The  chronology  of pregnancy is, unless otherwise specified, generally given as  gestational age , where the starting point is the beginning of the woman's  last menstrual period  (LMP), or the corresponding age of the gestation as estimated by a more accurate method if available. This model means that the woman is counted as being "pregnant" two weeks before  conception  and three weeks before  implantation .  Sometimes, timing may also use the  fertilization age , which is the age of the embryo since conception.


The  American Congress of Obstetricians and Gynecologists  recommends the following methods to calculate gestational age: [ 34 ]


Pregnancy is divided into three trimesters, each lasting for approximately three months. [ 4 ]  The exact length of each trimester can vary between sources.


Due date estimation  basically follows two steps:


The  American College of Obstetricians and Gynecologists  divides full term into three divisions: [ 39 ]


Naegele's rule  is a standard way of calculating the due date for a pregnancy when assuming a gestational age of 280 days at childbirth. The rule estimates the expected date of delivery (EDD) by adding a year, subtracting three months, and adding seven days to the origin of gestational age. Alternatively there are  mobile apps , which essentially always give consistent estimations compared to each other and correct for  leap year , while pregnancy wheels made of paper can differ from each other by 7 days and generally do not correct for leap year. [ 40 ]


Furthermore, actual childbirth has only a certain probability of occurring within the limits of the estimated due date. A study of singleton live births came to the result that childbirth has a  standard deviation  of 14 days when gestational age is estimated by first trimester  ultrasound , and 16 days when estimated directly by last menstrual period. [ 37 ]


Fertility  and  fecundity  are the respective capacities to  fertilize  and establish a clinical pregnancy and have a live birth.  Infertility  is an impaired ability to establish a clinical pregnancy and  sterility  is the permanent inability to establish a clinical pregnancy. [ 41 ]


The capacity for pregnancy depends on the  reproductive system ,  its development  and  its variation , as well as on the condition of a person.
 Women  as well as  intersex  and  transgender  people who have a functioning  female reproductive system  are capable of pregnancy. In some cases, someone might be able to produce fertilizable eggs, but might not have a womb or none that can sufficiently gestate, in which case they might find  surrogacy . [ 42 ]


Through an interplay of hormones that includes  follicle stimulating hormone  that stimulates  folliculogenesis  and  oogenesis  creates a mature  egg cell , the female  gamete .  Fertilization  is the event where the egg cell fuses with the male gamete,  spermatozoon . After the point of fertilization, the fused product of the female and male gamete is referred to as a  zygote  or fertilized egg. The fusion of female and male gametes usually occurs following the act of  sexual intercourse .  Pregnancy rates for sexual intercourse  are highest during the  menstrual cycle  time from some 5 days before until 1 to 2 days after ovulation. [ 43 ]  Fertilization can also occur by  assisted reproductive technology  such as  artificial insemination  and  in vitro fertilisation .


Fertilization (conception) is sometimes used as the initiation of pregnancy, with the derived age being termed  fertilization age . Fertilization usually occurs about two weeks before the  next  expected menstrual period.


A third point in time is also considered by some people to be the true beginning of a pregnancy: This is time of implantation, when the future fetus attaches to the lining of the uterus. This is about a week to ten days after fertilization. [ 44 ]


The sperm and the egg cell, which has been released from one of the female's two  ovaries , unite in one of the two  fallopian tubes . The fertilized egg, known as a  zygote , then moves toward the uterus, a journey that can take up to a week to complete. Cell division begins approximately 24 to 36 hours after the female and male cells unite. Cell division continues at a rapid rate and the cells then develop into what is known as a  blastocyst . The blastocyst arrives at the uterus and attaches to the uterine wall, a process known as  implantation .


The development of the mass of cells that will become the infant is called  embryogenesis  during the first approximately ten weeks of gestation. During this time, cells begin to differentiate into the various body systems. The basic outlines of the organ, body, and nervous systems are established. By the end of the embryonic stage, the beginnings of features such as fingers, eyes, mouth, and ears become visible. Also during this time, there is development of structures important to the support of the embryo, including the  placenta  and  umbilical cord . The placenta connects the developing embryo to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. The umbilical cord is the connecting cord from the embryo or fetus to the placenta.


After about ten weeks of gestational age—which is the same as eight weeks after conception—the embryo becomes known as a  fetus . [ 45 ]  At the beginning of the fetal stage, the risk of miscarriage decreases sharply. [ 46 ]  At this stage, a fetus is about 30 mm (1.2 inches) in length, the heartbeat is seen via ultrasound, and the fetus makes involuntary motions. [ 47 ]  During continued fetal development, the early body systems, and structures that were established in the embryonic stage continue to develop. Sex organs begin to appear during the third month of gestation. The fetus continues to grow in both weight and length, although the majority of the physical growth occurs in the last weeks of pregnancy.


Electrical  brain activity  is first detected at the end of week 5 of gestation, but as in  brain-dead  patients, it is primitive neural activity rather than the beginning of conscious brain activity. Synapses do not begin to form until week 17. [ 48 ]  Neural connections between the  sensory cortex  and  thalamus  develop as early as 24 weeks' gestational age, but the first evidence of their function does not occur until around 30 weeks, when minimal  consciousness ,  dreaming , and the ability to feel pain emerges. [ 49 ]


Although the fetus begins to move during the first trimester, it is not until the second trimester that movement, known as  quickening , can be felt. This typically happens in the fourth month, more specifically in the 20th to 21st week, or by the 19th week if the woman has been pregnant before. It is common for some women not to feel the fetus move until much later. During the second trimester, when the body size changes,  maternity clothes  may be worn.


During pregnancy, a woman undergoes many normal  physiological  changes, including  behavioral ,  cardiovascular ,  hematologic ,  metabolic ,  renal , and  respiratory  changes. Increases in  blood sugar ,  breathing , and  cardiac output  are all required. Levels of  progesterone  and  estrogens  rise continually throughout pregnancy, suppressing the  hypothalamic axis  and therefore the  menstrual cycle . A full-term pregnancy at an early age (less than 25 years) reduces the risk of  breast ,  ovarian , and  endometrial cancer , and the risk declines further with each additional full-term pregnancy. [ 50 ] [ 51 ]


The fetus is  genetically  different from its mother and can therefore be viewed as an unusually successful  allograft . [ 52 ]  The main reason for this success is increased  immune tolerance  during pregnancy, [ 53 ]  which prevents the mother's body from mounting an  immune system response  against certain triggers. [ 52 ]


During the first trimester,  minute ventilation  increases by 40 percent. [ 54 ]  The womb will grow to the size of a  lemon  by eight weeks. Many  symptoms and discomforts of pregnancy , such as nausea and  tender breasts , appear in the first trimester. [ 55 ]


During the second trimester, most women feel more energized and put on weight as the symptoms of  morning sickness  subside.  They begin to feel regular  fetal movements , which can become strong and even disruptive. [ citation needed ]


Braxton Hicks contractions  are sporadic  uterine contractions  that may start around six weeks into a pregnancy; however, they are usually not felt until the second or third trimester. [ 56 ]


Final weight gain takes place during the third trimester; this is the most weight gain throughout the pregnancy. The woman's abdomen will transform in shape as the fetus turns in a downward position ready for birth. The woman's  navel  will sometimes become convex, "popping" out, due to the expanding  abdomen . The uterus, the muscular organ that holds the developing fetus, can expand up to 20 times its normal size during pregnancy.


Head engagement , also called "lightening" or "dropping", occurs as the fetal head descends into a  cephalic presentation . While it relieves pressure on the upper abdomen and gives a renewed ease in breathing, it also severely reduces bladder capacity, resulting in a need to  void more frequently , and increases pressure on the pelvic floor and the rectum. It is not possible to predict when lightening will occur. In a first pregnancy it may happen a few weeks before the due date, though it may happen later or even not until labor begins, as is typical with subsequent pregnancies. [ 57 ]


It is during the third trimester that maternal activity and sleep positions may affect  fetal development  due to restricted  blood flow . For instance, the enlarged uterus may impede blood flow by compressing the  vena cava  when lying flat, a condition that can be relieved by lying on the left side. [ 58 ]


Childbirth, referred to as labor and delivery in the medical field, is the process whereby an infant is born. [ 59 ]


A woman is considered to be in labor when she begins experiencing regular uterine contractions, accompanied by changes of her cervix—primarily effacement and dilation. While childbirth is widely experienced as painful, some women do report painless labors, while others find that concentrating on the birth helps to quicken labor and lessen the sensations. Most births are successful vaginal births, but sometimes complications arise and a woman may undergo a  cesarean section .


During the time immediately after birth, both the mother and the  baby  are hormonally cued to bond, the mother through the release of  oxytocin , a hormone also released during  breastfeeding . Studies show that skin-to-skin contact between a mother and her newborn immediately after birth is beneficial for both the mother and baby. A review done by the  World Health Organization  found that skin-to-skin contact between mothers and babies after birth reduces crying, improves mother–infant interaction, and helps mothers to breastfeed successfully. They recommend that  neonates  be allowed to bond with the mother during their first two hours after birth, the period that they tend to be more alert than in the following hours of early life. [ 60 ]


In the ideal  childbirth , labor begins on its own when a woman is "at term". [ 17 ]
Events before completion of 37 weeks are considered preterm. [ 61 ]   Preterm birth  is associated with a range of complications and should be avoided if possible. [ 63 ]


Sometimes if a woman's  water breaks  or she has  contractions  before 39 weeks, birth is unavoidable. [ 62 ]  However, spontaneous birth after 37 weeks is considered term and is not associated with the same risks of a preterm birth. [ 59 ]  Planned birth before 39 weeks by  caesarean section  or  labor induction , although "at term", results in an increased risk of complications. [ 64 ]  This is from factors including  underdeveloped lungs of newborns , infection due to underdeveloped immune system, feeding problems due to underdeveloped brain, and  jaundice  from underdeveloped liver. [ 65 ]


Babies born between 39 and 41 weeks' gestation have better outcomes than babies born either before or after this range. [ 62 ]  This special time period is called "full term". [ 62 ]  Whenever possible, waiting for labor to begin on its own in this time period is best for the health of the mother and baby. [ 17 ]  The decision to perform an induction must be made after weighing the risks and benefits, but is safer after 39 weeks. [ 17 ]


Events after 42 weeks are considered  postterm . [ 62 ]  When a pregnancy exceeds 42 weeks, the risk of complications for both the woman and the fetus increases significantly. [ 66 ] [ 67 ]  Therefore, in an otherwise uncomplicated pregnancy, obstetricians usually prefer to induce labor at some stage between 41 and 42 weeks. [ 68 ]


