Operative vaginal delivery is required in times of maternal or  fetal distress  to assist in  childbirth  as an alternative to  caesarean section . [ 2 ]  Its use has decreased over the years in comparison to caesarean section. [ 2 ] [ 3 ]  The two main instruments used are rotational forceps and vacuum extractors, each with different complication risks. Possible complications introduced with the use of instruments for the mother include  pelvic floor  injury,  anal sphincter injury , bleeding, or cuts. [ 4 ] [ 5 ]  Possible complications to the infant include bruising to the scalp, retinal bleeding, and scrapes to the scalp and face. [ 5 ] [ 6 ]


When  fetal distress  occurs during the second stage of labor, operative vaginal delivery may be used in place of  caesarean section  which may pose additional risks after birth has progressed and the fetal head is deep in the  birth canal . Maternal exhaustion and fetal distress would also be indications for appropriate use of operative vaginal delivery. [ 2 ]


An analysis of multiple studies found that detecting the angle of the fetal head using an  ultrasound  is a reliable way to predict where uncomplicated operative vaginal delivery can be used, especially in first-time mothers. [ 7 ]


Definite contraindication include non-engagement of the fetal head, unknown fetal position, cervix not fully dilated, membranes not ruptured, known loss of minerals from fetal bone, and fetal disorders. [ 8 ]


Relative contraindication include less than 34 weeks of pregnancy, and less than 2400 grams of the total fetal weight. [ medical citation needed ]


Discharge from the hospital after operative vaginal delivery (2–3 days) is faster than after a  caesarean section , which requires 4 days for discharge. It is suggested that this decrease in in-hospital recovery time reflects a decrease in pain and an increase in post-birth mobility for the mother. [ 9 ]  Using operative vaginal delivery avoids the risks associated with repeat caesarian sections or vaginal births after caesarian sections for women who want to have additional pregnancies. [ 9 ]
Compared to caesarean section, operative vaginal delivery have been more beneficial, and has been recognized  to have a reduction in complications such as death,  venous thromboembolism , costs of procedure, time of recovery and infection. [ 10 ]


The process of operative vaginal delivery can cause damage to the  pelvic floor  and anal sphincter. Obstetric anal sphincter injury (OASI) is a complication that can lead to short term morbidity and long term loss of bowel movement control. OASI is observed in about 5.7% of first time mothers and 1.5% in people who have given birth before with no prior OASI. [ 4 ]   In an 8-year study done at sub-Saharan hospitals, out of 100,307 vaginal deliveries, 2.1% resulted in OASI with forceps delivery found to have a higher incidence rate of 8.6% compared to 1.3% in normal vaginal deliveries. [ 11 ]


While there does not appear to be a difference in long-term bowel or pelvic floor-related symptoms, studies of deliveries using forceps appear to show an association with being at an increased risk of long-term  fecal incontinence . [ 12 ]  Forceps also have been shown to cause facial injury to the fetus and further significant injury to the mother via third‐ or fourth‐degree tears, vaginal trauma, and fecal incontinence. Although vacuum extractions can cause less injuries to the mother, it can cause more injury to the fetus via scalp injury and  cephalhaematoma . [ 6 ]  Studies suggest that performing a  episiotomy  can reduce the risk of OASI in both forceps and vacuum-assisted deliveries. [ 13 ]


Additionally, operative vaginal delivery increases the risk for  postpartum hemorrhage  and  venous thromboembolism . [ 5 ]


While statistics specific to  PTSD  following operative vaginal delivery are not available, studies show that 3-4% of all women and 20% of women in high risk groups will develop post traumatic stress disorder after birth. Operative deliveries are recognized as a risk factor for PTSD. [ 14 ]


One of the risks of operative vaginal delivery for the newborn, more common with the use of a vacuum, is  cephalohematoma , or bruising under the scalp. [ 5 ]  Extensive bruising may increase the likelihood of clinically significant  hyperbilirubinemia . [ 15 ]  Most of the time increased levels of total serum bilirubin in newborns is a harmless occurrence, however with high enough levels there would be a concern for brain damage. [ 15 ]


Infants delivered by vacuum extraction have a higher rate of  retinal hemorrhage  compared to infants delivered without instrument assistance. [ 16 ]  It is believed that suction on the head increases intracranial pressure which may cause an increase in arterial blood pressure in the eye leading to retinal bleeding. [ 16 ]


Newborns undergoing operative delivery have a higher likelihood of experiencing  shoulder dystocia , a delivery emergency that may lead to further injury such as brachial plexus palsy. [ 17 ] [ 18 ]  Scalp and facial injuries leading to fractures and bleeding may be possible. [ 5 ]


Operative vaginal delivery has decreased as second stage caesarean section has become more common, [ 2 ]  in the United Kingdom 12.7% of women and up to 25% of first time mothers undergo operative vaginal delivery as of 2019. [ 14 ]  Globally, this percentage decreases to 2.6%. [ 19 ]  Between 2005 and 2013, 1.1% of vaginal deliveries in the United States were forceps-assisted. [ 3 ]


The procedure relies primarily on either a pair of  curved forceps blades  or a vacuum extractor that applies negative pressure inside the womb. The forceps are designed to reach the top of the fetal head and create the necessary traction to pull and rotate the baby out. On the other hand, the vacuum extractor uses a small metal or silicon cap that exerts negative pressure on the fetal scalp to facilitate pulling of the infant. [ 20 ]  Since vacuum extraction can cause less injuries to the mother than forceps-assisted delivery, it is the preferred technique in some countries. [ 21 ]


Rotational forceps are used to turn the head of the fetus so that it is in the correct position. [ 22 ]  Rotational forceps, also referred to as Kielland's forceps, were first described by Norwegian obstetrician  Christian Kielland  in 1908. Their use declined during the twentieth century because they were associated with risks to the mother and baby; however, both the  American Congress of Obstetricians and Gynecologists  and  Royal College of Obstetricians and Gynaecologists  (RCOG) from the United Kingdom support the use of rotational forceps by practitioners who have the experience and skill to do so. Neither organization has specific training guidelines, although the RCOG suggests that training should include direct senior supervision and an assessment of skills in the workplace. [ 9 ]


An analysis of 4 studies showed that the use of rotational forceps had low rates of  postpartum hemorrhage  and  obstetric anal sphincter injury  to the mother. Additionally, neonatal complication rates were similar to those seen with other methods for assisted birth, such as the use of a vacuum cup, manual rotation, or second-stage cesarean section. [ 9 ]


An additional analysis of 31 studies found that forceps were more likely to lead to vaginal birth than vacuum cups, but were more likely to have perineal tears to the anus or rectum. There was no difference in  postpartum hemorrhage  rates for the mother and no difference in  Apgar scores  to the baby post birth. [ 5 ]


Vacuum suction can have either rigid or flexible cups, and can be operated with handheld devices or a foot-operated electric pump. Evidence suggests that rigid cups may have higher success rates than soft cups, but may be more likely to cause fetal trauma. [ 5 ]


Injuries such as tears, cuts, or bruises to the birth canal, cervix, anus, or vaginal openings will be assessed and addressed. For example, tears to the vaginal openings will be stitched to prevent blood loss. [ 23 ]


Physical exam, hearing and vision tests, imaging will be assessed for the neonate for any signs of trauma. [ 24 ]  When forceps are used for operative vaginal delivery, the recovery process takes a little longer. When there are injuries such as tears, it takes about six weeks to heal. Stitches used for vaginal openings takes a month to fully absorb before they start disappearing completely. Wearing a postpartum  pad  is recommended when there is bleeding and to prevent infections. Healthcare providers should be consulted if excess pain occurs so that pain medications can be prescribed or gotten over-the-counter. [ better source needed ]   [ 25 ]


Operative vaginal delivery presents an opportunity for infection due to trauma to the tissue, vaginal examination and instrumentation, and  bladder catheterization  with 0.7–16% of operative vaginal births leading to infections. Guidelines from the  World Health Organization  (WHO) support the use of  intravenous antibiotics  for the mother as soon as possible after birth but can be used up to within 6 hours after birth. The recommended antibiotic combination would be  amoxicillin and clavulanic acid , but if they are not available antibiotics with similar activity can be used. [ 26 ]  Due to the use of either forceps or vacuum in operative vaginal deliveries, there has been an increase in maternal infection and in some cases, readmission after delivery due to the infection. The effectiveness of antibiotic  prophylaxis  was studied in both the use of either forceps or vacuum in operative delivery to reduce the risk of infection. The result showed that antibiotic prophylaxis has been shown to effectively reduce infections in operative vaginal deliveries, and should be used. [ 27 ]


