د زېږېدنې څخه مخکې د ماشوم د ودې بيالوژي

The Biology of Prenatal Development
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Table of Contents

Appendix A:
Calculations

Appendix B:
Ages & Stages

Back to Top

Program Index

Script & Footnotes

Bibliography

Full Names
of Journals Cited

Table of Contents

• • Chapter 1 – Introduction
  • Chapter 2 – Terminology
  •  
• THE EMBRYONIC PERIOD (THE FIRST 8 WEEKS)
• • EMBRYONIC DEVELOPMENT: THE FIRST 4 WEEKS
  • • Chapter 3 – Fertilization
    • Chapter 4 – DNA, Cell Division, and Early Pregnancy Factor (EPF)
    • Chapter 5 – Early Stages (Morula and Blastocyst) and Stem Cells
    • Chapter 6 – 1 to 1 1/2 Weeks: Implantation and Human Chorionic Gonadotropin (hCG)
    • Chapter 7 – The Placenta and Umbilical Cord
    • Chapter 8 – Nutrition and Protection
    • Chapter 9 – 2 to 4 Weeks: Germ Layers and Organ Formation
    • Chapter 10 – 3 to 4 Weeks: The Folding of the Embryo
    •  
  • EMBRYONIC DEVELOPMENT: 4 TO 6 WEEKS
  • • Chapter 11 – 4 Weeks: Amniotic Fluid
    • Chapter 12 – The Heart in Action
    • Chapter 13 – Brain Growth
    • Chapter 14 – Limb Buds and Skin
    • Chapter 15 – 5 Weeks: Cerebral Hemispheres
    • Chapter 16 – Major Airways
    • Chapter 17 – Liver and Kidneys
    • Chapter 18 – Yolk Sac and Germ Cells
    • Chapter 19 – Hand Plates and Cartilage
    •  
  • EMBRYONIC DEVELOPMENT: 6 TO 8 WEEKS
  • • Chapter 20 – 6 Weeks: Motion and Sensation
    • Chapter 21 – The External Ear and Blood Cell Formation
    • Chapter 22 – The Diaphragm and Intestines
    • Chapter 23 – Hand Plates and Brainwaves
    • Chapter 24 – Nipple Formation
    • Chapter 25 – Limb Development
    • Chapter 26 – 7 Weeks: Hiccups and Startle Response
    • Chapter 27 – The Maturing Heart
    • Chapter 28 – Ovaries and Eyes
    • Chapter 29 – Fingers and Toes
    •  
  • THE 8-WEEK EMBRYO
  • • Chapter 30 – 8 Weeks: Brain Development
    • Chapter 31 – Right- and Left-Handedness
    • Chapter 32 – Rolling Over
    • Chapter 33 – Eyelid Fusion
    • Chapter 34 – “Breathing” Motion and Urination
    • Chapter 35 – The Limbs and Skin
    • Chapter 36 – Summary of the First 8 Weeks
    •  
• THE FETAL PERIOD (8 WEEKS THROUGH BIRTH)
• • Chapter 37 – 9 Weeks: Swallows, Sighs, and Stretches
  • Chapter 38 – 10 Weeks: Rolls Eyes and Yawns, Fingernails & Fingerprints
  • Chapter 39 – 11 Weeks: Absorbs Glucose and Water
  • Chapter 40 – 3 to 4 Months (12 to 16 Weeks): Taste Buds, Jaw Motion, Rooting Reflex, Quickening
  • Chapter 41 – 4 to 5 Months (16 to 20 Weeks): Stress Response, Vernix Caseosa, Circadian Rhythms
  • Chapter 42 – 5 to 6 Months (20 to 24 Weeks): Responds to Sound; Hair and Skin; Age of Viability
  • Chapter 43 – 6 to 7 Months (24 to 28 Weeks): Blink-Startle; Pupils Respond to Light; Smell and Taste
  • Chapter 44 – 7 to 8 Months (28 to 32 Weeks): Sound Discrimination, Behavioral States
  • Chapter 45 – 8 to 9 Months (32 to 36 Weeks): Alveoli Formation, Firm Grasp, Taste Preferences
  • Chapter 46 – 9 Months to Birth (36 Weeks through Birth)
  •  
• APPENDIX A − CALCULATIONS
• • To the Sun and Back: Determining the Length of DNA in an Adult
  • A Tight Squeeze: Appreciating the Number of Bases Contained in the DNA of a Single Cell
  • Climate Control: Approximating the Normal Range of Embryonic and Fetal Body Temperature
  • The Beat Goes On: Estimating the Total Number of Heartbeats before Birth and Beyond
  •  
• 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.