The  postpartum period  also referred to as the  puerperium , is the postnatal period that begins immediately after delivery and extends for about six weeks. [ 59 ]  During this period, the mother's body begins the return to pre-pregnancy conditions that includes changes in hormone levels and uterus size. [ 59 ]


The beginning of pregnancy may be detected either based on symptoms by the woman herself, or by using  pregnancy tests . However, an important condition with serious health implications that is quite common is the  denial of pregnancy  by the pregnant woman. About 1 in 475 denials will last until around the 20th week of pregnancy. The proportion of cases of denial, persisting until delivery is about 1 in 2500. [ 69 ]  Conversely, some non-pregnant women have a very strong belief that they are pregnant along with some of the physical changes. This condition is known as a  false pregnancy . [ 70 ]


Most pregnant women experience a number of symptoms, [ 71 ]  which can signify pregnancy. A number of early  medical signs  are associated with pregnancy. [ 72 ] [ 73 ]  These signs include:


Pregnancy detection can be accomplished using one or more various  pregnancy tests , [ 75 ]  which detect hormones generated by the newly formed  placenta , serving as  biomarkers  of pregnancy. [ 76 ]  Blood and urine tests can detect pregnancy by 11 and 14 days, respectively, after fertilization. [ 77 ] [ 78 ]  Blood pregnancy tests are more  sensitive  than urine tests (giving fewer false negatives). [ 79 ]  Home pregnancy tests are urine tests, and normally detect a pregnancy 12 to 15 days after fertilization. [ 80 ]  A quantitative blood test can determine approximately the date the embryo was fertilized because  hCG  levels double every 36 to 72 hours before 8 weeks' gestation. [ 59 ] [ 78 ]  A single test of  progesterone  levels can also help determine how likely a fetus will survive in those with a  threatened miscarriage  (bleeding in early pregnancy), but only if the ultrasound result was inconclusive. [ 81 ]


Obstetric ultrasonography  can detect  fetal abnormalities , detect  multiple pregnancies , and improve gestational dating at 24 weeks. [ 82 ]  The resultant estimated  gestational age  and due date of the fetus are slightly more accurate than methods based on last menstrual period. [ 83 ]  Ultrasound is used to measure the  nuchal fold  in order to screen for  Down syndrome . [ 84 ]


Pre-conception counseling  is care that is provided to a woman or couple to discuss conception, pregnancy, current health issues and recommendations for the period before pregnancy. [ 87 ]


Prenatal medical care  is the medical and nursing care recommended for women during pregnancy, time intervals and exact goals of each visit differ by country. [ 88 ]  Women who are high risk have better outcomes if they are seen regularly and frequently by a medical professional than women who are low risk. [ 89 ]  A woman can be labeled as high risk for different reasons including previous complications in pregnancy, complications in the current pregnancy, current medical diseases, or social issues. [ 90 ] [ 91 ]


The aim of good prenatal care is prevention, early identification, and treatment of any medical complications. [ 92 ]  A basic prenatal visit consists of measurement of blood pressure,  fundal height , weight and fetal heart rate, checking for symptoms of labor, and guidance for what to expect next. [ 87 ]


Nutrition  during pregnancy is important to ensure healthy growth of the fetus. [ 16 ]  Nutrition during pregnancy is different from the non-pregnant state. [ 16 ]  There are increased energy requirements and specific micronutrient requirements. [ 16 ]  Women benefit from education to encourage a balanced energy and protein intake during pregnancy. [ 93 ]  Some women may need professional medical advice if their diet is affected by medical conditions, food allergies, or specific religious/ ethical beliefs. [ 94 ]  Further studies are needed to access the effect of dietary advice to prevent  gestational diabetes , although low quality evidence suggests some benefit. [ 95 ]  Adequate periconceptional (time before and right after conception)  folic acid  (also called folate or Vitamin B 9 ) intake has been shown to decrease the risk of fetal neural tube defects, such as  spina bifida . [ 96 ]  L-methylfolate, the bioavailable form of folate is also considered acceptable to take. L-methylfolate is best used by the 40% to 60% of the population with genetic polymorphisms that reduce or impair conversion of folic acid into its active form. [ 97 ]  The neural tube develops during the first 28 days of pregnancy, a urine pregnancy test is not usually positive until 14 days post-conception, explaining the necessity to guarantee adequate folate intake before conception. [ 80 ] [ 98 ]  Folate is abundant in  green leafy vegetables ,  legumes , and  citrus . [ 99 ]  In the United States and Canada, most wheat products (flour, noodles) are fortified with folic acid. [ 100 ]


The amount of healthy weight gain during a pregnancy varies. [ 101 ]  Weight gain is related to the weight of the baby, the placenta, extra circulatory fluid, larger tissues, and fat and protein stores. [ 16 ]  Most needed weight gain occurs later in pregnancy. [ 102 ]


The  Institute of Medicine  recommends an overall pregnancy weight gain for those of normal weight ( body mass index  of 18.5–24.9), of 11.3–15.9 kg (25–35 pounds) having a singleton pregnancy. [ 103 ]  Women who are underweight (BMI of less than 18.5), should gain between 12.7 and 18 kg (28–40 lb), while those who are  overweight  (BMI of 25–29.9) are advised to gain between 6.8 and 11.3 kg (15–25 lb) and those who are  obese  (BMI ≥ 30) should gain between 5–9 kg (11–20 lb). [ 104 ]  These values reference the expectations for a term pregnancy.


During pregnancy, insufficient or excessive weight gain can compromise the health of the mother and fetus. [ 102 ]  The most effective intervention for weight gain in underweight women is not clear. [ 102 ]  Being or becoming overweight in pregnancy increases the risk of complications for mother and fetus, including  cesarean section ,  gestational hypertension ,  pre-eclampsia ,  macrosomia  and  shoulder dystocia . [ 101 ]  Excessive weight gain can make losing weight after the pregnancy difficult. [ 101 ] [ 105 ]  Some of these complications are risk factors for  stroke . [ 106 ]


Around 50% of women of childbearing age in developed countries like the United Kingdom are overweight or obese before pregnancy. [ 105 ]  Diet modification is the most effective way to reduce weight gain and associated risks in pregnancy. [ 105 ]


Drugs used during pregnancy can have temporary or permanent effects on the fetus. [ 107 ]  Anything (including drugs) that can cause permanent deformities in the fetus are labeled as  teratogens . [ 108 ]  In the U.S., drugs were classified into categories A, B, C, D and X based on the  Food and Drug Administration  (FDA) rating system to provide therapeutic guidance based on potential benefits and fetal risks. [ 109 ]  Drugs, including some  multivitamins , that have demonstrated no fetal risks after controlled studies in humans are classified as Category A. [ 107 ]  On the other hand, drugs like  thalidomide  with proven fetal risks that outweigh all benefits are classified as Category X. [ 107 ]


The use of  recreational drugs  in pregnancy can cause various  pregnancy complications . [ 59 ]


Intrauterine exposure to  environmental toxins in pregnancy  has the potential to cause adverse effects on  prenatal development , and to cause  pregnancy complications . [ 59 ]  Air pollution has been associated with low birth weight infants. [ 116 ]  Conditions of particular severity in pregnancy include  mercury poisoning  and  lead poisoning . [ 59 ]  To minimize exposure to environmental toxins, the American College of Nurse-Midwives recommends: checking whether the home has  lead paint , washing all fresh  fruits  and  vegetables  thoroughly and buying  organic  produce, and avoiding cleaning products labeled "toxic" or any product with a warning on the label. [ 117 ]


Pregnant women can also be exposed to  toxins in the workplace , including airborne particles. The effects of wearing an  N95 filtering facepiece respirator  are similar for pregnant women as for non-pregnant women, and wearing a respirator for one hour does not affect the fetal heart rate. [ 118 ]


Pregnant women or those who have recently given birth in the U.S. are  more likely to be murdered  than to die from obstetric causes. These homicides are a combination of intimate partner violence and firearms. Health authorities have called the violence "a health emergency for pregnant women", but say that pregnancy-related homicides are preventable if healthcare providers identify those women at risk and offer assistance to them. [ 119 ] [ 120 ] [ 121 ]


Most women can continue to engage in sexual activity, including  sexual intercourse , throughout pregnancy. [ 122 ]  Research suggests that during pregnancy both sexual desire and frequency of sexual relations decrease during the first and third trimester, with a rise during the second trimester. [ 123 ] [ 124 ] [ 125 ] [ 126 ]  Sex during pregnancy is a low-risk behavior except when the healthcare provider advises that sexual intercourse be avoided for particular medical reasons. [ 122 ]  For a healthy pregnant woman, there is no single  safe  or  right  way to have sex during pregnancy. [ 122 ]


Regular  aerobic exercise  during pregnancy appears to improve (or maintain) physical fitness. [ 127 ]   Physical exercise  during pregnancy appears to decrease the need for  C-section [ 128 ]  and reduce time in labor, [ 129 ]  and even vigorous exercise carries no significant risks to babies [ 130 ]  while providing significant health benefits to the mother. Studies show that performing light moderate intensity and strength exercises while pregnant does not harm the mother’s cardiovascular system and may limit excessive weight gain. [ 131 ] [ additional citation(s) needed ]


The American College of Sports and Medicine recommends pregnant women should participate in at least 150 minutes/week of moderate exercise. [ 132 ]  These forms of exercise should avoid heavy lifting, hot temperatures, and high impact sports. The Clinical Practice Obstetrics Committee of Canada recommends that "All women without contraindications should be encouraged to participate in aerobic and strength-conditioning exercises as part of a healthy lifestyle during their pregnancy". [ 133 ]  Although an upper level of safe exercise intensity has not been established, women who were regular exercisers before pregnancy and who have uncomplicated pregnancies should be able to engage in high intensity exercise programs without a higher risk of prematurity, lower birth weight, or gestational weight gain. [ 130 ]   In general, participation in a wide range of recreational activities appears to be safe, with the avoidance of those with a high risk of falling such as horseback riding or skiing or those that carry a risk of abdominal trauma, such as soccer or hockey. [ 134 ]


Bed rest , outside of research studies, is not recommended as there is potential harm and no evidence of benefit. [ 135 ]


During pregnancy, women can experience a loss of postural stability, pelvic incontinence, back pain, and fatigue, among other symptoms. [ citation needed ]  Resistance training has been found to reduce pregnancy symptoms and reduce postpartum complications. [ citation needed ]  Provided that women also regularly participate in low-impact training, strength training can improve pelvic girdle pain severity postpartum. [ 136 ]  When incorporating exercises that focus on pelvic muscle strength, they can help reduce pain and stress urinary incontinence. [ 136 ]