The concept of forceps for vaginal delivery was invented by Peter Chamberlin in the 1600 which helped became the instrument used in operative vaginal delivery. The use of this instrument for operative vaginal delivery dates back to the 1600's. Throughout history, over 700 types of forceps have been reinvented and gone through modifications to make sure forceps are safe in operative vaginal delivery. [ 28 ]  Half of first-time mothers had forceps-assisted deliveries in the 1960s. [ 5 ]


The vacuum extractor was developed in the mid-1900s, and its use in delivery became more common than forceps in 1992. [ 5 ]  James Young Simpson in 1849 invented the air tractor used in vacuum extraction to help with operative vaginal delivery. In the early 1950's, Tage Malmstrom developed a modern vacuum extraction that came with modifications for delivery. [ 29 ]


A  parity progression ratios  (PPR) is a measure commonly used in demography to study  fertility .  The PPR is simply the  proportion  of women with a certain number of children who go on to have another child.
Calculating the PPR, also known as

 a

 x

 {\displaystyle a_{x}}

 , can be achieved by using the following  formula :


a

 x

 =

 (women with at least

 x
 +
 1

  children ever born)

 /

  (women with at least

 x

  children ever born)

 {\displaystyle a_{x}={\text{(women with at least }}x+1{\text{ children ever born) }}/{\text{ (women with at least }}x{\text{ children ever born)}}}

 [ 1 ]


In more  developed countries  where two-child families are seen as the norm

 a

 2

 {\displaystyle a_{2}}

  (or the proportion of women with two children who go on to have a third) is of critical importance in determining overall fertility levels.


a

 0

 {\displaystyle a_{0}}

  is simply the proportion of women who become mothers.


Changing hormone levels during pregnancy and postpartum as well as parental experience cause changes in the parental brain. Both the father and mother undergo distinct biological changes as they transition to parents, but the changes that occur in the  paternal brain  are not as well studied. Similar to the changes that occur in the maternal brain, the same areas of the brain ( amygdala ,  hypothalamus ,  prefrontal cortex ,  olfactory bulb  etc.) are activated in the father, and hormonal changes occur in the paternal brain to ensure display of parenting behavior. In only 5% of  mammalian  species, including humans, the father plays a significant role in caring for his young. Paternal caregiving has independently evolved multiple times in mammals, and can appear in some species under captivity. [ 1 ]


Paternal behavior in humans takes many forms, including feeding, carrying, and playing with one's child. [ 2 ]


The same neural systems that motivate maternal behavior also are responsible for paternal behaviors. There is evidence for this in rodents; the same neurons in a small region of the hypothalamus responsible for maternal behavior is also responsible for paternal behavior. Specifically,  galanin  neurons in the  medial preoptic area  of the  hypothalamus  are responsible for parental motivation. The  medial preoptic area  activates the  mesolimbic dopamine  system, typically a reward pathway but is also responsible for motivation to approach offspring. [ 3 ]  Parental empathy is thought to rely on the thalamocingulate pathway. [ 4 ]  These brains areas and others are activated and made sensitive to infants with changing hormonal levels and increased sensitivity to hormones by up-regulating hormonal receptors. [ 1 ]


The embodied simulation network (anterior insula; premotor areas; inferior parietal lobule) are significantly activated in the paternal brain while watching or hearing their own infants compared to unknown infants. [ 5 ]


In humans, in addition to the subcortical areas there is recruitment of higher order neural systems to respond to infant cues such as the  neocortex  and the  prefrontal cortex . [ 4 ]


fMRI studies have looked at brain activation in response to cues such as a baby's cry and show that this exposure activates the  prefrontal cortex  and the  amygdala  in both fathers and mothers, but not in non-parents.


Fathers show activation of the emotional regulation network, just like mothers, as seen in activation of the anterior insula, inferior frontal gyrus, hippocampus, and medial prefrontal cortex. [ 5 ]  This network is associated with caregiving sensitivity, and may become more robust through direct involvement in caregiving.


Fathers show activation in mentalization-related brain areas in response to their infant. These regions are important for processing others' emotional cues and mental states, allowing fathers to understand and process the emotional state of their infant. [ 5 ]


Changes in  neurogenesis  in the  prefrontal cortex  of the paternal brain have been linked in some species to recognition of kin. In father rats, just as in the mother rats, a decrease in  neurogenesis  in the  hippocampus  occurs  postpartum . Just like in mothers, fathers also have increased levels of  glucocorticoids  which are thought to suppress the production of new cells in the brain.


Marmoset  fathers have enhanced dendritic spine density in the  prefrontal cortex . This increase correlates with increase in  vasopressin  receptors in this area of the paternal brain. With age, this effect is reversed, and is therefore believed to be driven by father-infant interactions.


Human males show changes in gray matter and cortical thickness after becoming fathers. [ 6 ]  After becoming fathers, males show decreases in gray matter volume in the orbitofrontal cortex, posterior cingulate cortex and insula, and show increases in gray matter volume in the hypothalamus, amygdala and striatum and lateral prefrontal cortex, regions that are important for parental motivation. [ 7 ]


An increase in levels of  oxytocin ,  glucocorticoids ,  estrogen  and  prolactin  occur in the paternal brain. These hormonal changes occur through the father's interaction with the mother and his offspring.


Testosterone  levels have been shown to decrease with the onset of parenthood. Fathers experience large declines in both waking and evening levels of testosterone in comparison to nonfathers. [ 8 ]  Childcare has been shown to correlate with declining levels of testosterone, with more time spent with the child corresponding to a greater decline in testosterone. [ 8 ]  This relationship also has been found in fathers that  cosleep  with their child. [ 9 ]  The level of  testosterone  in the paternal brain also correlates with the effectiveness of the father's response to the baby's cry.


Oxytocin  has been shown to correlate with many aspects of paternal care, but its mechanisms and the systems involved are not fully understood. Oxytocin is associated with behaviors involving contact with the child. Increases in oxytocin following high contact interactions have been shown in correlational studies. [ 10 ]  Oxytocin's interactions with other hormones is thought to be responsible for creating variability in parent behaviors such as sensitivity to infant cues and parent-child synchrony. It is being researched as a possible area for intervention in parents that are considered high risk (premature birth, postpartum depression, environmental conditions). [ 11 ]


Prolactin  levels rise in males after becoming fathers in many species, including those that do not lactate. [ 12 ]  They are highest during the infantile period of the offspring, and positively correlate with caregiving. Increased prolactin corresponds to different behavioral changes in different species. In some bird species it is shown to correlate with increased gathering of resources. In humans, it has been shown to correlate with many aspects of care such as the level of involvement in care and increased exploratory play with the child. [ 13 ]  Increased levels of  prolactin  in the paternal brain has also been correlated with a more positive response to the infant's cry.


Experienced fathers of newborns show a significantly greater increase in prolactin after hearing their baby's cries or holding their babies than first-time fathers, suggesting that learning is important for males to develop responsiveness. [ 14 ]


In prairie voles, the neuropeptide  vasopressin  was found to induce paternal behaviors in virgin-offspringless males suggesting it has a critical role. [ 15 ]


Cortisol concentrations are highest just prior to birth in both mothers and fathers. [ 16 ]  Higher basal cortisol and higher cortisol in response to holding the infant is associated with greater paternal behavior in men. [ 17 ]


The term  physiological prematurity  (also described as  altriciality ) refers to the fact that compared to most animals, humans are born in a premature biological state. Although  sensory organs  and skeletal and muscular systems are largely developed prenatally, human babies at the time of their  birth  are completely helpless and dependent on intensive care. This is in contrast to the maturity at birth found in other higher  mammals  (e.g. elephants, horses).


According to the Swiss biologist  Adolf Portmann , it is a characteristic feature of humans that due to their early birth, many developmental processes do not happen in isolation, but embedded in a sociocultural environment. Due to their complete dependence, humans are particularly amenable for social interactions and their environmental condition, which, according to Portmann, is a precondition for cultural and intellectual learning.