---

Table of Contents

Appendix A:
Calculations

Appendix B:
Ages & Stages

Back to Top

Program Index

Script & Footnotes

Bibliography

Full Names
of Journals Cited

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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 Müller, 2001, 92.
^[5] O’Rahilly and Müller, 1987, 9.
^[6] Spraycar, 1995, 377 & 637.
^[7] O’Rahilly and Müller, 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 Müller, 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 Müller, 2001, 87.
^[12] This convention, termed “postfertilization age“ by O’Rahilly, has been long preferred by embryologists. [see Mall, 1918, 400; O’Rahilly and Müller, 1999b, 39; O’Rahilly and Müller, 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.

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^[13] Quote from Moore and Persaud, 2003, 16; From O’Rahilly and Müller, 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 Müller, 2001, 8. [Carnegie Stage 1]
^[14] O’Rahilly and Müller, 2001, 25: “The term ‘egg’ should be discarded from human embryology.“ From O’Rahilly and Müller, 1987, 9: “The term ‘egg’ is best reserved for a nutritive object frequently seen on the breakfast table.“
^[15] O’Rahilly and Müller, 2001, 23-24.
^[16] O’Rahilly and Müller, 2001, 30.
^[17] Dorland and Bartelmez, 1922, 372; Gasser, 1975, 1; Mall, 1918, 421; O’Rahilly and Müller, 2001, 31.
^[18] Gasser, 1975, 1; O’Rahilly and Müller, 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 Müller, 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.

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^[30] Gasser, 1975, 1; O’Rahilly and Müller, 2001, 37; Spraycar, 1995, 1130: “Morula“ is derived from the Latin word morus meaning “mulberry.“ [Carnegie Stage 2]
^[31] O’Rahilly and Müller, 2001, 39. [Carnegie Stage 3]
^[32] Gasser, 1975, 1; O’Rahilly and Müller, 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 Müller, 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 Müller, 2001, 43.
^[36] Cunningham et al., 2001, 20 & 26-27; O’Rahilly and Müller, 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 Müller, 2001, 78-79.
^[39] For a detailed description of umbilical cord formation see Florian, 1930.

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^[40] O’Rahilly and Müller, 2001, 39.
^[41] Moore and Persaud, 2003, 50; O’Rahilly and Müller, 2001, 82. [Carnegie Stages 5 & 6]; In humans, the term “yolk sac“ has fallen out of favor among some embryologists (including O’Rahilly and Müller) 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 Müller, 2001, 82.
^[43] O’Rahilly and Müller, 1987, 29; O’Rahilly and Müller, 2001, 43. [Carnegie Stages 4-5]
^[44] O’Rahilly and Müller, 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; Müller and O’Rahilly, 1983, 419-420 & 429; O’Rahilly and Gardner, 1979, 123 & 129; O’Rahilly and Müller, 1984, 422; O’Rahilly and Müller, 1987, 90; O’Rahilly and Müller, 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 Müller, 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 Müller, 1987, 86. [Carnegie Stage 9]
^[50] Campbell, 2004, 14; Carlson, 2004, 116 & 446; Navaratnam, 1991, 147-148; O’Rahilly and Müller, 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 Müller, 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.

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^[55] Gasser, 1975, 30; O’Rahilly and Müller, 2001, 80.
^[56] O’Rahilly and Müller, 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 Müller, 1985, 148 & 151; O’Rahilly and Müller, 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 Müller, 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 Müller, 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 Müller, 1999a, 115; van Dongen and Goudie, 1980, 193. [Carnegie Stage 14]
^[64] Moore, 1980, 938.
^[65] Guyton and Hall, 2000, 663-677.

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

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^[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 5½ weeks postfertilization age]; Humphrey, 1964, 99: earliest reflex 5½ 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 Müller, 1999a, 336: 5½ 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 6½ weeks [adjusted to postfertilization age].
^[72] Goodlin, 1979, D-128.
^[73] Karmody and Annino, 1995, 251; O’Rahilly and Müller, 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 Müller, 1987, 213; Sadler, 2005, 66; Spencer, 1960, 9; Timor-Tritsch et al., 1990, 287.
^[77] O’Rahilly and Müller, 1987, 202-203.
^[78] Borkowski and Bernstine, 1955, 363 (cited by Bernstine, 1961, 63 & 66; O’Rahilly and Müller, 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.