Engaging in regular exercise and physical activity has been shown to be beneficial during pregnancy. Acute bouts of  high intensity interval training  can help decrease the risks of health complications associated with pregnancy, maintain a healthy body fat percentage during pregnancy, as well as improve overall well-being. [ 137 ]  Pregnant women who participated in high intensity interval training have been shown to undergo physical improvements in body composition after intervention as well as show general improvement in cardiorespiratory fitness and exercise tolerance. [ 138 ]  Taking part in this style of exercise, similarly to moderate intensity continuous training, has also been shown to improve glycemic response and insulin sensitivity. [ 139 ]  There are specific concerns to be avoided with exercise during pregnancy such as overheating, fall-risk, and remaining in a supine position for an extended period of time. Inexperienced individuals new to high-intensity interval training could potentially increase their risk for negative conditions associated with hypertension, such as pre-eclampsia. [ 140 ]


It has been suggested that  shift work  and exposure to bright light at night should be avoided at least during the last trimester of pregnancy to decrease the risk of psychological and behavioral problems in the newborn. [ 141 ]


The children of women who had high stress levels during pregnancy are slightly more likely to have  externalizing behavioral problems  such as impulsivity. [ 138 ]   The behavioral effect was most pronounced during early childhood. [ 138 ]


The increased levels of  progesterone  and  estrogen  during pregnancy make  gingivitis  more likely; the  gums  become edematous, red in colour, and tend to bleed. [ 142 ]  Also a  pyogenic granuloma  or "pregnancy tumor", is commonly seen on the labial surface of the papilla. Lesions can be treated by local debridement or deep incision depending on their size, and by following adequate  oral hygiene  measures. [ 143 ]  There have been suggestions that severe  periodontitis  may increase the risk of having  preterm birth  and  low birth weight ; however, a Cochrane review found insufficient evidence to determine if  periodontitis  can develop adverse birth outcomes. [ 144 ]


In low risk pregnancies, most health care providers approve flying until about 36 weeks of gestational age. [ 145 ]  Most airlines allow pregnant women to fly short distances at less than 36 weeks, and long distances at less than 32 weeks. [ 146 ]  Many airlines require a doctor's note that approves flying, especially at over 28 weeks. [ 146 ]  During flights, the risk of  deep vein thrombosis  is decreased by getting up and walking occasionally, as well as by avoiding dehydration. The exposure to cosmic radiation is negligible for most travelers. For pregnant women, even the longest intercontinental fight would expose them less than 15% of both the  NCRPM  and  ICRP  limit. [ 147 ] [ 146 ]   Full body scanners  do not use ionizing radiation, and are safe in pregnancy. [ 148 ]


To prepare for the birth of the baby, health care providers recommend that parents attend antenatal classes during the third trimester of pregnancy. Classes include information about the process of labor and birth and the various kinds of births, including both vaginal and  caesarean delivery , the use of forceps, and other interventions that may be needed to safely deliver the infant. Types of pain relief, including relaxation techniques, are discussed.  Partners or others who may plan to support a woman during her labor and delivery learn how to assist in the birth. [ citation needed ]


It is also suggested that a birth plan be written at this time. A birth plan is a written statement that outlines the desires of the mother during labor and delivery of the baby.  Discussing the birth plan with the midwife or other care provider  gives parents a chance to ask questions and learn more about the process of labour. [ 149 ]


In 1991 the  WHO  launched the  Baby-Friendly Hospital Initiative , a global program that recognizes birthing centers and hospitals that offer optimal levels of care for giving birth. Facilities that have been certified as "Baby Friendly" accept visits from expecting parents to familiarize them with the facility and the staff. [ 150 ]


Each year, ill health as a result of pregnancy is experienced (sometimes permanently) by more than 20 million women around the world. [ 151 ]  In 2016, complications of pregnancy resulted in 230,600 deaths down from 377,000 deaths in 1990. [ 12 ]  Common causes include  bleeding  (72,000),  infections  (20,000),  hypertensive diseases of pregnancy  (32,000),  obstructed labor  (10,000), and  pregnancy with abortive outcome  (20,000), which includes  miscarriage ,  abortion , and  ectopic pregnancy . [ 12 ]


The following are some examples of pregnancy complications:


There is also an increased  susceptibility and severity of certain infections in pregnancy .


Miscarriage is the most common complication of early pregnancy.  It is defined as the loss of an embryo or fetus before it is able to survive independently.  The most common symptom of miscarriage is vaginal bleeding with or without pain. The miscarriage may be evidenced by a clot-like material passing through and out of the vagina. [ 156 ]   About 80% of miscarriages occur in the first 12 weeks of pregnancy. The underlying cause in about half of cases involves chromosomal abnormalities. [ 157 ]


Stillbirth is defined as fetal death after 20 or 28 weeks of pregnancy, depending on the source. It results in a baby born without signs of life.  Each year about 21,000 babies are stillborn in the U.S. [ 158 ]  Sadness, anxiety, and guilt may occur after a miscarriage or a stillbirth.  Emotional support may help with processing the loss. [ 159 ]  Fathers may experience grief over the loss as well.  A large study found that there is a need to increase the accessibility of support services available for fathers. [ 160 ]


A pregnant woman may have a  pre-existing disease , which is not directly caused by the pregnancy, but may cause  complications  to develop that include a potential risk to the pregnancy; or a disease may develop during pregnancy.


An abortion is the termination of an embryo or fetus via medical method. It is usually done within the first trimester, sometimes in the second, and rarely in the third. Reasons for  pregnancies being undesired  are broad. [ 165 ]  Many jurisdictions restrict or prohibit abortion, with  rape  being the most legally permissible exception. [ 166 ]


Family planning , as well as the availability and use of  contraception , along with increased  comprehensive sex education , has enabled many to prevent pregnancies when they are not desired. Schemes and funding to support education and the means to prevent pregnancies when they are not intended have been instrumental and are part of the third of the  Sustainable Development Goals  (SDGs) advanced by the  United Nations . [ 167 ]


Modern reproductive medicine offers many forms of assisted reproductive technology for couples who stay childless against their will, such as  fertility medication ,  artificial insemination ,  in vitro  fertilization  and  surrogacy .


Medical imaging  may be  indicated  in pregnancy because of  pregnancy complications , disease, or routine  prenatal care .  Medical ultrasonography  including  obstetric ultrasonography , and  magnetic resonance imaging (MRI)  without  contrast agents  are not associated with any risk for the mother or the fetus, and are the imaging techniques of choice for pregnant women. [ 168 ]   Projectional radiography ,  CT scan  and  nuclear medicine imaging  result in some degree of  ionizing radiation  exposure, but in most cases the  absorbed doses  are not associated with harm to the baby. [ 168 ]  At higher dosages or frequency, effects can include  miscarriage ,  birth defects  and  intellectual disability . [ 168 ]


About 213 million pregnancies occurred in 2012 of which 190 million were in the  developing world  and 23 million were in the developed world. [ 11 ]  This is about 133 pregnancies per 1,000 women aged 15 to 44. [ 11 ]  About 10% to 15% of recognized pregnancies end in miscarriage. [ 2 ]  Globally, 44% of pregnancies are  unplanned . Over half (56%) of unplanned pregnancies are aborted. In countries where  abortion is prohibited , or only carried out in circumstances where the mother's life is at risk, 48% of unplanned pregnancies are  aborted illegally . Compared to the rate in countries where abortion is legal, at 69%. [ 27 ]


Of pregnancies in 2012, 120 million occurred in Asia, 54 million in Africa, 19 million in Europe, 18 million in Latin America and the Caribbean, 7 million in North America, and 1 million in  Oceania . [ 11 ]  Pregnancy rates are 140 per 1000 women of childbearing age in the developing world and 94 per 1000 in the developed world. [ 11 ]


The rate of pregnancy, as well as the ages at which it occurs, differ by country and region. It is influenced by a number of factors, such as cultural, social and religious norms; access to contraception; and rates of education. The  total fertility rate  (TFR) in 2013 was estimated to be highest in  Niger  (7.03 children/woman) and lowest in  Singapore  (0.79 children/woman). [ 169 ]


In Europe, the average childbearing age has been rising continuously for some time. In Western, Northern, and Southern Europe, first-time mothers are on average 26 to 29 years old, up from 23 to 25 years at the start of the 1970s. In a number of European countries (Spain), the mean age of women at first childbirth has crossed the 30-year threshold.


This process is not restricted to Europe. Asia, Japan and the United States are all seeing average age at first birth on the rise, and increasingly the process is spreading to countries in the developing world like China, Turkey and Iran. In the US, the average age of first childbirth was 25.4 in 2010. [ 170 ]


In the United States and United Kingdom, 40% of pregnancies are  unplanned , and between a quarter and half of those unplanned pregnancies were  unwanted pregnancies . [ 171 ] [ 172 ]


In the US, a woman's educational attainment and her marital status are correlated with childbearing: the percentage of women unmarried at the time of first birth drops with increasing educational level. In other words: among uneducated women, a large fraction (~80%) have their first child while they are unmarried. By contrast, few women with a bachelor's degree or higher (~25%) have their first child while unmarried. However, this phenomenon also has a strong generational component: in 1996, about 50% of women without a university degree had their first child being unmarried while that number increased to ~85% in 2018. Similarly, in 1996, only 4% of women with a BA degree or similar had their first child being unmarried. In 2018, that fraction increased to ~25%. [ 173 ]


Many countries have various legal regulations in place to protect pregnant women and their children. Many countries have laws against  pregnancy discrimination . [ 174 ]


Maternity Protection Convention  ensures that pregnant women are exempt from activities such as night shifts or carrying heavy stocks.  Maternity leave  typically provides paid leave from work during roughly the last trimester of pregnancy and for some time after birth. Notable extreme cases include Norway (8 months with full pay) and the United States (no paid leave at all except in some states).