Popularly called the  fourth trimester  of pregnancy, using a label coined by US pediatrician  Harvey Karp  in his book  The Happiest Baby on the Block , the relative underdevelopment of human newborns compared to other primates is believed to be due to evolutionary pressures related to  walking upright . [ 1 ]


Placenta accreta  occurs when all or part of the  placenta  attaches abnormally to the  myometrium  (the muscular layer of the  uterine wall ). Three grades of abnormal placental attachment are defined according to the depth of attachment and invasion into the muscular layers of the uterus:


Because of abnormal attachment to the myometrium, placenta accreta is associated with an increased risk of heavy bleeding at the time of attempted vaginal delivery. The need for transfusion of blood products is frequent, and surgical removal of the uterus ( hysterectomy ) is sometimes required to control life-threatening bleeding. [ 1 ]


Rates of placenta accreta are increasing. As of 2016, placenta accreta affects an estimated 1 in 272 pregnancies. [ 2 ]


An important risk factor for placenta accreta is  placenta previa  in the presence of a uterine scar. Placenta previa is an independent risk factor for placenta accreta. Additional reported risk factors for placenta accreta include maternal age and  multiparity , other prior  uterine surgery , prior uterine curettage, uterine irradiation,  endometrial ablation , Asherman syndrome,  uterine leiomyomata ,  uterine anomalies , and smoking.


The condition is increased in incidence by the presence of  scar tissue  i.e.  Asherman's syndrome  usually from past uterine surgery, especially from a past  dilation and curettage , [ 3 ]  (which is used for many indications including  miscarriage ,  termination , and  postpartum hemorrhage ),  myomectomy , [ 4 ]  or  caesarean section . A thin  decidua  can also be a contributing factor to such  trophoblastic  invasion. Some studies suggest that the rate of incidence is higher when the  fetus  is female. [ 5 ]  Other risk factors include low-lying placenta, anterior placenta, congenital or acquired uterine defects (such as  uterine septa ),  leiomyoma , ectopic implantation of placenta (including  cornual pregnancy ). [ 6 ] [ 7 ] [ 8 ]


Pregnant women above 35 years of age who have had a caesarian section and now have a placenta previa overlying the uterine scar have a 40% chance of placenta accreta. [ 9 ]


The placenta forms an abnormally firm and deep attachment to the uterine wall. There is absence of the  decidua basalis  and incomplete development of the  Nitabuch's layer . [ 10 ]  There are three forms of placenta accreta, distinguishable by the depth of penetration.


When the  antepartum  diagnosis of  placenta accreta  is made, it is usually based on  ultrasound  findings in the second or  third trimester . Sonographic findings that may be suggestive of  placenta accreta  include:


Unfortunately, the diagnosis is not easy and is affected by a significant interobserver variability. [ 11 ]  In doubtful cases it is possible to perform a  nuclear magnetic resonance  (MRI) of the pelvis, which has a very good sensitivity and specificity for this disorder. [ 12 ]   MRI findings associated with placenta accreta include dark T2 bands, bulging of the uterus, and loss of the dark T2 interface. [ 13 ]


Although there are isolated case reports of  placenta accreta  being diagnosed in the  first trimester  or at the time of abortion <20 weeks' gestational age, the predictive value of first-trimester ultrasound for this diagnosis remains unknown. Women with a  placenta previa  or "low-lying placenta" overlying a uterine scar early in pregnancy should undergo follow-up imaging in the third trimester with attention to the potential presence of  placenta accreta .


The exact incidence of maternal mortality related to placenta accreta and its complications is unknown, but it is significant, [ 14 ]  especially if the urinary bladder is involved [ 15 ]


Treatment may be delivery by caesarean section and abdominal  hysterectomy  if placenta accreta is diagnosed before birth. [ 16 ] [ 17 ]   Oxytocin  and  antibiotics  are used for post-surgical management. [ 18 ]  When there is partially separated placenta with focal accreta, removal of placenta may be reasonable if maternal status is stable. If it is important to save the woman's uterus (for future pregnancies) then resection around the placenta may be successful. Conservative treatment can also be uterus sparing but may not be as successful and has a higher risk of complications. [ 17 ]
Techniques include:


In cases where there is invasion of placental tissue and blood vessels into the bladder, it is treated in similar manner to abdominal pregnancy and manual placental removal is avoided. However, this may eventually need hysterectomy and/or partial  cystectomy . [ 10 ]


If the patient decides to proceed with a vaginal delivery, blood products for transfusion and an anesthesiologist are kept ready at delivery. [ 19 ]


The reported incidence of placenta accreta has increased from approximately 0.8 per 1000 deliveries in the 1980s to 3 per 1000 deliveries in the past decade.


Incidence has been increasing with increased rates of caesarean deliveries, with rates of 1 in 4,027 pregnancies in the 1970s, 1 in 2,510 in the 1980s, and 1 in 533 for 1982–2002. [ 20 ]  In 2002,  ACOG  estimated that incidence has increased 10-fold over the past 50 years. [ 8 ]  The risk of placenta accreta in future deliveries after caesarian section is 0.4-0.8%. For patients with  placenta previa , risk increases with number of previous caesarean sections, with rates of 3%, 11%, 40%, 61%, and 67% for the first, second, third, fourth, and fifth or greater number of caesarean sections. [ 21 ]


Post-maturity syndrome  is the condition of a baby born after a  post-term pregnancy , first described by Stewart H. Clifford in 1954. [ 1 ]  Post-maturity refers to any baby born after 42 weeks gestation, or 294 days past the first day of the mother's last menstrual period. Less than 6 percent of all babies are born after this time. [ 2 ]  The syndrome develops in about 20% of human pregnancies continuing past the expected delivery date. [ 3 ]


Features of post-maturity syndrome include  oligohydramnios  (a deficiency of  amniotic fluid ); [ 4 ]   meconium aspiration  (breathing  meconium  in the amniotic fluid); and  macrosomia  (being overly large). The syndrome also causes fetal problems like dry peeling skin, overgrown nails, abundant scalp hair, visible creases on palms and soles, absence of  vernix caseosa , loss of subcutaneous fat, and green or yellow skin colour due to  meconium  staining.


Post-maturity refers to any baby born after 42 weeks gestation or 294 days past the first day of the mother's last menstrual period. [ 2 ]  Although pregnancy is said to last nine months, health care providers track pregnancy by weeks and days. The estimated delivery date, also called the estimated due date or EDD, is calculated as 40 weeks or 280 days from the first day of the last menstrual period. Only 4 percent (1 in 20) women will deliver on their due date. [ 5 ]  The terms Post-maturity or "Post-term" are both words used to describe babies born after 42 weeks. The terms "post-maturity" and "post-term" are interchangeable. [ 6 ]  As there are many definitions for prolonged pregnancy the incidence varies from 2 to 10%. When incidence is taken as delivery beyond 42 weeks it is 10%, if it is taken according to the delivered baby's weight and length it is 2%. [ 7 ]


In most cases, continued fetal growth between 39 and 43 wk gestation results in an macrosomic, or overly large infant. However, sometimes the  placenta  involutes, and multiple  infarcts  and villous degeneration cause  placental insufficiency syndrome . In this syndrome, the fetus receives inadequate nutrients and oxygen from the mother, resulting in a thin (due to soft-tissue wasting), small-for-gestational-age, undernourished infant with depleted  glycogen  stores. The baby may have birth weight of 4 kg and length of 54 cm but these findings are variable, even the baby may have underweight. [ 7 ]


Post-maturity is more likely to happen when a mother has had a post-term pregnancy before. After one post-term pregnancy, the risk of a second post-term birth increases by 2 to 3 times. [ 8 ]  Other, minor risk factors include an older or obese mother, a white mother, male baby, or a family history of post-maturity. [ 9 ]  Maternal risks include  obstructed labor , perennial damage, instrumental  vaginal delivery , a  Cesarean section , infection, and  postpartum hemorrhage . [ 10 ]  Accurate pregnancy due dates can help identify babies at risk for post-maturity. Ultrasound examinations early in pregnancy help establish more accurate dating by measurements taken of the fetus. [ 6 ]  Pregnancies complicated by  gestational diabetes ,  hypertension , or other high-risk conditions should be managed according to guidelines for those conditions. [ 11 ]