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^[79] O’Rahilly and Müller, 1985, 155: “The nipple appears at stages 17 and 18.“ [41-44 days postfertilization]; Wells, 1954, 126.
^[80] O’Rahilly and Müller, 2001, 221; Streeter, 1948, 187.
^[81] Carlson, 2004, 189; O’Rahilly and Gardner, 1972, 293; O’Rahilly and Gardner, 1975, 19; O’Rahilly and Müller, 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 Müller, 2001, 320. [Carnegie Stage 20]
^[88] Andersen et al., 1965, 646; O’Rahilly, 1966, 35; O’Rahilly and Müller, 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 Müller, 1987, 257.
^[90] O’Rahilly and Gardner, 1975, 11; O’Rahilly and Müller, 1987, 262.

Page 10

^[91] O’Rahilly and Müller, 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 Müller, 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 Müller, 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 Müller, 2001, 169.
^[106] Pringle, 1988, 176.
^[107] O’Rahilly and Müller, 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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^[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 Müller, 2001, 465; Pearson, 1980, 39-41.
^[116] O’Rahilly and Müller, 1984, 425. See also Campbell, 2004, 29.
^[117] O’Rahilly, 1977a, 128; O’Rahilly, 1977b, 53; O’Rahilly and Müller, 2001, 327.
^[118] O’Rahilly and Müller, 2001, 25 & 322.
^[119] Campbell, 2004, 28 & 35; O’Rahilly and Müller, 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 into the abdomen during the ninth or tenth week.]
^[125] Cunningham et al., 2001, 133.
^[126] O’Rahilly and Müller, 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] Koldovský et al., 1965, 186.
^[130] O’Rahilly and Müller, 2001, 336; Wilson, 1926, 29.

Page 12

^[131] Brenner, 1976, 561.
^[132] Lecanuet and Schaal, 1996, 3; Miller, 1982, 169; Mistretta and Bradley, 1975, 80.
^[133] Abramovich and Gray, 1982, 296; Ramón 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 Müller, 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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^[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 Müller, 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 Müller, 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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^[155] Open eyes are visualized by 4D ultrasound following 22 weeks postfertilization per Campbell 2002, 3; De Lia, 2002, personal communication; O’Rahilly and Müller, 2001, 465. For a detailed ultrastructural study of the union between the upper and lower eyelids see Andersen et al., 1967, 293.
^[156] Birnholz and Benacerraf, 1983, 517 (cited by Drife, 1985, 778); See also Campbell, 2002, 3: Professor Stuart Campbell correctly points out that the eyes of the fetus are closed most of the time and a true blink requires the eyes to be open. Perhaps the “blink-startle“ response would be more accurately termed “squint-startle.“
^[157] Lecanuet and Schaal, 1996, 9.
^[158] Visser et al., 1989, 285.
^[159] Gerhardt, 1990, 299; Petrikovsky et al., 1993, 548-549; Pierson, 1996, 21 & 26.
^[160] Natale et al., 1988, 317.
^[161] Growth of the human brain, 1975, 6; Mancuso and Palla, 1996, 290.
^[162] Isenberg et al., 1998, 773-774.
^[163] Robinson and Tizard, 1966, 52.
^[164] Noback et al., 1996, 263.
^[165] Lecanuet and Schaal, 1996, 3.
^[166] Lecanuet and Schaal, 1996, 3; Liley, 1972, 102; Moore and Persaud, 2003, 219; Reinis and Goldman, 1980, 227.
^[167] Liley, 1972, 100.
^[168] England, 1983, 29.

Page 15

^[169] Glover and Fisk, 1999, 882; Hepper and Shahidullah, 1994, F81.
^[170] Connors et al., 1989, 932; de Vries et al., 1985, 117; Patrick et al., 1980, 26 & 28; Visser et al., 1992, 178.
^[171] DiPietro et al., 2002, 2: “One of the hallmarks of development before birth is the coalescence of patterns of fetal and behavioral and cardiac function into behavioral states, which is widely viewed as reflective of the developing integration of the central nervous system.“
^[172] Lauria et al., 1995, 467.
^[173] Moore and Persaud, 2003, 108.
^[174] Schaal et al., 2000, 729.
^[175] Liley, 1972, 100.
^[176] Moore and Persaud, 2003, 131.
^[177] Cunningham et al., 2001, 252.