In the United States, some actions that result in miscarriage or stillbirth, such as beating a pregnant woman, are considered crimes. One law that does so is the federal  Unborn Victims of Violence Act . In 2014, the American state of  Tennessee  passed a law which allows prosecutors to charge a woman with criminal assault if she uses illegal drugs during her pregnancy and her fetus or newborn is harmed as a result. [ 175 ]


However, protections are not universal.  In  Singapore , the  Employment of Foreign Manpower Act  forbids current and former  work permit  holders from becoming pregnant or giving birth in Singapore without prior permission. [ 176 ] [ 177 ]  Violation of the Act is punishable by a fine of up to  S$ 10,000 (US$7300) and  deportation , [ 176 ] [ 178 ]  and until 2010, their employers would lose their $5,000 security bond. [ 179 ]


Teenage pregnancy  is also known as  adolescent  pregnancy. [ 180 ]  The  WHO  defines adolescence as the period between the ages of 10 and 19 years. [ 181 ]  Adolescents face  higher health risks than women who give birth at age 20 to 24 and their infants are at a higher risk for preterm birth, low birth weight, and other severe neonatal conditions. Their children continue to face greater challenges, both behavioral and physical, throughout their lives. Teenage pregnancies are also related to social issues, including  social stigma , lower educational levels, and poverty. [ 182 ] [ 180 ]   Studies show that female adolescents are often in abusive relationships at the time of their conceiving. [ 183 ]


Nurse-Family Partnership  (NFP) is a non-profit organization operating in the United States and the UK designed to serve the needs of low income young mothers who may have special needs in their first pregnancy.  Each mother served is partnered with a registered nurse early in her pregnancy and receives ongoing nurse home visits that continue through her child's second birthday. NFP intervention has been associated with improvements in maternal health, child health, and economic security. [ 184 ] [ 185 ]


There are significant racial imbalances in pregnancy and neonatal care systems. [ 186 ]  Midwifery guidance, treatment, and care have been related to better birth outcomes. Diminishing racial inequities in health is an increasingly large public health challenge in the United States. Despite the fact that average rates have decreased, data on neonatal mortality demonstrates that racial disparities have persisted and grown. The death rate for African American babies is nearly double that of white neonates. According to studies,  congenital defects ,  SIDS ,  preterm birth , and  low birth weight  are all more common among African American babies. [ 187 ]


Midwifery care has been linked to better birth and postpartum outcomes for both mother and child. It caters to the needs of the woman and provides competent, sympathetic care, and is essential for maternal health improvement. The presence of a  doula , or birth assistant, during labor and delivery, has also been associated with improved levels of satisfaction with medical birth care. Providers recognized their profession from a historical standpoint, a link to African origins, the diaspora, and prevailing African American struggles. Providers participated in both direct clinical experience and activist involvement. Advocacy efforts aimed to enhance the number of minority birth attendants and to promote the benefits of woman-centered birth care to neglected areas. [ 187 ]


Transgender people have experienced significant advances in societal acceptance in recent years leaving many health professionals unprepared to provide quality care. A 2015 report suggests that "numbers of transgender individuals who are seeking family planning, fertility, and pregnancy services could certainly be quite large".
Regardless of prior hormone replacement therapy treatments, the progression of pregnancy and birthing procedures for  transgender people who carry pregnancies  are typically the same as those of  cisgender  women [ 188 ]  however, they may be subjected to discrimination, which can include a variety of negative social, emotional, and medical experiences, as pregnancy is regarded as an exclusively female activity. According to a study by the  American College of Obstetricians and Gynecologists , there is a lack of awareness, services, and medical assistance available to pregnant trans men. [ 189 ]


In most cultures, pregnant women have a special status in society and receive particularly gentle care. [ 190 ]  At the same time, they are subject to expectations that may exert great psychological pressure, such as having to produce a son and heir. In many traditional societies, pregnancy must be preceded by marriage, on pain of ostracism of mother and  (illegitimate) child .


Overall, pregnancy is accompanied by numerous customs that are often subject to ethnological research, often rooted in  traditional medicine  or religion. The  baby shower  is an example of a modern custom. Contrary to  common misconception , women historically in the  United States  were not expected to seclude themselves during pregnancy, as was popularized by  Gone With the Wind . [ 191 ] [ 192 ]


Pregnancy is an important topic in  sociology of the family . The prospective child may preliminarily be placed into numerous  social roles . The parents' relationship and the relation between parents and their surroundings are also affected.


A  belly cast  may be made during pregnancy as a keepsake.


Images of pregnant women, especially small  figurines , were made in traditional cultures in many places and periods, though it is rarely one of the most common types of image. These include ceramic figures from some  Pre-Columbian  cultures, and a few figures from most of the ancient Mediterranean cultures. Many of these seem to be connected with  fertility . Identifying whether such figures are actually meant to show pregnancy is often a problem, as well as understanding their role in the culture concerned.


Among the oldest surviving examples of the depiction of pregnancy are prehistoric figurines found across much of  Eurasia  and collectively known as  Venus figurines . Some of these appear to be pregnant.


Due to the important role of the  Mother of God  in  Christianity , the Western visual arts have a long tradition of depictions of pregnancy, especially in the biblical scene of the  Visitation , and devotional images called a  Madonna del Parto . [ 193 ]


The unhappy scene usually called  Diana and Callisto , showing the moment of discovery of  Callisto 's forbidden pregnancy, is sometimes painted from the Renaissance onwards. Gradually, portraits of pregnant women began to appear, with a particular fashion for "pregnancy portraits" in elite portraiture of the years around 1600.


Pregnancy, and especially pregnancy of unmarried women, is also an important motif in literature. Notable examples include  Thomas Hardy 's 1891 novel  Tess of the d'Urbervilles  and Goethe's 1808 play  Faust .


A  pregnancy test  is used to determine whether a female is  pregnant  or not. The two primary methods are testing for the female pregnancy hormone ( human chorionic gonadotropin  (hCG)) in blood or urine using a pregnancy test kit, and scanning with  ultrasonography . [ 1 ]  Testing blood for hCG results in the earliest detection of pregnancy. [ 2 ]  Almost all pregnant women will have a positive urine pregnancy test one week after the first day of a missed menstrual period. [ 3 ]


Identified in the early 20th century,  human chorionic gonadotropin  (hCG) is a  glycoprotein hormone  that rises quickly in the first few weeks of pregnancy, typically reaching a peak at 8- to 10-weeks  gestational age . [ 4 ] [ 5 ]  hCG is produced by what will become the  placenta . [ 6 ]  hCG testing can be performed with a blood ( serum ) sample (typically done in a medical facility) or with urine (which can be performed in a medical facility or at home). The assays used to detect the presence of hCG in blood or urine are generally reliable and inexpensive. Secretion of hCG can occur as soon as 6 days following ovulation and on average 8–10 days following ovulation; this is the earliest hCG can be detected in a blood sample. [ 7 ] [ 5 ] [ 8 ]   The hCG concentration in blood is higher than in urine. Therefore, a blood test can be positive while the urine test is still negative. [ 9 ] [ 10 ]


Qualitative tests (yes/no or positive/negative results) look for the presence of the  beta subunit of human chorionic gonadotropin  in blood or urine. For a qualitative test the thresholds for a positive test are generally determined by an hCG cut-off where at least 95% of pregnant women would get a positive result on the day of their first missed period. [ 11 ]  Qualitative urine pregnancy tests vary in sensitivity. High-sensitivity tests are more common and typically detect hCG levels between 20 and 50 milli-international units/mL (mIU/mL). Low-sensitivity tests detect hCG levels between 1500 and 2000 mIU/mL and have unique clinical applications, including confirmation of medication abortion success. [ 12 ]  Qualitative urine tests available for home use are typically designed as  lateral flow tests .


Quantitative tests measure the exact amount of hCG in the sample. Blood tests can detect hCG levels as low as 1 mIU/mL, and typically clinicians will diagnose a positive pregnancy test at 5mIU/mL. [ 11 ]


Qualitative test: 20 to 50 mIU/mL, depending on test


Low-sensitivity:


Qualitative test: 1500-2000 mIU/mL, depending on test


5 to 10 mIU/mL, depending on test


Quantitative test:


1 to 2 mIU/mL for an ultrasensitive test


There is a multilevel urine pregnancy test (MLPT) that measures hCG levels semiquantitatively. The hCG levels are measured at <25, 25 to 99, 100 to 499, 500 to 1999, 2000 to 9999, and >10,000 mIU/mL. This test has utility for determining the success of medication abortion. [ 13 ] [ 14 ]


Obstetric ultrasonography  may also be used to detect and diagnose pregnancy. It is very common to have a positive at-home urine pregnancy test before an ultrasound. Both  abdominal  and  vaginal  ultrasound may be used, but vaginal ultrasound allows for earlier visualization of the pregnancy. With  obstetric ultrasonography  the  gestational sac  (intrauterine fluid collection) can be visualized at 4.5 to 5 weeks  gestation , the  yolk sac  at 5 to 6 weeks gestation, and  fetal pole  at 5.5 to 6 weeks gestation. Ultrasound is used to diagnose  multiple gestation , which cannot be diagnosed based on the presence of hCG in urine or blood. [ 15 ]  Determination of the  gestational age  of the  embryo / fetus  is an additional benefit of ultrasound compared to hCG tests. [ 16 ]


A systematic review published in 1998 showed that home pregnancy test kits, when used by experienced technicians, are almost as accurate as professional laboratory testing (97.4%). When used by consumers, however, the accuracy fell to 75%: the review authors noted that many users misunderstood or failed to follow the instructions included in the kits. [ 17 ]


False positive  pregnancy test results are rare and may occur for several reasons, including:


Spurious  evaporation lines  may appear on many home pregnancy tests if read after the suggested 3–5 minute window or reaction time, independent of an actual pregnancy. False positives may also appear on tests used past their expiration date. [ 20 ]


False positive pregnancy test can happen due to 'phantom hCG' which is due to people having human antianimal or heterophilic antibodies. [ 21 ]


False positives can also be caused by (in order of incidence) quiescent pregnancy, pituitary sulfated hCG, heterophilic antibody, familial hCG syndrome and cancer. [ 22 ]


Urine tests can be falsely positive in those that are taking the medications:  chlorpromazine ,  promethazine ,  phenothiazines ,  methadone , [ 19 ]   aspirin ,  carbamazepine  and drugs that cause high urinary pH. [ 23 ]


False negative  readings can occur when testing is done too early. hCG levels rise rapidly in early pregnancy and the chances of false negative test results diminish with time (increasing  gestational age ). [ 24 ]  Less sensitive urine tests and qualitative blood tests may not detect pregnancy until three or four days after implantation. [ 25 ]   Menstruation  occurs on average 14 days after ovulation, so the likelihood of a false negative is low once a menstrual period is late. Ovulation may not occur at a predictable time in the  menstrual cycle . A number of factors may cause an unexpectedly early or late ovulation, even for people with a history of regular menstrual cycles. [ 26 ]  Medical providers often struggle to 'rule out' pregnancy for medical testing or treatment that cannot be conducted during pregnancy before they can do an accurate urine pregnancy test. [ 27 ]


More rare, false negative results can also occur due to a " hook effect ", where a sample with a very high level of hCG is tested without dilution, causing an invalid result. [ 28 ]