Pregnancy and Infant Loss Remembrance Day  is an annual day of remembrance observed on October 15 for  pregnancy  loss and infant death, which includes  miscarriage ,  stillbirth ,  SIDS ,  ectopic pregnancy , termination for medical reasons, [ 1 ]  and the death of a  newborn . [ 2 ] [ 3 ]  Pregnancy and infant loss is a common experience that has historically been complicated by broadly applied social and cultural  taboos  to stay silent, a condition that the  World Health Organization  advocates reversing in favor of open expression. [ 4 ]  A growing number of public figures have come out in support of open expression, with many leading by example through the disclosure of their personal experiences of pregnancy loss and infant death. [ 5 ] [ 6 ] [ 7 ]


Pregnancy and Infant Loss Remembrance Day is observed in locations including Canada, [ 2 ]  United States, [ 8 ]  Australia, [ 3 ]  Ireland, [ 9 ]   and the United Kingdom. [ 10 ]  Recognition of the holiday has grown since the early 2000s. The day of remembrance includes candle-lighting vigils and a Wave of Light, a worldwide lighting of buildings and monuments. [ 9 ]


Pregnancy and Infant Loss Remembrance Day serves to promote greater awareness and support for the estimated 1 in 4 individuals and families whose lives are irrevocably altered by the death of their children during pregnancy, at birth, and in infancy. Experiences of loss vary for each individual and family unit; common effects include  depression ,  anxiety , changes in relationships, development of unhealthy coping mechanisms, and  Post Traumatic Stress Disorder (PTSD) . [ 11 ]  These effects are often underestimated, misunderstood, or overlooked by health care professionals, friends, and family members, especially when concerning pregnancy loss related bereavement and subsequent grief. [ 12 ] [ 13 ]


Advocates believe that formalized day of observation increases public awareness and promotes greater research and understanding to aide in the creation and establishment of programs, resources and services to support and provide assistance to survivors of baby loss and their families, enabling them to overcome their trauma and integrate their bereavement into their life in a healthy manner. [ 14 ]


In 2017, the  World Health Organization  (WHO) reported that there were 4.1 million deaths of infants that were less than one year old. [ 15 ]  WHO estimated an annual occurrence of 2.6 million stillbirths [ 16 ]  and between 17 and 22 percent of pregnancies that result in miscarriage. [ 17 ]  A growing number of public figures have disclosed their personal experiences of pregnancy loss and infant death including  Nicole Kidman ,  Whitney Huston ,  Gweneth Paltrow ,  Ali Wong ,  Michelle Obama ,  Chrissy Tiegan ,  John Legend ,  Meghan Duchess of Sussex  and  Mark Zuckerberg . [ 5 ] [ 6 ] [ 7 ] [ 18 ]


Individual citizens have worked with their representatives to introduce legislation at the municipal, state, provincial and national levels of government in an effort to have October 15 recognized as Pregnancy and Infant Loss Remembrance Day. As of March 2021, the day has been formally recognized in the United States, Canada, and Australia while the United Kingdom observes October 15 as part of their Baby Loss Awareness Week.


International Pregnancy and Infant Loss Remembrance Day is observed in several localities but is not universally recognized. Individuals, families, and organizations from around the world continue to promote greater public awareness of the prevalence of baby loss and the intense grief that often accompanies the experience. [ 11 ] [ 12 ]  The number of locations that officially observe October 15 as Pregnancy and Infant Loss Remembrance Day has grown since the early 2000s.


The official awareness colors of the cause are pink and blue [ 3 ] [ 9 ] [ 10 ]  and are used for the  campaign's awareness ribbon .


Founded in 2003, the Wave of Light invites baby loss families, friends, loved ones and supporting organizations from around the world to join in honor and remembrance on October 15 at 7:00 pm in all time zones. [ 10 ] [ 19 ]  Beginning in the first time zone, illuminations and candles remain lit for a period of at least one hour, with the next time zone lighting in its turn, moving westward as the Wave of Light circumnavigates the globe. Buildings, landmarks, monuments, and venues are illuminated [ 9 ]  while individuals, families, friends, and supporting organizations participate in lighting candles in remembrance. [ 10 ]


The  United States Congress , by Senate Joint Resolution 314, designated the month of October 1988 as "Pregnancy and Infant Loss Awareness Month and authorized and requested the President to issue a proclamation in observance of this month which  Ronald Reagan  then formalized on October 25, 1988. [ 20 ] [ 21 ]


In 2001, Robyn Bear, Lisa Brown, and Tammy Novak initiated a campaign and petitioned the federal government and state governors of the United States to make October 15 an official holiday titled Pregnancy and Infant Loss Remembrance Day. [ 22 ] [ 23 ] [ additional citation(s) needed ]  Concurrent Resolution 222, which supported the goals and ideals of National Pregnancy and Infant Loss Remembrance Day, was passed in the  U.S. House of Representatives  on September 28, 2006. [ 8 ]


According to the registered charity the  Stillbirth and Neonatal Death Society  (Sands), the first Baby Loss Awareness Day was held in the United Kingdom on October 15, 2002 after a group of parents were inspired by the Pregnancy & Infant Loss Remembrance Day in the United States. [ 19 ]  Baby Loss Awareness Week has been in observance in the UK from October 9–15, since 2003, [ 10 ] [ 24 ] [ 25 ]  when the event was expanded into a week, the same year the first official Wave of Light was observed in the UK. [ 19 ]


In 2016, Labor MP  Vicky Foxcroft  offered personal testimony in support of the week of remembrance. [ 25 ]


In 2005,  New Brunswick  was the first Canadian province to observe Pregnancy and Infant Loss Remembrance Day, an action granted by the  New Brunswick Department of Health and Wellness  on October 12, 2005. [ 14 ] [ better source needed ]  New Brunswick Minister of Health and Wellness  Elvy Robichaud  called on provincial residents to provide "support, education, and awareness for grieving parents who have lost children during pregnancy or shortly after birth" due to miscarriage and infant death being "a source of grief, often silent, for mothers, fathers, siblings, and grandparents." [ 27 ]


In 2008,  Manitoba  recognized the holiday through Bill 226. [ 28 ]  In 2015,  Ontario  enacted Bill 141 which designated October 15 as Pregnancy and Infant Loss Awareness Day, with support for further research and program development. [ 29 ]  In 2017,  Nova Scotia  began to observe the holiday on October 15, as Pregnancy and Infant Loss Awareness Day, via Bill 38. [ 30 ]


As of 2018, the holiday was nationally recognized in Canada. [ 31 ]


In May 2008, Nicole Ballinger of  New South Wales  (NSW) contacted her  Members of Parliament  (MPs) to request help in creating an official Pregnancy and Infant Loss Remembrance Day. [ 32 ]  Ballinger worked with MPs  Joanna Gash  and  Shelley Hancock  from 2008 to 2011 to get an official remembrance day declared. [ 33 ]  On 15 October 2011, Pregnancy and Infant Loss Remembrance Day was officially declared in NSW.


John and Kate De'Laney campaigned for recognition of Pregnancy and Infant Loss Remembrance Day in  Western Australia  (WA). After Kate De'Laney wrote a letter to Premier  Colin Barnett  to bring Pregnancy and Infant Loss Remembrance Day to greater attention, the WA State Government passed a bipartisan agreement to officially recognize the holiday on October 15, 2014. [ 34 ]


The De'Laney's worked with Senator  Kristina Keneally  to make October 15 nationally recognised by the Australian Parliament. Senators Keneally, Bilyk, McCarthy, and Polley, moved a motion in the upper house Australian Government to make Pregnancy and Infant Loss Remembrance Day an official Australian holiday and on February 17, 2021, the motion, put to the members of the lower house, passed unopposed. [ 35 ]


Pregnancy fetishism  (also known as  maiesiophilia  or  maieusophoria ) is a context where  pregnancy  is seen by individuals or cultures as an erotic phenomenon. [ 1 ] [ 2 ]  It may involve sexual attraction to women who are pregnant or appear pregnant, attraction to  lactation , or attraction to particular stages of pregnancy such as impregnation or  childbirth . [ 3 ]


There are no particular or preferred elements within maiesiophilia that are common to all maiesiophiliacs. Some may pursue fantasies that are concerned with the circumstances in which a subject may give birth, or to the conditions to which the pregnant subject may find themselves acting upon, such as approaches to mobility, sleeping, and dressing, even morning sickness could be considered attractive, however all of this depends on the person. Particularly an enlarged abdomen is the reason for the attractiveness as well as more psychological aspects such as signs of fertility.