Page 16

Appendix A − Calculations

To the Sun and Back: Determining the Length of DNA in an Adult

Given:

1.      The DNA molecule measures 3.4×10^-9 meters per 10 base pairs.^[178]

2.      There are 3 billion (3×10⁹) base pairs per cell.

3.      There are an estimated 100 trillion (10¹⁴) cells per adult.

4.      The distance from the earth to the sun is approximately 93 million miles.

5.      There are 2.54 centimeters (cm) per inch.

Step 1   Compute the length of DNA in a single cell:

3.4×10^-9 meters/10 base pairs ×  3×10⁹ base pairs/cell = 1.02 meters of DNA per cell

Step 2   Compute the total length of DNA in an adult’s 100 trillion cells:

1.02 meters of DNA/cell × 10¹⁴ cells  =  1.02×10¹⁴ meters of DNA per adult*

Step 3   Convert 1.02×10¹⁴ meters to miles:

1.02×10¹⁴ meters × 100 cm/meter × 1inch/2.54 cm × 1 foot/12 inches × 1 mile/5,280 feet
 = 6.3379×10¹⁰miles of DNA

Step 4   Compute how many round trips from the earth to the sun:

6.3379×10¹⁰ miles of DNA ÷ (93,000,000 miles/trip × 2 trips/round trip) =

Therefore, the DNA in a single adult, if oriented in linear fashion, would exceed 63 billion miles in length. This is long enough to extend from the earth to the sun and back––340 times.

* Approximately 25 trillion red blood cells are present in the adult.^[179] It should be noted that red blood cells contain DNA early in their maturation phase but this DNA degenerates and is not present in the mature form. This calculation includes the DNA from red blood cells.

^[178] Lodish et al., 2000, 104.
^[179] Guyton and Hall, 2000, 2.

Page 17

A Tight Squeeze: Appreciating the Number of Bases Contained in the DNA of a Single Cell

The following page contains a list of 3,808 capital letters each of which represents a single base.

Given:

1.      A, G, T, and C each represent a base within the DNA of a single cell.

2.      Each line contains 68 letters without spaces representing 68 bases.

3.      Each page contains 56 lines. (Page size: 8½ × 11 inches, font: Times New Roman, font size: 10, spaces between letters: none, lines: single spaced, margins: as shown)

4.      Each cell contains 3 billion base pairs equaling 6 billion bases.

The calculation of the number of pages required to list all DNA bases in a single cell is as follows:

68 bases/line × 56 lines/page  =  3,808 bases/page

6,000,000,000 bases/cell ÷ 3,808 bases/page  =  1,575,630 pages/cell

Page 18

Climate Control: Approximating the Normal Range of Embryonic and Fetal Body Temperature

Given:

1.      The placenta maintains embryonic and fetal temperature between 0.5 ºC and 1.5 ºC above maternal core temperature.^[180]

2.      Maternal core temperature is approximately 99.6º Fahrenheit.

3.      The formula to convert temperature from Fahrenheit (ºF) to Celsius (ºC) is:

ºC = 5/9 (ºF - 32)

The calculation to compute the range of embryonic and fetal body temperature is as follows:

Step 1             Convert maternal core temperature to Celsius:

Maternal core temperature in ºC: ºC = 5/9 (99.6 - 32) = 37.56 ºC

Step 2             Compute lower and upper ranges of fetal body temperature in Celsius:

Lower range (Celsius) = maternal core temperature + 0.5 ºC = 37.56 + 0.5 = 38.2 ºC

Upper range (Celsius) = maternal core temperature + 1.5 ºC = 37.56 + 1.5 = 39.2 ºC

Step 3             Convert results to Fahrenheit:

ºC = 5/9 (ºF - 32)                     9/5 ºC = (ºF - 32)                     ºF = 9/5 ºC + 32

Substituting to find the lower limit of fetal body temperature

ºF = 9/5 ºC + 32                      ºF = 9/5 (38.16) + 32   ºF = 100.7º

Substituting to find the upper limit of fetal body temperature

ºF = 9/5 ºC + 32 ºF = 9/5 (39.16) + 32   ºF = 102.5º

Summary of Normal Embryonic and Fetal Body Temperature Range

^[180] Liley, 1972, 101.