Pregnancy tests may be used to predict if a pregnancy is likely to continue or is abnormal.  Miscarriage, or spontaneous abortion or pregnancy loss , is common in early pregnancy. [ 29 ]  Serial quantitative blood tests may be done, usually 48 hours apart, and interpreted based on the knowledge that hCG in a viable normal pregnancy rises rapidly in early pregnancy. For example, for a starting hCG level of 1,500 mIU/ml or less, the hCG of continuing, normal pregnancy will increase at least 49% in 48 hours. However, for pregnancies with a higher starting hCG, between 1,500 and 3,000 mIU/ml, the hCG should rise at least 40%; for a starting hCG greater than 3,000 mIU/ml, the hCG should increase at least 33%. [ 30 ]  Failure to rise by these minimums may indicate that the pregnancy is not normal, either as a  failed intrauterine pregnancy  or a possible  ectopic pregnancy . [ 30 ]


Ultrasound  is also a common tool for determining viability and location of a pregnancy. Serial ultrasound may be used to identify non-viable pregnancies, as pregnancies that do not grow in size or develop expected structural findings on repeated ultrasounds over a 1–2 week interval may be identified as abnormal. [ 31 ]  Occasionally, a single ultrasound may be used to identify a pregnancy as non-viable; for example, an embryo that is greater than a certain size but that lacks a visible heart beat may be confidently determined to be not viable without the need for follow up ultrasound for confirmation. [ 31 ]


Research has identified at least one other possible marker that may appear earlier and exclusively during pregnancy. For example,  early pregnancy factor  (EPF) can be detected in blood within 48 hours of  fertilization , rather than after implantation. [ 32 ]  However, its reliable use as a pregnancy test remains unclear as studies have shown its presence in physiological situations besides pregnancy, and its application to humans remains limited. [ 33 ]


Records of attempts at pregnancy testing have been found as far back as the  ancient Greek  and  ancient Egyptian  cultures. The ancient Egyptians watered bags of  wheat  and  barley  with the urine of a possibly pregnant woman. Germination indicated pregnancy. The type of grain that sprouted was taken as an indicator of the fetus's sex. [ 35 ]   Hippocrates  suggested that a woman who had missed her period should drink a solution of  honey  in water at bedtime: resulting abdominal distention and cramps would indicate the presence of a pregnancy.  Avicenna  and many physicians after him in the  Middle Ages  performed  uroscopy , a nonscientific method to evaluate urine.


Selmar Aschheim  and  Bernhard Zondek  introduced testing based on the presence of  human chorionic gonadotropin  (hCG) in 1928. [ 36 ]  Early studies of hCG had concluded that it was produced by the  pituitary gland . In the 1930s, Doctor  Georgeanna Jones  discovered that hCG was produced not by the pituitary gland, but by the  placenta . This discovery was important in relying on hCG as an early marker of pregnancy. [ 37 ]  In the Aschheim and Zondek test, an infantile female  mouse  was injected subcutaneously with urine of the woman to be tested, and the mouse later was killed and dissected. Presence of  ovulation  indicated that the urine contained hCG and meant that the subject was pregnant. A similar test was developed  using immature rabbits . Here, too, killing the animal to check her ovaries was necessary.


At the beginning of the 1930s,  Hillel Shapiro  and Harry Zwarenstein, who were researchers at the  University of Cape Town , discovered that if urine from a pregnant woman was injected into the South African  Xenopus  frog and the frog ovulated, this indicated that the subject was pregnant. This test, known as the  frog test , was used throughout the world from the 1930s to 1960s, with  Xenopus  frogs being exported in great numbers. [ 38 ] [ 39 ]  Shapiro's advisor,  Lancelot Hogben , claimed to have developed the pregnancy test himself, but this was refuted by both Shapiro and Zwarenstein in a letter to the  British Medical Journal . A later article, independently authored, granted Hogben credit for the principle of using  Xenopus  to determine gonadotropin levels in a pregnant woman's urine, but not for its usage as a functional pregnancy test. [ 40 ]


Hormonal pregnancy tests such as  Primodos  and  Duogynon  were used in the 1960s and 1970s in the UK and Germany. These tests involved taking a dosed amount of hormones, and observing the response a few days later. A pregnant woman does not react, as she is producing the hormones in pregnancy; a subject who is not pregnant responds to the absence of the hormone by beginning a new menstrual cycle. While the test was (is) generally considered accurate, research advancements have replaced it with simpler techniques. [ 41 ]


Immunologic pregnancy tests were introduced in 1960 when Wide and  Gemzell  presented a test based on in-vitro hemagglutination inhibition. This was a first step away from in-vivo pregnancy testing [ 42 ] [ 43 ]  and initiated a series of improvements in pregnancy testing leading to the contemporary at-home testing. [ 43 ]  Direct measurement of  antigens , such as hCG, was made possible after the invention of the  radioimmunoassay  in 1959. [ 44 ]  Radioimmunoassays require sophisticated apparatus and special radiation precautions and are expensive.


Organon International  obtained the first patent on a home pregnancy test in 1969, two years after product designer  Margaret Crane  noticed that the laboratory testing procedure was relatively simple and made a prototype.  The product became available in Canada in 1971, and the United States in 1977, after delays caused by concerns over sexual morality and the ability of potentially pregnant women to perform the test and cope with the results without a doctor. [ 45 ]


Another home pregnancy testing kit was based on the work of  Judith Vaitukaitis  and Glenn Braunstein, who developed a sensitive hCG assay at the  National Institutes of Health . [ 46 ] [ 47 ]  That test went onto the market in 1978. [ 48 ]
In the 1970s, the discovery of  monoclonal antibodies  led to the development of the relatively simple and cheap  immunoassays , such as agglutination-inhibition-based assays and  sandwich ELISA , used in modern home pregnancy tests.  Tests are now so cheap that they can be mass-produced in a general publication and used for advertising. [ 49 ]


Prenatal stress,  also known as  prenatal maternal stress,  occurs when an  expectant mother  is exposed to psychosocial or physical  stress . This can be brought on by daily events or environmental hardships. [1] [2]  According to the  Developmental Origins of Health and Disease  (DOHaD), a wide range of  environmental factors  a woman may experience during the  perinatal period  can contribute to biological impacts and changes in the fetus that then cause health risks later in the child's life. Health risks include impaired  cognitive development ,  low birth weight ,  mental disorders , and gender specific deficits in the offspring. [ 1 ] [ 2 ]


Studies explore the way that prenatal stress impacts the fetus's development. One of the ways the body responds to stress is via the hypothalamic-pituitary-adrenal (HPA) axis. [ 3 ]  Expectant mothers that experience high levels of stressors trigger a response from the HPA axis. This then triggers the release of glucocorticoids. This increases the level of glucocorticoid in the mother and the fetus. [ 3 ]  Studies show that elevated levels of glucocorticoids can affect neurodevelopment in the fetus. [ 4 ]


Some research includes studies like McKenna et al. suggesting that the idea of pregnancy can cause an increased risk of psychopathology and these exposures during gestation impacts epigenetic. [ 5 ]  The mother's usage of selective serotonin repute inhibitors (SSRIs) was observed while the epigenetic age of the child was calculated through fetal  umbilical cord  blood. [ 5 ]


Saboory et al. found that prenatal psychosocial stress can cause delays in child growth and development through assessing the child's weight, height and head circumference every two months after they were born. [ 6 ]  They also assessed the child's cognitive development through the use of the Ages and Stages Questionnaire (ASQ). [ 6 ]


Another study, Brannigan et al. focused on how prenatal stress contributes to personality disorders by looking at children decades later born from mothers who spent time in a mental health clinic in Finland. [ 7 ]


All of this research had found negative correlations between prenatal stress and the child's development.


A study by Sandman and Davis  [ 8 ]  shows that the timing of prenatal stress is crucial to understanding how prenatal stress affects prenatal and postnatal development.  Cortisol  is often used to measure stress as it is a hormone that is released during stressful events. If an expectant mother is experiencing a stressful event such as income insecurity or being a teenage mother, cortisol is secreted as a result. [ 9 ]  However, as demonstrated by Sandman and Davis, the timing of cortisol release can sometimes have a harmful effect on development and sometimes not depending on when in pregnancy stress is experienced. [ 8 ]  Prenatal stress can increase the likelihood of maternal and endocrinological problems. Prenatal stress can even cause the embryo to arrive earlier than expected.


Sandman and Davis studied "125 full- term infants at 3, 6, and 12 months of age" [ 8 ]  to determine the effects of maternal cortisol timing differences on development. They found that "exposure to elevated concentrations of cortisol early in gestation was associated with a slower rate of development over the 1st year and lower mental development scores at 12 months" and "elevated levels of maternal cortisol late in gestation were associated with accelerated cognitive development and higher scores at 12 months". [ 8 ]  Overall, cortisol's effects on infant cognitive development are dependent upon the timing of cortisol release. [ 8 ]  Furthermore, prenatal stress can have an effect on fetal development by causing obesity, diabetes, cardiovascular disease, and other problems.


Poor eating habits and lack of physical activity are not the only contributing factors to prenatal stress on the baby. Stress on the mother during pregnancy can lead to issues in cognitive development, social development and more. [ 10 ]   A great deal of brain development happens during the fetal period in pregnancy and the progress happens rapidly in this stage. [ 11 ]  Since there is such a large amount of growth occurring during this time-period in the child's life, there are a lot of outside factors in the environment that can affect this development. [ 11 ]  These outside factors could be anything from poor nutrition, excess cortisol levels or even genetic influences. The fetus's development can be impacted through the level of the placenta, and there is evidence to show how prenatal stress can have consequences on the placenta and in turn the fetus during pregnancy. [ 10 ]


The resulting effects can impact many different areas of the developing child's brain, such as the hypothalamus, corpus callosum, amygdala, hippocampus, and cerebellum. Animal studies have shown that prenatal stress may result in reduced hippocampus volumes and amygdala nuclei volumes, both of which may have a negative impact on memory. [ 12 ]  There is indirect evidence to suggest that prenatal stress could alter the size and morphology of the corpus callosum, and it is known that alterations in the corpus callosum are observed in  autism ,  ADHD , and  schizophrenia . [ 12 ]  Furthermore, alterations to the cerebellum may also be involved in autism, ADHD, and schizophrenia, and prenatal stress may also play a role in altering the physiology of the cerebellum. Studies done in rats have shown that prenatal stress may affect the size and number of granule cells in the cerebellum, as well as cause an increase in the number of Purkinje cells. [ 12 ]  Also shown in rats, there is evidence to suggest that prenatal stress can result in the feminization of males by reducing the volume one of the hypothalamic nuclei that is involved in the sexual behavior of males. [ 12 ]


These impacts have mostly been noted in animal studies because of the concerns that surround human studies with prenatal stress. [ 10 ]  The ethical concerns with human studies and prenatal stress have led to little to no studies showing the direct impacts stress can have on fetal development, and it has shown to be difficult to draw inferences and connections between the animal studies and human pregnancies. [ 10 ]  It has been suggested that one way to monitor the impact of stress on the infant's development is through the mother's exposure to  natural disasters . There has been some research analyzing how natural disasters such as hurricanes can affect fetal development when the mother is exposed during pregnancy. [ 13 ]  This research showed that there were impacts psychologically on the children who were exposed to this type of stress in the womb, in terms of increased risk for developing childhood psychopathologies. [ 13 ]  Natural disaster research like this has shown the effects of stress on pregnancy without the issues that surround human research and is able to show results within humans instead of drawing from other animals.