The naked appearance of actress  Demi Moore  in the advanced stage of pregnancy on the cover of  Vanity Fair  magazine in 1991 marked the beginning of a period which has since seen pregnancy presented by celebrities as a glamorous state of living, while also creating a market for photographers to produce images of pregnant mothers, and for fashion stylists to introduce "pregnancy styling" to their business. [ 4 ]


Pregnancy has proven to be a very popular topic in the world of  internet pornography , where searches for 'pregnancy porn' spiked on  Pornhub  in 2017, with searches increasing 20% since 2014. [ 5 ]


Impregnation fantasies are characterized by the arousal or gratification from the possibility, consequences, or risk of impregnation through unprotected  vaginal sex . Impregnation fantasies are often indulged by reading  erotic literature  and role playing with a partner.


Pregnancy  is a potential result of  rape . It has been  studied in the context of war , particularly  as a tool for genocide , as well as in other unrelated contexts, such as rape by a stranger,  statutory rape ,  incest , and  underage pregnancy . The  scientific consensus  is that rape is at least as likely to lead to pregnancy as  consensual sexual intercourse , with some studies suggesting rape may actually result in higher rates of pregnancy than consensual intercourse. [ 1 ] [ 2 ] [ 3 ]


Rape can cause difficulties during and after pregnancy, with potential negative consequences for both the victim and a resulting child. [ 4 ]  Medical treatment following a rape includes testing for, preventing, and managing pregnancy. A woman who becomes pregnant after a rape may face a decision about whether to have an  abortion , to raise the child, or to make an  adoption  plan. In some countries where abortion is illegal after rape and incest, over 90% of pregnancies in girls age 15 and under are due to rape by family members. [ 5 ]


The false belief that pregnancy can almost never result from rape was widespread for centuries. In Europe, from medieval times well into the 18th century, a man could use a woman's pregnancy as a legal defense to "prove" that he could not have raped her. A woman's pregnancy was thought to mean that she had enjoyed the sex and, therefore, consented to it. In recent decades, some  anti-abortion  organizations and politicians (such as  Todd Akin ) who oppose legal abortion in cases of rape have advanced claims that pregnancy very rarely arises from rape, and that the practical relevance of such exceptions to  abortion law  is therefore limited or non-existent. [ 6 ] [ 7 ] [ 8 ]


Estimates of the numbers of pregnancies from rape vary widely. [ 9 ] [ 10 ]  Recent estimates suggest that rape conception happens between 25,000 and 32,000 times each year in the U.S.
In a 1996 three-year  longitudinal study  of more than 4,000 American women, physician Melisa Holmes estimated from data from her study that forced sexual intercourse causes over 32,000 pregnancies in the United States each year. [ 11 ]  Physician Felicia H. Stewart and economist James Trussell estimated that the 333,000 assaults and rapes reported in the US in 1998 caused about 25,000 pregnancies, and up to 22,000 of those pregnancies could have been prevented by prompt medical treatment, such as  emergency contraception . [ 12 ]  Other analyses indicate a much lower rate. The Rape, Abuse and Incest National Network, a charity based in Washington, D.C., reached a much lower figure calculated using estimates from the Justice Department's 2005 National Crime Victimization Survey. The network took that survey's annual average of 64,080 rapes committed in 2004 and 2005 and applies the 5 percent pregnancy rate to reach an estimate of 3,204 pregnancies a year from rape. [ 10 ]


A 1996 study of 44 cases of rape-related pregnancy estimated that in the United States, the pregnancy rate is 5.0% per rape among victims of reproductive age (aged 12 to 45). [ 11 ] [ 13 ]  A 1987 study also found a 5% pregnancy rate from rape among 18- to 24-year-old college students in the US. [ 14 ]  A 2005 study placed the rape-related pregnancy rate at around 3–5%. [ 15 ]


A study of  Ethiopian  adolescents who reported being raped found that 17% subsequently became pregnant, [ 16 ]  and rape crisis centres in  Mexico  reported the figure the rate of pregnancy from rape at 15–18%. [ 17 ]   Estimates of rape-related pregnancy rates may be inaccurate since the crime is under-reported, resulting in some pregnancies from rape not being recorded as such, [ 15 ]  or alternately, social pressure may mean some rapes are not reported if no pregnancy results.


Most studies suggest that conception rates are independent of whether insemination is due to rape or consensual sex. [ 18 ]


Some analysts have suggested that the rate of conception may be higher from insemination due to rape. [ 19 ] [ 20 ] [ 21 ] [ 22 ]  Psychologist Robert L. Smith states that some studies have reported "unusually high rates of conception following rape". [ 19 ]  He cites a paper by C.A. Fox and Beatrice Fox, reporting that biologist Alan Sterling Parkes had speculated in personal correspondence that "there is a high conception rate in rape, where hormonal release, due to fear or anger, could produce reflex ovulation". [ 20 ]  Smith also cites veterinary scientist Wolfgang Jöchle, who "proposed that rape may induce ovulation in human females". [ 21 ] [ 22 ]  Literary scholar  Jonathan Gottschall  and economist Tiffani Gottschall argued in a 2003  Human Nature  article that previous studies of rape-pregnancy statistics were not directly comparable to pregnancy rates from consensual intercourse, because the comparisons were largely uncorrected for such factors as the use of  contraception . Adjusting for these factors, they estimated that rapes are about twice as likely to result in pregnancies (7.98%) as "consensual, unprotected penile-vaginal intercourse" (2–4%). They discuss a variety of possible explanations and advance the  hypothesis  that rapists tend to target victims with biological "cues of high  fecundity " or subtle indications of ovulation. [ 3 ]


In contrast, psychologists Tara Chavanne and Gordon Gallup Jr., found that women in the ovulatory phase of their menstrual cycle reduce risk-taking behaviors, which could theoretically reduce the likelihood of rape during fertile periods. [ 23 ]  Anthropologist  Daniel Fessler  disputed these findings, saying, "analysis of conception rates reveals that the probability of conception following rape does not differ from that following consensual coitus". [ 18 ]


Sociobiologists  and  evolutionary psychologists  have hypothesized that causing pregnancy by rape may be a  mating strategy  in humans, as a way for males to ensure the survival of their genes by passing them on to future generations. [ 24 ]  Randy Thornhill and  Craig T. Palmer  are key popularizers of this hypothesis. They assert that most rape victims are women of childbearing age and that many cultures treat rape as a crime against the victim's husband. They state that rape victims suffer less emotional distress when they are subjected to more violence, and that married women and women of childbearing age experience greater psychological distress after a rape than do girls, single women or post-menopausal women. [ 25 ]  Rape-pregnancy rates are crucial in evaluating these theories, because a high or low pregnancy rate from rape would determine whether such adaptations are favored or disfavored by  natural selection . [ 3 ]


In 1995–1996, the journal  Family Planning Perspectives  published a study by the  Guttmacher Institute , a sexual health research and policy organization, on  statutory rape  (sexual intercourse with a minor) and resulting pregnancies. It drew on other research [ 26 ] [ 27 ]  to conclude that "at least half of all babies born to minor women are fathered by adult men", and that "although relatively small proportions of 13–14-year-olds have had intercourse, those who become sexually active at an early age are especially likely to have experienced coercive sex: Seventy-four percent of women who had intercourse before age 14 and 60% of those who had sex before age 15 report having had a forced sexual experience". Because of difficulties in bringing such cases to trial, however, "data from the period 1975–1978 ... indicate that, on average, only 413 men were arrested annually for statutory rape in California, even though 50,000 pregnancies occurred among underage women in 1976 alone". [ 28 ]  In that state, it was found that two thirds of babies born to school-age mothers were fathered by adult men. [ 26 ]


