 1980, 232.
^[138] Hepper et al., 1997, 1820.
^[139] Mancia, 1981, 351.
^[140] Bates, 1979, 419.
^[141] Poissonnet et al., 1983, 7; Poissonnet et al., 1984, 3: In a study of 488 fetuses, Poissonnet�s group found that adipose tissue (fat) appears in the face�from 14 weeks postfertilization. By 15 weeks, fat appears in the abdominal�wall, back, kidneys, and shoulders. By 16 weeks, fat is also present throughout the upper and lower limbs.
^[142] Pringle, 1988, 178. [Thirteenth week postfertilization]
^[143] Pringle, 1988, 179.
^[144] Sorokin and Dierker, 1982, 720; Leader, 1995, 595: �Some pregnant women reported fetal�flutters as early as 12 weeks (quickening).� Women also tend to accurately recognize fetal movement�at earlier fetal ages during second and subsequent pregnancies as compared to first pregnancies.
^[145] Spraycar, 1995, 1479; Timor-Tritsch et al., 1976, 70.

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Chapter 41 4 to 5 Months (16 to 20 Weeks): Stress Response, Vernix Caseosa, Circadian Rhythms

By 16 weeks, procedures involving the insertion of a needle into the abdomen of the fetus trigger a hormonal stress response releasing noradrenalin, or norepinephrin (nor-ep'i-nef'rin), into the bloodstream.^[146]

In the respiratory system, the bronchial tree is now nearly complete.^[147]

A protective white substance, called vernix caseosa (ver'niks caseo'sa), now covers the fetus. Vernix protects the skin from the irritating effects of amniotic fluid.^[148]

From 19 weeks fetal movement, breathing activity, and heart rate begin to follow daily cycles called circadian (ser-kā'dē-ăn) rhythms.^[149]

Chapter 42 5 to 6 Months (20 to 24 Weeks): Responds to Sound; Hair and Skin; Age of Viability

By 20 weeks the cochlea, which is the organ of hearing, has reached adult size^[150] within the fully developed inner ear. From now on, the fetus will respond to a growing range of sounds.^[151]

Hair begins to grow on the scalp.

All skin layers and structures are present, including hair follicles and glands.^[152]

By 21 to 22 weeks after fertilization, the lungs gain some ability to breathe air.^[153] This is considered the age of viability because survival outside the womb becomes possible for some fetuses.^[154]

^[146] Giannakoulopoulos et al., 1999, 494 & 498-499; Glover and Fisk, 1999, 883; Smith et al., 2000, 161. Cortisol levels also rise after invasive procedures following 21 weeks postfertilization - see Giannakoulopoulos et al., 1994, 80.
^[147] DiFiore and Wilson, 1994, 221-222; Pringle, 1988, 178. [There is some disagreement among experts regarding when the bronchial tree�is complete. Some say completion occurs as early as 16 weeks postfertilization while others say it occurs after birth.]
^[148] Campbell, 2004, 48; Moore and Persaud, 2003, 107; O�Rahilly and M�ller, 2001, 168.
^[149] de Vries et al., 1987, 333; Goodlin and Lowe, 1974, 349; Okai et al., 1992, 391 & 396; Romanini and Rizzo, 1995, 121; For a description of the circadian system�see Rosenwasser, 2001, 127; From Vitaterna et al., 2001, 92: Glossary: �Circadian: A term derived from the Latin phrase �circa diem,� meaning �about a day;� refers to biological variations or rhythms with a cycle of approximately 24 hours.�
^[150] Lecanuet and Schaal, 1996, 5-6; Querleu et al., 1989, 410.
^[151] Glover and Fisk, 1999, 882; Hepper and Shahidullah, 1994, F81; Querleu et al., 1989, 410; Sorokin and Dierker, 1982, 725 & 730; Valman and Pearson, 1980, 233-234.
^[152] Pringle, 1988, 180.
^[153] Hansen and Corbet, 1998, 542.
^[154] O�Rahilly and M�ller, 2001, 92, report the age�of viability�as 20 weeks postfertilization; Draper et al., 1999, 1094, report a survival�rate of 2% at 20 weeks postfertilization, 6% at 21 weeks, and 16% at 22 weeks. Moore and Persaud, 2003, 103, report viability�at 22 weeks; Wood et al., 2000, 379, report survival rates of 11% at 21 weeks, 26% at 22 weeks and 44% at 23 weeks (postfertilization weeks) based on premature�birth�data from the United Kingdom during 1995. Cooper et al. 1998, 976, (Figure 2) report infants with a birth weight over 500 grams experienced�survival rates (all approximate) of 28% at 21 weeks postfertilization, 50% at 22 weeks, 67% at 23 weeks, and� 77% at 24 weeks. Draper et al., 2003, updated their previously published survival tables for premature infants and now report an overall survival rate of 7% at 20 weeks, 15% at 21 weeks, 29% at 22 weeks, 47% at 23 weeks and 65% at 24 weeks. [All ages corrected to reflect postfertilization age.] These survival tables are available online at http://bmj.bmjjournals.com/cgi/content/full/319/7217/1093/DC1. Their methodology is described in their earlier paper (Draper et al., 1999, 1093-1094.) Note: These published survival tables reflect postmenstrual ages. Hoekstra et al., 2004, e3, report a survival rate of 66% at 23 weeks and 81% at 24 weeks �gestational age� [not specifically defined] for premature births from 1996 to 2000 at their center in Minneapolis, Minnesota.

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