Prenatal distress has been shown to increase the risk that the offspring will develop a mental disorder as well as the severity of some symptoms. Typical disorders that are increased due to prenatal distress include autism, the severity of ADHD, and the development of mood disorders. [ 14 ]  Prenatal stress disrupts multiple developmental systems within the individual carrying offspring. One of the disrupted processes is hormone production. Maternal exposure to excess dihydrotestosterone, progestin, and norethindrone have been linked to a higher risk of offspring developing ASD. [ 15 ]  A 2008 study found that children whose mothers experienced moderate to severe stress during their pregnancy tended to develop symptoms that more frequently fell on the severe side of the ADHD severity spectrum. This distinction was made in comparison to those with ADHD whose mothers were not exposed to prenatal stressors. [ 16 ]  This increased development of ADHD from heightened prenatal distress can be due to many factors, one of the more popular and founded claims being the neurological development of the offspring. Exposure to stress during the process of pregnancy affects fetal brain development and predisposes offspring to the development of a multitude of mental disorders. [ 17 ]  Many studies have found that there is an association between ADHD and lessened functioning within the prefrontal cortex (PFC). This area of the brain plays a crucial role in attention regulation as well as behavioral and emotional control. The PFC right hemisphere in particular has been linked to decreased size in individuals who have ADHD. [ 18 ]  This is notable due to the important role of the PFC right hemisphere which is behavioral inhibition, a common struggle for individuals with ADHD. Prenatal distress has also been linked to the development of mood disorders such as depression or anxiety. A 2019 study found that prenatal distress, specifically during the first 20 weeks of gestation, was linked to higher mood dysregulation and lower grey matter (GM) volume. [ 19 ]  The lessening of grey matter volume is a detrimental loss because of the multitude of functions that this structure is essential for. Grey matter is found throughout the central nervous system and is crucial for motor function, memory, and emotions. [ 20 ]  The reduction of GM volume is impactful in many negative ways which is another contributing factor that can lead to the development of mental disorders in children that experience in utero stress.


Stress during the development of the fetus can be inherited and change the gene expression in the fetus. [ 21 ]  This change is an  epigenetic  change that modifies but does not affect the building of the DNA sequence. This modification will affect whether the gene is turned off or on and will lead to  Transgenerational Stress Inheritance . [ 22 ]


One of the pathways that has been studied is the inheritance of  disrupted heterochromatin. Heterochromatin is important in many functions of the cell mostly in gene regulation. During high levels of stress during pregnancy dATF-2, which is required for formation of heterochromatin, will phosphorylate and disrupt the formation. This will lead to the release of dATF-2 from the heterochromatin, which then can be inherited in offspring. [ 23 ]


Another pathway that prenatal stress can interfere with fetal development is telomere length. [ 24 ]  A telomere is a structure of repetitive DNA sequences that can be found at the end of chromosomes. They are made up of the same short DNA sequence that is repeated multiple times and serve to protect the ends of chromosomes so they do not become damaged. [ 25 ]  Another function of telomeres is to allow chromosomes to properly function in the process of replication. However, each time a cell divides, the telomeres loses length and becomes shorter. After repeated replications they will eventually become so short that the cell is unable to divide any further and the cell will die. [ 24 ]  When offspring are exposed to prenatal distress during development it can affect the length of the offspring's telomeres, more specifically it can result in shortened telomeres. [ 26 ]  Shortened telomeres have been linked to multiple issues including shortened lifespan and increased risk of diseases. [ 27 ]  Typically, telomeres shorten substantially with increasing age, and telomere length is thus a bioindicator of aging. However, prenatal stress puts offspring at an increased state of vulnerability by shortening the telomeres and leaving less room for shortening as the offspring continue to age. [ 26 ]


Prenatal stress inhibits the masculinization of the male brain by inhibiting the growth of the sexually cluster of cells of the preoptic area. Prenatal stress does have an effect on brain sexual differentiation after measuring the volume of the sexually dimorphic nucleus of the preoptic area of both female and males in the control and stressed groups.


Previous studies found that a decrease in testosterone is seen in pups of prenatally stressed mothers. Authors suggest this may cause the reduced in the sexually dimorphic nucleus of the preoptic area and says it is similar to the effects of neonatal castration. Also, stressed males had larger sexually dimorphic nucleus of the preoptic area at birth, but then at 20 and 60 days are found to only have 50% of the volume of the control males. Whereas control males are two times larger than control females on days 20 and 60, but the stressed males show no statistical difference to control females on respective days. These findings show support that the male brain is not showing the expected sexual dimorphism when prenatally stressed. [ 28 ]


Another study led by Kerchner et al. investigated the volume of the medial  amygdala  and the two compartments posterodorsal and the posteroventral in mice that also were prenatally stressed. Posterodorsal is thought to show organizational and activational effects from  gonadal steroids . The medial amygdala for the control and stressed males was 85% larger than females with the males (stressed and control) resembling each other.


To look for specific regions within the medial amygdala that may have been affected, data showed that both the posterodorsal and posteroventral, all male groups were larger in volume than the females, but male groups did not significantly differ from each other. This study confirmed that the medial amygdala is sexually dimorphic; the males are larger than the females.


The posterodorsal and posteroventral were shown to be sexually dimorphic too. The writer suggested that these areas may act similarly to sexually dimorphic nucleus of the preoptic area in response to testosterone, but prenatal stress did not show an effect on the medial amygdala as it does on the sexually dimorphic nucleus of the preoptic area. Also, the posteroventral was 40% larger in control males than females. These results were thought to be caused by the sensitive period of the medial amygdala which is in the first days after birth. The medial amygdala, posterodorsal and posteroventral all show to be resistant against demasculinization from prenatal stress. [ 29 ]  A longitudinal study done on prenatal stress and gender roles showed that prenatal stress only plays a small part in the gender roles the offspring takes on and mentions it has more to do with older siblings, maternal use of alcohol and/or tobacco, maternal education, and the observance or teaching of “traditional sex roles” from the parents. [ 30 ]


Pups that underwent prenatal stress showed lower plasma testosterone when compared to the control pups. This is caused by the disruption of prenatal development which did not allow the complete masculinization of the prenatally stressed pups’ central nervous system. In humans, prenatal stress affects development differently in boys and girls. Males may exhibit less masculine characteristics as a result of prenatal stress, whereas females may exhibit less feminine characteristics. Prenatal stress, on the other hand, can have serious consequences for both genders. [ 2 ]


Particularly in the striatum of the prenatally stressed male pups showed an increase in  vanilmandelic acid ,  dopamine ,  serotonin ,  5-hydroxyindoleacetic acid  which all can affect sexual behavior. The prenatally stressed male pups showed a significant latency in mounting behavior when compared to controls. [ 31 ]


When performing the radial arm maze task, prenatally stressed male rats showed a greater increase in dopamine than prenatally stressed females, which is thought to facilitate impairment in the males but improve female performance. Females who were prenatally stressed also had an effect on corticosterone secretion.


Being prenatally stressed increased the anxiety response of the female rats. Yet, it had no effect on the males. [ 32 ]


Prenatal stress has increased as a result of the recent changes caused by the COVID-19 pandemic. Researchers are attempting to determine how the pandemic relates to prenatal stress, why so many women are experiencing stress and anxiety, and how these issues can be avoided. Researchers conducted a study by developing a questionnaire for pregnant women that included age, sex, race, health insurance status, financial status, any pregnancy risks, medical conditions, treatments, doctor's appointments, how many appointments were canceled due to COVID-19, and stress levels on a scale of mild, moderate, and severe. Three-quarters of the research participants were white or non-Hispanic, according to the questionnaire. There were 280 women who reported mild cases, 170 who reported moderate cases, and 171 who reported severe cases. Following the questionnaire, researchers discovered that mothers were experiencing high levels of anxiety and stress because they were afraid of contacting the covid virus and having the virus affect their fetus, having one person in the delivery room, and making online appointments without being checked in person. As a result, researchers proposed that there should be in-person engagement for the mother, information provided to the mother about COVID-19 and the protocols to reduce the risk of contacting it, and consistent check-in appointments to check the mother's mental health status. [ 33 ]


Prenatal stress and negative mood during pregnancy has been shown to increase the risk for poor childbirth outcomes and postnatal maternal mood problems. Prenatal distress can interfere with the mother-infant attachment and child development outcomes. [ 34 ] [ 35 ]  Despite the clear association between prenatal stress and child outcomes, women do not receive screening, prevention, or treatment for mood or stress concerns. [ 36 ] [ 37 ]


It is essential to examine interventions that aim to reduce anxiety, depression, and stress during pregnancy.  Mindfulness-based stress reduction  has been demonstrated to reduce anxiety and depression for people with stress-related and chronic medical conditions. [ 38 ]


One pilot study shows promise for the potential of a mindfulness-based intervention to reduce negative affect and anxiety of women during pregnancy. Based out of the California Pacific Medical Center Research Institute, investigators Dr. Cassandra Vieten and Dr. John Astin conducted a wait-list control pilot study that tested a group-based mindfulness intervention. There were 31 women enrolled in the study: 13 women were assigned to the intervention and 18 women were assigned to the control group.


Measures of anxiety, negative affect, positive affect, depression, mindfulness, perceived stress, and affect regulation were taken before intervention or control was assigned and after the intervention or control was completed. Measures were repeated at a follow-up visit 3 months after the intervention or control was completed. The investigators found a significant decrease in anxiety (p<.05) and negative affect (p <.04) in women who completed the mindfulness based intervention, but not a significant decrease in depression, positive affect, mindfulness, affect regulation, and perceived stress.


These results suggest that mindfulness intervention during pregnancy reduce anxiety and negative affect of mothers.  This study is a promising start to the potential impact that mindfulness based interventions could have on reducing prenatal stress, and thereby improving child outcomes. [ 39 ]


In  obstetrics , the  presentation  of a  fetus  about to be  born  specifies which  anatomical part  of the fetus is leading, that is, is closest to the  pelvic inlet  of the  birth canal . According to the leading part, this is identified as a  cephalic ,  breech , or  shoulder  presentation. A  malpresentation  is any presentation other than a vertex presentation (with the top of the head first).