Sexual abuse early in life can lead young women to feel a lack of control over their sexual lives, decrease their future likelihood of using  contraceptives  such as condoms, and increase their chances of becoming pregnant or acquiring  sexually transmitted infections . [ 17 ]  A 2007 paper by  Child Trends [ 29 ]  examined studies from 2000 to 2006 to identify links between sexual abuse and teenage pregnancy, starting with Blinn-Pike et al.'s 2002  metastudy  of 15 studies since 1989. [ 30 ]  It found that childhood sexual abuse has a "significant association" with adolescent pregnancy. Direct connections have been demonstrated both by retrospective studies examining antecedents to reported pregnancies and prospective studies, which track the lives of sex abuse victims and "can be helpful for determining causality". [ 29 ] : 3    The more severe forms of abuse, such as rape and incest, entail a greater risk of adolescent pregnancy. [ 29 ] : 4  [ 31 ] [ 32 ]  Although some researchers suggest that pregnancy could be a choice made to escape a "bad situation", it may also be "a direct result of unwanted intercourse", which one study found to be the case for about 13% of participants in a  Texas  parenting program. [ 29 ] : 4  [ 33 ]


In  Nicaragua , between 2000 and 2010, around 172,500 births were recorded for girls under 14, representing around 13% of the 10.3 million births during that period. These were attributed to poverty, laws forbidding abortion for rape and incest, lack of access to justice, and beliefs held in the culture and legal system. [ 5 ] [ 34 ]  A 1992 study in  Peru  found that 90% of babies delivered to mothers aged 12–16 were conceived through rape, typically by a father, stepfather, or other close relative. [ 5 ] [ verification needed ]  In 1991 in  Costa Rica , the figure was similar, with 95% of adolescent mothers under 15 having become pregnant through rape. [ 5 ] [ verification needed ]


Many of the youngest documented birth mothers in history experienced  precocious puberty  and were impregnated as a result of rape, including  incest . The youngest, Peruvian  Lina Medina , was impregnated when she was four and had a live birth in 1939, at age five. [ 35 ]


Rape has been used as a weapon of  psychological warfare  for centuries, to terrorize, humiliate, and undermine the morale of the enemy. Rape was also used as an act of  ethnic cleansing  to produce babies that share the perpetrators' ethnicity. [ 36 ]   Forced pregnancy  has been noted in places including  Bangladesh ,  Darfur , and  Bosnia . [ 37 ]  More broadly, pregnancy commonly results from wartime rape that was perpetrated without the intention of impregnating the enemy, as has been found in conflicts in  East Timor ,  Liberia ,  Kosovo , and  Rwanda . [ 37 ]   Gita Sahgal  of  Amnesty International  commented that, rather than being primarily about "spoils of war" or sexual gratification, rape is often used in ethnic conflicts as a way for attackers to perpetuate social control and redraw ethnic boundaries. [ 38 ]  Children may be born to women and girls forced to "marry" abductors and occupiers; this happened in the  Indonesian occupation of East Timor  and in the  Lord's Resistance Army 's conflict in  Uganda . [ 39 ]


Rape during war is recognized under  United Nations Security Council Resolution 1820  as a  war crime  and a  crime against humanity . [ 40 ]  "Forced pregnancy" is specifically enumerated as a war crime and crime against humanity in the  Rome Statute , which was the "first international criminal tribunal ever officially to criminalize forced pregnancy". [ 41 ]


Children born as the result of wartime rape may be identified with the enemy and grow up stigmatized and excluded by their communities; they may be denied basic rights or even killed before reaching adulthood. [ 37 ]  Children are particularly at risk for such abuse when they are visibly identifiable as sharing half their ethnicity with the occupying forces, as in the case of half-Arab children of Darfuri women raped by  janjaweed  soldiers as part of the  war in Darfur . [ 42 ]   Children of war rape are also at risk due to neglect by traumatized mothers unable to provide sufficient care. [ 42 ]


In 1937 the Japanese army took over  Nanking , which at the time was the capital of China. In the resulting seven-week occupation known as the  Rape of Nanking , as many as 80,000 women were raped. [ 43 ]  Chinese women and girls of all ages were raped, mutilated, tortured, sexually enslaved, and killed; unknown numbers of them were left pregnant. [ 43 ]  Many pregnant Nanking women killed themselves in 1938, and others committed  infanticide  when their babies were born. [ 43 ]  During the rest of the 20th century there was no record of any Chinese woman acknowledging her child as having been born as a result of the Rape of Nanking. [ 43 ]


During the 1992–1995  Bosnian War , pregnancy from rape was used to perpetrate  genocide . There were reports of deliberately created "rape camps" intended to impregnate captive Muslim and Croatian women. Women were reported to have been kept in confinement until their pregnancies had advanced beyond a stage at which abortion would be safe. [ 44 ]  In the context of a  patrilineal  society, in which children inherit their father's ethnicity, such camps were intended to create a new generation of Serbian children. [ 44 ]  The women's group  Tresnjevka  claimed that more than 35,000 women and children were held in such Serb-run camps. [ 45 ] [ 46 ] [ 47 ]  Estimates range from 20,000 [ 48 ]  to 50,000 [ 49 ]  victims. [ 50 ] [ 51 ] [ 52 ]  Feryal Gharahi of  Equality Now  reported: [ 53 ]


After the Bosnian War, the  International Criminal Court  updated its statute to prohibit "confin[ing] one or more women forcibly made pregnant, with the intent of affecting the ethnic composition of any population". [ 54 ]


Immediate post-rape protocols call for medical professionals to assess the likelihood that a victim will become pregnant in their assessment of the physical damage done to the woman. Protocol for gaining a history of the use of contraceptives, as a woman's use of  birth control pills  or other contraceptives before a rape affect her chance of becoming pregnant. [ 55 ]   Treatment protocols also call for clinicians to provide access to  emergency contraception  and counseling on abortion in countries where it is legal. [ 56 ]   High-dose estrogen pills were tried as an experimental treatment after rape in the 1960s, and in 1972 Canadian physician  A. Albert Yuzpe  and his colleagues began systematic studies on the use of  ethinylestradiol  and  norgestrel  to provide emergency contraception after an assault. These treatments reduced the rate of pregnancy after rape by 84%. [ 57 ]  This method is now called the  Yuzpe regimen . [ 58 ]  Before being treated with pregnancy prevention measures, a rape victim is given a  HCG   pregnancy test  to determine whether she was already pregnant before the rape. [ 59 ]


When being discharged from emergency care, clinicians provide information about pregnancy as well as other complications such as infection and emotional trauma. [ 59 ]  While a woman who has become pregnant during the past 48 hours will test negative for pregnancy in an HCG pregnancy test (unless she was already pregnant before the rape), pregnancy resulting from the rape can be detected at the two-week follow-up visit. [ 60 ]


Decisions of whether to end a rape-related pregnancy or carry it to term, and whether to keep the child or place the child for adoption can be severely traumatizing for a woman. [ 61 ]
Abortion rates for pregnancies due to rape vary significantly by culture and demographics; women who live in countries where abortion is illegal must often give birth to the child or secretly undergo a dangerous,  unsafe abortion . [ 17 ]   Some women do not wish to get abortions for religious or cultural reasons. [ 62 ]   In a third of cases, rape-related pregnancies are not discovered until the second  trimester of pregnancy , which may reduce a woman's options, particularly if she doesn't have easy access to legal abortion or is still recovering from the trauma of the rape itself. [ 63 ]


In the United States, 1 percent of 1,900 women questioned in 1987 listed rape or incest as the reason for having an abortion; of these, 95 percent named other reasons as well. [ 64 ]
A 1996 study of thousands of US women showed that, of pregnancies resulting from rape, 50% were  aborted , 12% resulted in  miscarriage , and 38% were brought to term and either placed for adoption or raised. [ 13 ]  Peer-reviewed studies have reported from 38% of American women to 90% of Peruvian adolescents carrying the pregnancy to term. [ 11 ] [ 65 ]  In  Lima , Peru, where abortion is illegal, 90% of girls aged 12 to 16 who became pregnant through rape carried the child to term. [ 65 ]
Of all children born, 1% are placed for adoption; the number of children conceived from rape who are placed for adoption was found to be about 6% in one study and 26% in another. [ 66 ]
When a mother commits  neonaticide , killing an infant younger than 24 hours old, the child's birth being the result of rape is a main cause, although other psychological and situational factors are generally present. [ 67 ]  Some people turn to drugs or alcohol to cope with emotional trauma after a rape; use of these during pregnancy can harm the fetus. [ 68 ]