Page 19

The Beat Goes On: Estimating the Total Number of Heartbeats Before Birth and Beyond

The Embryonic Period

Various authors agree the heart rate peaks at 7 weeks. Reported heart rates vary however. Van Heeswijk et al. report a peak heart rate of 167 ± 8 beats per minute (bpm)^[181] while Leeuwen et al. report a peak rate of 175 bpm.^[182] Van Lith et al. report the median fetal heart rate peaks at 177 bpm at 7 weeks.^[183] One hundred seventy (170) bpm has been chosen as the peak heart rate for illustration purposes in this calculation. The heart rate for the various weeks from 7 through 38 have been calculated via linear interpolations^[184] assuming heart rates of 170 bpm at 7 weeks and 140 bpm at term or 38 weeks.^[185]

(Note: Heart rates are estimated. Living conditions and individual experience can and will vary.)

The Fetal Period

Counting the Beats of a Lifetime

The Postnatal Period from Birth to 80 Years

^[181] van Heeswijk et al., 1990, 153.
^[182] Leeuwen et al., 1999, 265.
^[183] van Lith et al., 1992, 741.
^[184] See Appendix A.
^[185] DiPietro et al., 1996, 2559.
^[186] Age appropriate pediatric heart rates adapted from Bates, 1987, 541.

Page 20

Appendix B − Relating Embryonic Age & Stage

O'Rahilly and Müller's Age Assignments vs. Carnegie Stages, 1987 to 2001

* PF Days = Postfertilization Days

There is international agreement among embryologists that human development during the embryonic period be divided into 23 stages (which were initially proposed by Mall, described by Streeter, and amended by O'Rahilly and Müller in 1987).^[190] These have come to be known as Carnegie Stages. Particular internal and external features are required for inclusion in any given embryonic stage. These stages are independent of age and length and the use of the term 'stage' should be reserved for reference to this system per O'Rahilly and Müller in multiple publications.

Along with nearly-universal acceptance of the human embryonic staging system, a variety of age assignments have been proposed for each embryonic stage. Streeter believed the embryonic period spanned a 47- to 48-day period instead of the 56-day period accepted today. The Endowment for Human Development adopts the convention set forth by O'Rahilly and Müller in 1987 which has received widespread, but not universal, acceptance. O'Rahilly and Müller have since proposed amending this convention in light of transvaginal ultrasound data through a personal communication with Dr. Josef Wisser in 1992.^[191] These alternate proposals are provided for the interested reader.

For instance, the onset of embryonic cardiac contraction (onset of the heartbeat) has long been described as a Carnegie Stage 10 or possibly a late Stage 9 event.^[192] We report this event occurring at an age of 3 weeks, 1 day (22 days) postfertilization using the 1987 convention. Others may report this occurrence at 28 or 29 days as shown above. Of interest is a paper by Wisser and Dirschedl who reported using transvaginal ultrasound to visualize the embryonic heartbeat 23 days postfertilization in two embryos fertilized in vitro “with exactly known … age” and “in embryos from 2 mm of greatest length onwards.”^[193] This finding most closely coincides with the 1987 age convention. Schats et al. reported the earliest cardiac activity at 25 days after follicle aspiration in embryos conceived in vitro.^[194] Tezuka et al. reported the earliest cardiac activity at 23 days postfertilization in embryos conceived naturally.^[195]

There is considerable variation in normal human development during the postnatal period. The prenatal period is no different with variations in the size, rate of growth, and order of appearance of some structures or functions. No one knows the exact age range for each stage with absolute certainty. These approximations may change in the future as additional knowledge is gained through careful, published research.

^[187] O'Rahilly and Müller, 1987, 3. Greatest length data is essentially uniform throughout the various texts.
^[188] O'Rahilly and Müller, 1999a. Various pages.
^[189] O'Rahilly and Müller, 2001, 490. Table A-1 – essentially unchanged from the 1996 edition. The 2001 convention differs only slightly from the 1999 convention as shown.
^[190] O'Rahilly and Müller, 2001, 3.
^[191] O'Rahilly and Müller, 1999a, 13.
^[192] See footnote #51.
^[193] Quotes from Wisser and Dirschedl, 1994, 108.
^[194] Schats et al., 1990, 989.
^[195] Tezuka, 1991, 211.

Page 21

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Full Names of Journals Cited

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Program Index

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