Thus the various presentations are:


Reproductive endocrinology and infertility  ( REI ) is a surgical  subspecialty  of  obstetrics and gynecology  that trains physicians in  reproductive medicine  addressing  hormonal  functioning as it pertains to  reproduction  as well as the issue of  infertility . While most REI specialists primarily focus on the treatment of  infertility , reproductive endocrinologists are trained to also test and treat hormonal dysfunctions in females and males outside infertility. Reproductive endocrinologists have specialty training (residency) in  obstetrics and gynecology  (ob-gyn) before they undergo sub-specialty training (fellowship) in REI.


Reproductive surgery  is a related specialty, where a physician in ob-gyn or  urology  further specializes to operate on anatomical disorders that affect  fertility . [ 1 ]


In a number of countries, the pathway to become a subspecialist in REI is regulated. Thus, in the  United States , for instance, the  American Board of Obstetrics and Gynecology  (ABOG) and  American Osteopathic Board of Obstetrics and Gynecology  set the standards for subspecialists to become certified. After four years of training in Obstetrics and Gynecology, a three-year approved  fellowship  needs to be successfully completed. Then, to become board certified in reproductive endocrinology and infertility, one must first complete  board certification  in  obstetrics and gynecology  (written and oral exams), and then certify in reproductive endocrinology and infertility (written and oral exams).


In the United States, fellowship in  reproductive endocrinology and infertility  usually takes 3 years, and is offered in 40 centers across the country as of 2013. [ 2 ]


In the  European Union , the  European Board and College of Obstetrics and Gynaecology  (EBCOG) has accreditation centers for a subspecialist training program in  reproductive medicine  at 4 centers across the EU as of 2012. [ 3 ]


In  Australia  and  New Zealand , a training program in  reproductive endocrinology and infertility  takes 3 years, and is offered in 15 centers across the two countries. [ 4 ]


In  India , Assisted Reproductive Technology bill has been passed in parliament.  [1]  This bill mandates  gyncelogists  or andrologists to have 3 years of experience in recognized ART centers to conduct procedures such as  IVF , PGT.


Reproductive endocrinologists Certified by ACOG often belong to a specific medical society named  Society for Reproductive Endocrinology and Infertility  (SREI). As a condition of full membership, medical practitioners must be ACOG-certified in the reproductive endocrinology and infertility subspecialty. [ 5 ]


Also, many  academic journals in obstetrics and gynaecology  dedicate many articles to reproductive endocrinology and infertility.


Retained placenta  is a condition in which all or part of the  placenta  or membranes remain in the  uterus  during the third stage of  labour . [ 1 ]  Retained placenta can be broadly divided into:


A retained placenta is commonly a cause of postpartum  haemorrhage , both primary and secondary. [ 1 ]


Retained placenta is generally defined as a placenta that has not undergone  placental expulsion  within 30 minutes of the baby’s birth where the third stage of labor has been managed actively. [ 2 ]


Risks of retained placenta include hemorrhage and infection. After the placenta is delivered, the uterus should contract down to close off all the blood vessels inside the uterus. If the placenta only partially separates, the uterus cannot contract properly, so the blood vessels inside will continue to bleed. A retained placenta thereby leads to hemorrhage. [ 3 ]


Drugs, such as intraumbilical or intravenous oxytocin, are often used in the management of placental retention. [ 4 ]  It is useful ensuring the bladder is empty. [ 2 ]  However,  ergometrine  should not be given as it causes tonic uterine contractions which may delay placental expulsion. [ 2 ]  Controlled  cord traction  has been recommended as a second alternative after more than 30 minutes have passed after stimulation of uterine contractions, provided the uterus is contracted. [ 2 ]  Manual extraction may be required if cord traction also fails, [ 2 ]  or if heavy ongoing bleeding occurs. There is currently uncertainty about the effectiveness of anaesthesia or analgesia for manual extraction, in terms of pain and the risk of postpartum haemorrhage. [ 5 ]  Very rarely a curettage is necessary to ensure that no remnants of the placenta remain (in rare conditions with very adherent placenta such as a  placenta accreta ).


However, in birth centers and attended home birth environments, it is common for licensed care providers to wait for the placenta's birth up to 2 hours in some instances.


Retention  of  fetal membranes  (afterbirth) is observed more frequently in cattle than in other animals. In a normal condition, a cow’s placenta is expelled within a 12-hour period after calving. [ 6 ]


Rh disease  (also known as  rhesus  isoimmunization ,  Rh (D) disease , or  rhesus incompatibility , and blue baby disease) is a type of  hemolytic disease of the fetus and newborn  (HDFN).  HDFN due to anti-D antibodies is the proper and currently used name for this disease as the Rh blood group system actually has more than 50 antigens and not only the D-antigen. The term "Rh Disease" is commonly used to refer to HDFN due to anti-D antibodies, and prior to the discovery of anti-Rh o (D)  immune globulin, it was the most common type of HDFN. The disease ranges from mild to severe, and occurs in the second or subsequent pregnancies of  Rh-D negative  women when the biologic father is Rh-D positive.


Due to several advances in modern medicine, HDFN due to anti-D is preventable by treating the mother during pregnancy and soon after delivery with an  injection  of  anti-Rh o (D) immune globulin  (Rhoclone, Rhogam, AntiD).  With successful mitigation of this disease by prevention through the use of anti-Rh o (D)  immune globulin, other antibodies are more commonly the cause of HDFN today.


During pregnancy, there is normally a barrier between maternal and fetal blood called the placenta, a temporary organ that connects a mother’s uterus to the umbilical cord to provide nutrients and oxygen to the fetus. However, in certain circumstances, small amounts of fetal blood cells may enter the mother’s circulation. Certain types of events where this occurs are during childbirth, miscarriage or abortion, trauma, and invasive procedures such as amniocentesis. Once the fetal Rh-positive red blood cells enter the bloodstream of a Rh-negative mother, they are recognized as foreign. The mother’s immune system reacts to the Rh-positive red blood cells the same way that it would respond to something like a virus or bacteria, activating B cells — a type of white blood cell that is key to the triggering of an immune response. These activated B cells then differentiate into plasma cells, which produce anti-D antibodies. After the primary exposure, some of these B cells become memory cells, that remember the original exposure and produce IgG antibodies, which are smaller and can cross the placental barrier. Once they cross this barrier, they are into the fetal bloodstream, binding to fetal Rh-positive cells, triggering opsonization, which marks the red blood cells for destruction. The fetal spleen and liver then begin to break down those red blood cells, thinking that they are a foreign invader when in reality they are they are just mismatched. [ 1 ]


Symptoms of Rh disease include yellowish amniotic fluid and enlarged spleen, liver or heart or buildup of fluid in the abdomen of the fetus. [ 2 ]


During the first pregnancy, the Rh- mother's initial exposure to fetal Rh+ red blood cells (RBCs) is usually not sufficient to activate her Rh-recognizing B cells. However, during delivery, the placenta separates from the uterine wall, causing umbilical cord blood to enter the maternal circulation, which results in the mother's proliferation of IgM-secreting plasma B cells to eliminate the fetal Rh+ cells from her blood stream.  IgM   antibodies  do not cross the  placental barrier , which is why no effects to the fetus are seen in first pregnancies for Rh-D mediated disease. However, in subsequent pregnancies with Rh+ fetuses, the IgG memory B cells mount an immune response when re-exposed, and these  IgG  anti-Rh(D) antibodies  do  cross the placenta and enter  fetal circulation . These antibodies are directed against the  Rhesus (Rh) factor , a protein found on the surface of the fetal RBCs. The antibody-coated RBCs are destroyed by IgG antibodies binding and activating complement pathways. [ 4 ]


The resulting anemia has multiple sequelae: [ 5 ] [ 6 ] [ 7 ]


The destruction of RBCs leads to elevated bilirubin levels ( hyperbilirubinemia ) as a byproduct. This is not generally a problem during pregnancy, as the maternal circulation can compensate. However, once the infant is delivered, the immature system is not able to handle this amount of bilirubin alone and  jaundice  or  kernicterus  (bilirubin deposition in the brain) can develop which may lead to brain damage or death. Sensitizing events during pregnancy include  c-section ,  miscarriage ,  therapeutic abortion ,  amniocentesis ,  ectopic pregnancy , abdominal trauma and  external cephalic version . However, in many cases there was no apparent sensitizing event. Approximately 50% of Rh-D positive infants with circulating anti-D are either unaffected or only mildly affected requiring no treatment at all and only monitoring. An additional 20% are severely affected and require transfusions while still in the uterus. This pattern is similar to other types of HDFN due to other commonly encountered antibodies (anti-c, anti-K, and Fy(a)). [ citation needed ]


In the United States, it is a standard of care to test all expecting mothers for the presence or absence of the RhD protein on their RBCs. However, when medical care is unavailable or prenatal care not given for any other reason, the window to prevent the disease may be missed. In addition, there is more widespread use of molecular techniques to avoid missing women who appear to be Rh-D positive but are actually missing portions of the protein or have hybrid genes creating altered expression of the protein and still at risk of HDFN due to Anti-D. [ 8 ] [ 9 ]


Blood is generally drawn from the biological father to help determine fetal antigen status. [ 11 ]  If he is homozygous for the antigen, there is a 100% chance of all offspring in the pairing to be positive for the antigen and at risk for HDFN. If he is heterozygous, there is a 50% chance of offspring to be positive for the antigen. [ 12 ]


The protection that is offered today against Rh incompatibility involved preventive measures that primarily utilize Rh immunoglobulin, also known as RhoGAM. [ 13 ]  The aim of these treatments are to prevent the mother’s immune system from becoming sensitized to the Rh antigen, which reduces the risk of hemolytic disease in future pregnancies. RhoGAM, Rh Immunoglobulin Administration, is a product that contains antibodies to the Rh D antigen, it is used to prevent the mother from developing an immune response to fetal red blood cells. RhIg ‘coats’ any Rh-positive fetal red blood cells that enter the mother’s bloodstream, effectively ‘hiding’ them from the mother’s immune system. RhoGAM is typically administered at around 28 weeks of pregnancy, then again within 72 hours after childbirth. It is also given during other events that happen during pregnancy like miscarriages, ectopic pregnancies, amniocentesis, and abdominal trauma  [ 14 ]