When a mother chooses to raise her child conceived in rape, the traumatic effect of the rape and the child's blood relationship to the rapist has the potential to create some psychological challenges, but the circumstance of conception is no guarantee to cause psychological problems. [ 66 ] [ 69 ]
If a woman decides to keep and raise the child, she may have difficulty accepting it, and both mother and child face ostracism in some societies. [ 70 ]


Mothers may also face legal difficulties. In most US states, the rapist maintains parental rights. [ 71 ]  Research by legal scholar Shauna Prewitt indicates that the resulting continued contact with the rapist is damaging for women who keep the child. [ 71 ]  She wrote in 2012 that in the US, 31 states allow rapists to assert custody and visitation rights over children conceived through rape. [ 69 ]


Children whose births result from rape have been killed by their mothers at various times in history. During ancient and medieval times, such  infanticide  was not prohibited (however,  penance  was expected of these mothers in medieval Europe). [ 63 ]


Beliefs that rape could not lead to pregnancy were widespread in both legal and medical opinion for centuries. [ 72 ] [ 73 ]   Galen , an ancient Greek physician, believed that a woman must experience pleasure to release "seed" and become pregnant, and could not derive such pleasure from nonconsensual sex. [ 74 ]  Galen's thinking influenced understanding from medieval England to  Colonial America . [ 74 ]   Aristotle  disagreed, as he believed that "women's bodies were not hot enough to produce semen". [ 75 ]  Female reproduction was, in many ways, viewed through the lens of male reproductive processes, imagining that female organs functioned as inverted versions of male organs, and hence  orgasm  was required for conception. [ 72 ]


Centuries later, in medieval Europe, the belief that pregnancy could not occur without consent was still standard; in fact, conception by a woman was considered a legitimate defense against charges of rape. [ 73 ]  The belief was codified in the medieval British law texts  Fleta [ 72 ]  and  Britton .  Britton  states: [ 76 ]


If the defendant confesses the fact, but says that the woman at the same time conceived by him, and can prove it, then our will is that it be adjudged no felony, because no woman can conceive if she does not consent.


Medieval literary scholar Corinne Saunders acknowledged a difficulty in determining how widely held was the belief that pregnancy implies consent, but concluded that it influenced "at least some justices", citing a 1313 case in Kent. [ 77 ]  Against this, in his popular 12th-century  Dragmaticon , the early  Scholastic  philosopher  William of Conches  noted the objection of  Geoffrey of Plantagenet — count  of  Anjou  in  France  and father of  King Henry   II  of  England —to Galen's idea, stating that it was certain that some rape resulted in births; William acknowledged that this occurred but averred that it was merely proof that some or all women experienced involuntary carnal pleasure from the act despite their lack of rational consent. [ 78 ]  However, the same rationale was used as an explanation for the supposed infrequency of births among  prostitutes . [ 78 ]


By the late 1700s, scientists no longer universally accepted the view that pregnancy was impossible without pleasure, although this view was still common. [ 79 ]  A 1795 British legal text,  Treatise of Pleas of the Crown , disparaged the belief's legal utility and its biological veracity: [ 73 ] [ 80 ]


Also it hath been said by some to be no rape to force a woman who conceives at the time; for it is said, that if she had not consented, she could not have conceived, but this opinion seems very questionable, not only because the previous violence is no way extenuated by such a subsequent consent, but also because, if it were necessary to shew that the woman did not conceive, the offender could not be tried till such time as it might appear whether she did or did not, and likewise because the philosophy of this notion may very well be doubted of.


The 1814 British legal text  Elements of Medical Jurisprudence  by  Samuel Farr  claimed that conception "probably" could not occur without a woman's "enjoyment", so that an "absolute rape" was unlikely to lead to pregnancy. [ 72 ] [ 81 ]  On the other hand, in the US in an 1820 court case in the  Arkansas Territory  a man pleaded not guilty to rape charges because the victim became pregnant, but the court rejected the argument: [ 82 ]


The old notion that if the woman conceive, it could not be a rape, because she must have in such case have consented, is quite exploded.  Impregnation, it is well known, does not depend on the consciousness or volition of the female. If the uterine organs be in a condition favorable to impregnation, this may take place as readily as if the intercourse was voluntary.


In more recent times, opponents of legal abortion have argued that pregnancy resulting from rape is rare. [ 7 ] [ 2 ]  In a 1972 article, physician and anti-abortion activist  Fred Mecklenburg  argued that pregnancy from rape is "extremely rare", adding that a woman exposed to the trauma of rape "will not  ovulate  even if she is 'scheduled' to". [ 83 ]  Blythe Bernhard wrote in  The Washington Post , "That article has influenced two generations of anti-abortion activists with the hope to build a medical case to ban all abortions without any exception." [ 84 ]


Historian Ian Talbot has written about how countries with  Quran -based  Islamic codes  on rape and pregnancy use Sura  An-Nur , verse 2, as a legal basis: "The law of evidence in all sexual crimes required either self-confession or the testimony of four upright ( salah ) Muslim males. In the case of a man, self-confession involved a verbal confession. For women however medical examinations and pregnancy arising from rape were admissible as proof of self-guilt." [ clarification needed ]  Under Islamic law, a woman can kill her rapist. [ 85 ]


Pregnancy from rape can also occur when the victim is male and the rapist is female. Many such cases involve the  statutory rape  of underage boys by adult women who subsequently became pregnant. In Kansas,  Hermesmann v. Seyer  established that a 13-year-old male victim of rape can be held liable to pay  child support  for a baby that results from the rape, and later cases in the United States have held likewise. [ 86 ] [ 87 ] [ 88 ]


The  Pregnancy Outcome Prediction (POP) Study [ 1 ]  is a  prospective cohort study  of 4,512 women who have  never given birth , recruited at the  Rosie Hospital  (Cambridge, UK) between January 2008 and July 2012. [ 2 ] [ 3 ]


The Principal Investigator is Gordon Smith [ 4 ]  of the Department of Obstetrics and Gynaecology ( University of Cambridge , UK). Lab work using the biobank of samples is led by Stephen Charnock-Jones [ 5 ]  of the same department. The POP study is supported by the Women’s Health and Paediatrics [ 6 ]  theme of the  National Institute for Health Research  (NIHR)  Cambridge Biomedical Research Centre  (BRC), [ 7 ]  which is based at the Cambridge Biomedical Campus (UK). Other funding sources for the projects related to the POP study are the Medical Research Council (UK), the NIHR, the  Wellcome Trust , the  British Heart Foundation , and the Stillbirth and Neonatal Death Society (now known as  Sands ), as well as Industry supported studies.


In 2007, Cambridge (UK) received funding from NIHR to establish a comprehensive Biomedical Research Centre (BRC). The Cambridge BRC Women’s Health and Paediatrics theme focuses on tackling the origins, treatment and prevention of many of the health issues that affect women during their reproductive years. The bulk of the Cambridge BRC funding for the first five years of the theme supported the POP study.


Over recent years, we have witnessed a great improvement in population-based screening methods for fetal abnormalities as a result of technological developments in ultrasound, biochemical screening and molecular genetics. However, the methods for screening the low risk population for other complications of pregnancy such as fetal growth restriction (FGR), pre-eclampsia and stillbirth have remained largely unchanged for the past 20–30 years. The UK  National Institute for Clinical Excellence  (NICE) has highlighted a number of research priorities in their guidelines for pregnancy care. These include a focus on improving the screening of apparently healthy pregnant women and identify those at high risk of complications. This area is the main focus of the POP study.


Nulliparous women with a viable singleton pregnancy were recruited to the POP study when attending their dating ultrasound scan at The Rosie Hospital (Cambridge, UK). The only clinical exclusion criterion was multiple pregnancy. Participants had serial ultrasound scans and blood obtained at recruitment, 20, 28 and 36 weeks of gestation. DNA samples and height/weight measurements of the partners were also collected. After delivery, biopsies of the placenta, placental membranes, umbilical cord, and a sample of cord blood were collected. [ 8 ]  Thorough design of the POP study and careful sample collection allowed the creation of an extensive, optimally phenotyped biobank of complicated and healthy pregnancies, including approximately 230,000 blood and tissue samples stored in -80 °C freezers, 24,000 formalin fixed placental biopsies, and 4,000 paternal DNA samples.