In Arar, Saudi Arabia, results of a study showed that women had a low level of knowledge regarding maternal-fetal blood incompatibility (about 38% of the studied mothers during the research, had knowledge about Rh incompatibility). Regarding their knowledge about anti-D, researchers found that; 68.5% of the mothers had knowledge about it, while only 51% of the mothers had knowledge about the administration of prophylactic anti D after delivery. [ 15 ]


As medical management advances in this field, it is important that these patients be followed by high risk obstetricians/maternal-fetal medicine, and skilled neonatologists postpartum to ensure the most up to date and appropriate standard of care [ citation needed ]


In 1939 Drs.  Philip Levine  and  Rufus E. Stetson  published their findings about a 25-year-old mother who had a  stillborn  baby that died of  hemolytic disease of the newborn . [ 19 ]  Both parents were  blood group  O, so the husband's blood was used to give his wife a  blood transfusion  due to blood loss during delivery. However, she had a severe  transfusion reaction . Since both parents were blood group O, which was believed to be compatible for transfusion, they concluded that there must be a previously undiscovered blood group  antigen  that was present on the husband's red blood cells (RBCs) but not present on his wife's. This suggested for the first time that a mother could make blood group antibodies because of immune sensitization to her  fetus 's RBCs as her only previous exposure would be the earlier pregnancy. They did not name this blood group antigen at the time, which is why the discovery of the  rhesus  blood type is credited to Drs.  Karl Landsteiner  and  Alexander S. Wiener [ 20 ]  with their first publication of  their tables  for  blood-typing  and cross-matching in 1940, which was the culmination of years of work. However, there were multiple participants in this scientific race and almost simultaneous publications on this topic. Levine published his theory that the disease known as erythroblastosis fetalis was due to Rh alloimmunization in 1941 while Landsteiner and Wiener published their method to type patients for an antibody causing transfusion reactions, known as “Rh". [ 21 ] [ 22 ] [ 23 ]


The first treatment for Rh disease was an  exchange transfusion  invented by Wiener [ 24 ]  and later refined by Dr. Harry Wallerstein. [ 25 ]  Approximately 50,000 infants received this treatment. However, this could only treat the disease after it took root and did not do anything to prevent the disease. In 1960,  Ronald Finn , in  Liverpool , England proposed that the disease might be prevented by injecting the at-risk mother with an antibody against fetal red blood cells (anti-RhD). [ 26 ]  Nearly simultaneously, Dr. William Pollack, [ 27 ]  an immunologist and protein chemist at  Ortho Pharmaceutical Corporation , and Dr. John Gorman (blood bank director at Columbia-Presbyterian) with Dr. Vincent Freda (an obstetrician at  Columbia-Presbyterian Medical Center ), came to the same realization in New York City. The three of them set out to prove it by injecting a group of male prisoners at  Sing Sing Correctional Facility  with antibody provided by Ortho, obtained by a fractionation technique developed by Pollack. [ 28 ]


Animal studies had previously been conducted by Dr. Pollack using a rabbit model of Rh. [ 29 ]  This model, named the rabbit HgA-F system, was an animal model of human Rh, and enabled Pollack's team to gain experience in preventing hemolytic disease in rabbits by giving specific HgA antibody, as was later done with Rh-negative mothers. One of the needs was a dosing experiment that could be used to determine the level of circulating Rh-positive cells in an Rh-negative pregnant female derived from her Rh-positive fetus. This was first done in the rabbit system, but subsequent human tests at the University of Manitoba conducted under Dr. Pollack's direction confirmed that anti-Rh o (D) immune globulin could prevent alloimmunization during pregnancy. [ citation needed ]


Ms. Marianne Cummins was the first at risk woman to receive a prophylactic injection of anti-Rh o (D) immune globulin (RHIG) after its regulatory approval. [ 30 ]  Clinical trials were set up in 42 centers in the US, Great Britain, Germany, Sweden, Italy, and Australia. RHIG was finally approved in England and the United States in 1968. [ 31 ]  The FDA approved the drug under the brand name RhoGAM, with a fixed dose of 300 μg, to be given within three days (72 hours) postpartum. Subsequently, a broader peripartum period was approved for dosing which included prophylaxis during pregnancy. Within a year, the antibody had been injected with great success into more than 500,000 women. Time magazine picked it as one of the top ten medical achievements of the 1960s. By 1973, it was estimated that in the US alone, over 50,000 babies' lives had been saved. The use of Rh immune globulin to prevent the disease in babies of Rh negative mothers has become standard practice, and the disease, which used to claim the lives of 10,000 babies each year in the US alone, has been virtually eradicated in the developed world. In 1980,  Cyril Clarke ,  Ronald Finn ,  John G. Gorman , Vincent Freda, and William Pollack each received an  Albert Lasker Award  for Clinical Medical Research for their work on rhesus blood types and the prevention of Rh disease. [ citation needed ]


Rh o (D) immune globulin  ( RhIG ) is a medication used to prevent  RhD isoimmunization  in mothers who are  RhD negative  and to treat  idiopathic thrombocytopenic purpura  (ITP) in people who are  Rh positive . [ 2 ]  It is often given both during and following  pregnancy . [ 2 ]  It may also be used when RhD-negative people are given RhD-positive blood. [ 2 ]  It is given by  injection into muscle  or a  vein . [ 2 ]  A single dose lasts 12 weeks. [ 2 ]  It is made from  human blood plasma . [ 3 ]


Common side effects include  fever , headache, pain at the site of injection, and  red blood cell breakdown . [ 2 ]  Other side effects include  allergic reactions ,  kidney problems , and a very small risk of viral infections. [ 2 ]  In those with ITP, the amount of red blood cell breakdown may be significant. [ 2 ]  Use is safe with  breastfeeding . [ 2 ]  Rho(D) immune globulin is made up of  antibodies  to the  antigen  Rh o (D) present on some  red blood cells . [ 2 ]  It is believed to work by blocking a person's immune system from recognizing this antigen. [ 2 ]


Rh o (D) immune globulin came into medical use in the 1960s, [ 4 ]  following the pioneering work of  John G. Gorman . In 1980, Gorman shared the  Lasker-DeBakey Clinical Medical Research Award  for pioneering work on the  rhesus blood group system . [ 5 ]


RhIG is on the  World Health Organization's List of Essential Medicines . [ 6 ] [ 7 ]


Even in normal pregnancies, a small number of fetal blood cells enters the maternal bloodstream (fetomaternal hemorrhage). If a mother is RhD negative, but the fetus is RhD positive, the mother's immune system may develop an immune response (develops  antibodies ) to the unfamiliar RhD antigens from the fetus. This process is called  RhD alloimmunization . Alloimmunization usually has minimal effect on the first such pregnancy; but, in a second such pregnancy, pre-existing maternal RhD IgG antibodies can cross the placenta in enough amounts to damage fetal red blood cells. This condition is called  erythroblastosis fetalis  and can be fatal to the fetus. [ 8 ]


The RhD status of the fetus is determined by genetic inheritance. In a pregnancy where the mother is RhD negative and the father is RhD positive, the probability of the fetus having RhD positive blood is dependent on whether the father is  homozygous  for RhD (i.e., both RhD alleles are present) or  heterozygous  (i.e., only one RhD allele is present). If the father is homozygous, the fetus will necessarily be RhD positive, as the father will necessarily pass on a RhD positive allele. If the father is heterozygous, there is a 50% chance that the fetus will be RhD positive, as he will randomly pass on either the RhD positive allele or not. [ 9 ] : 130  . Not all Rh-negative patients are capable of being immunized to the RhD antigen, and mothers may only become immunized after many repeated pregnancies. The risk of  hemolytic disease  (including due to RhD) significantly increases if the mother has had a past transfusion of Rh-positive blood.  [ 10 ]


Exposure to fetal blood cells that can cause RhD alloimmunization can happen during normal pregnancy and delivery, miscarriage, amniocentesis, cordocentesis, chorionic villus sampling, external cephalic version, or trauma. [ 3 ] [ 8 ]  92% of women who develop an anti-D during pregnancy do so at or after 28 weeks gestation. [ 11 ] [ 9 ] [ 12 ]


In an RhD negative mother, RhIG can temporarily prevent sensitization of the maternal immune system to RhD  antigens , with each 100 μg of anti-D being able to neutralize about 4 mL of fetal blood. [ 13 ]  With the widespread use of RhIG,  Rh disease  of the  fetus  and  newborn  has almost disappeared in the developed world. The risk that an RhD negative mother can be  alloimmunized  by a RhD positive fetus can be reduced from approximately 16% to less than 0.1% by the appropriate administration of RhIG. [ 11 ] [ 9 ] [ 14 ]  In data collected from communities in Canada, without treatment as many as 14% of affected fetuses are stillborn, 30% of affected live births almost certainly fatal without treatment, and 30% with severe  jaundice  that untreated risks brain damage from  kernicterus . [ 8 ]
 [ 15 ] . Prior to effective transfusion therapy, the mortality rate of hemolytic disease was 70-80%, dropping to 30-50% with small transfusions and 13-33% for more aggressive transfusions before RhIg treatments were introduced.  [ 10 ]


The  American College of Obstetricians and Gynecologists  (ACOG) recommends that all RhD negative mothers, regardless of fetal blood type, receive RhIG at about 28 weeks gestation, and again shortly after delivery in the case of an RhD positive or RhD unknown baby. [ 16 ]  It should be given within 3 days of a potential exposure to Rh positive blood from the baby such as may occur during second and third trimester miscarriage, amniocentesis, cordocentesis, chorionic villus sampling, external cephalic version, trauma, or delivery (amounts detailed in the next section). [ 8 ]  It is given by intramuscular injection as part of modern routine  antenatal  care. Despite excellent results, the medication retains an FDA  Pregnancy Category  C. [ citation needed ]


RhIG is recommended in the UK after antenatal pathological events that are likely to cause a feto–maternal hemorrhage. Applicable 'pathologic events' include accidents that may induce fetomaternal hemorrhage (motor vehicle accidents, falls, abdominal trauma), following obstetric/gynecologic procedures during pregnancy, and at the time of threatened- or spontaneous-/elective  abortions , regardless of gestational age. RhIG is also recommended after normal delivery, with amounts detailed in the next section. [ 13 ]


There is insufficient evidence that the use of Rho(D) immune globulin after a spontaneous miscarriage is needed and a  Cochrane review  recommends that local practices be followed. [ 17 ]


Rh immune globulin is composed of IgG antibodies and therefore is able to cross the placenta. In rare cases this can cause a baby to have a weakly positive  direct antiglobulin test  (DAT) due to sensitization of fetal cells from mothers who have received multiple doses of RhIG. However, no treatment is necessary as the clinical course is benign. [ 18 ]