The types of samples collected during the POP study reflect, first of all, the focus on the role of the placenta and its altered development and function in several major complications of pregnancy. Second, they reflect the interest in circulating biomarkers since, despite years of intensive research, screening for these conditions is still largely based upon clinical grounds rather than ultrasonic and/or biochemical assessment of placental function. Therefore the projects based on the samples from the POP study have the following aims:


Multiple projects based on this data have been published and many are currently on-going [ as of? ] . The key findings obtained so far studying the samples from the POP study are (see paragraph “Research papers” for a complete list of publications):


To externally validate the POP study findings, some of the above projects also involved collaboration with investigators from the  Born in Bradford  study. [ 17 ] [ 20 ]  Moreover, additional collaborations included the Cambridge University School of Biological Sciences (in particular, the Centre for Trophoblast Research, [ 22 ]  a major international centre for placental research including >20 research groups), the  Cancer Research UK  (CRUK) Cambridge Institut and the  Wellcome Sanger Institute . These studies also benefited from collaborations with industrial partners such as GE Healthcare and Roche.


The Pregnancy Outcome Prediction study 2 ( POPS2 ) is a prospective cohort study funded by the Wellcome Trust.  Recruitment to the study  started in January 2020. The first POP study generated a simple screening test which is strongly predictive for pre-eclampsia and FGR at term. The test combines maternal risk factors, ultrasound measurements and levels of placentally-derived proteins in maternal serum (sFlt-1:PlGF ratio). The goal of POPS2 is to collect similar data and samples from approximately 4,500 unselected nulliparous women to address the following aims:


Pregnancy Outcome Prediction Study: transgenerational and adults review (POPStar) is a follow-up study of the original POP study, conducted by the Department of Obstetrics and Gynaecology in collaboration with the  Department of Paediatrics  (both University of Cambridge). The study is funded by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) and the children’s charity, Action Medical Research.


POPStar looks at the long-term health and development of the children and the mothers of the POP study cohort. POPStar started in June 2020, when the children were between 8 and 12 year old. The study is based on the link between routinely-collected data (e.g. from the UK  National Health Service  and the  Department for Education ) and the results from POP study in order to determine which pregnancy parameters could predict a high risk of health or developmental problems. Using the existing and follow-up data collected during the POP and POPStar studies, the research team aims to make connections between conditions during pregnancy and current maternal and children health.


Pregnancy rate  is the  success rate  for getting  pregnant . It is the percentage of all attempts that leads to pregnancy, with attempts generally referring to menstrual cycles where  insemination  or any artificial equivalent is used, which may be simple  artificial insemination  (AI) or AI with additional  in vitro fertilization  (IVF).


There is no universally accepted definition of the term. Thus in IVF pregnancy rates may be based on initiated treatment cycles, cycles that underwent  oocyte retrieval , or cycles where an  embryo transfer  was performed. In terms of outcome, "pregnancy" may refer to a positive  pregnancy test , evidence of a pregnancy with a "viable" fetus or  implantation . Furthermore, pregnancy rates can be influenced in IVF by transferring multiple embryos that may result in  multiple births . A strict definition in the IVF setting would refer to the singleton pregnancy rate that determines how many live singletons are born in relation to initiated IVF cycles.


In some cases, success rates include delivery or presence of a live baby (preferably specified as  delivery rate  or  live  birth rate  respectively).


In IVF or its derivatives,  fertilization rate  may be used to measure how many oocytes become fertilized by sperm cells. A fertilization rate of zero in one cycle, where no oocytes become fertilized, is termed a  total fertilization failure . [ 1 ]  Repeated  ICSI  treatment may be useful or necessary in couples with total fertilization failure. [ 1 ]


Implantation rate is the percentage of embryos which successfully undergo  implantation  compared to the number of  embryos transferred  in a given period. In practice, it is generally calculated as the number of intrauterine  gestational sacs  observed by  transvaginal ultrasonography  divided by the number of transferred embryos. [ 2 ]  As an example, one center in the United States reported an implantation rate in  IVF  of 37% at a maternal age of less than 35 years, 30% at 35 to 37 years, 22% at 38 to 40 years, and 12% at 41 to 42 years. [ 3 ]


Successful implantation of the  zygote  into the  uterus  is most likely 8 to 10 days after conception. If the zygote has not implanted by day 10, implantation becomes increasingly unlikely in subsequent days. [ 4 ]


Live birth rate is the percentage of all cycles that lead to live birth, and is the pregnancy rate adjusted for  miscarriages  and  stillbirths .
For instance, in 2007, Canadian clinics reported a live birth rate of 27% with  in vitro fertilisation . [ 5 ]


There is a substantial connection between  age and female fertility .  Menarche , the first menstrual period, usually occurs around 12–13, although it may happen earlier or later, depending on each girl. After  puberty , female fertility increases and then decreases, with  advanced maternal age  causing an increased risk of  female infertility .


A 2001 review suggested a  paternal age effect  on fertility, where older men have decreased pregnancy rates. [ 7 ]


The time with the highest likelihood of pregnancy resulting from  sexual intercourse  covers the  menstrual cycle  time from some 5 days before until 1 to 2 days after ovulation. [ 10 ]  In a 28‑day cycle with a 14‑day luteal phase, this corresponds to the second and the beginning of the third week. A variety of methods have been developed to help individual women estimate the relatively fertile and the relatively infertile days in the cycle; these systems are called  fertility awareness .


There are many  fertility testing  methods, including  urine test  kits that detect the  LH surge  that occurs 24 to 36 hours before ovulation; these are known as ovulation predictor kits (OPKs). [ 11 ]  Computerized devices that interpret basal body temperatures, urinary test results, or changes in saliva are called  fertility monitors . Fertility awareness methods that rely on cycle length records alone are called  calendar-based methods . [ 12 ]  Methods that require observation of one or more of the three primary fertility signs ( basal body temperature ,  cervical mucus , and cervical position) [ 13 ]  are known as symptoms-based methods. [ 12 ]


For optimal pregnancy chance, there are recommendations of sexual intercourse every 1 or 2 days, [ 14 ]  or every 2 or 3 days. [ 15 ]  Studies have shown no significant difference between different  sex positions  and pregnancy rate, as long as it results in  ejaculation  into the  vagina . [ 16 ]  According to the  American Pregnancy Association , the following factors of sexual intercourse may increase pregnancy chances:


Generally, the pregnancy rate for artificial insemination is 10–15% per  menstrual cycle  using ICI, [ 17 ]  and 15–20% per cycle for IUI. [ 17 ]


With enhanced technology, the pregnancy rates are substantially higher today [ when? ]  than a couple of years ago. In 2006, Canadian clinics reported an average pregnancy rate of 35%. [ 5 ]


Pregnancy-specific biological substances , which include the  placenta ,  umbilical cord ,  amniotic fluid , and  amniotic membrane  are being studied for a number of health uses. [ 1 ]  For example, Placental-derived stem cells are being studied so they can serve as a potential treatment method for  cell therapy . [ 2 ]  Hepatocyte-like cells (HLC) are generated from differentiated human amniotic epithelial cells (hAEC) that are abundant in the placenta. [ 2 ] [ 3 ]  HLC may replace  hepatocytes  for hepatocyte transplantation to treat acute or chronic liver damage. [ 3 ]


Recent research has shown that the placenta and placenta derivatives are being regenerative cell therapies and also includes immunological features. Placenta structures consist of unique physiognomies. Placenta's structure not only regulates its function but also gives the probability of efficient use in clinics and in biotechnology. [ 4 ]


According to a research study by Bhattacharya N.,  Anemia  caused by  Diabetes mellitus  in patients with  albuminuria  can be treated with  cord blood transfusion . [ 5 ]  The research showed increased in  albumin  per gram of  creatinine  that assessed for albuminuria for patients that received cord blood transfusions. [ 5 ]


This  pharmacology -related article is a  stub . You can help Wikipedia by  expanding it .


Pregnancy vegetarianism  is the practice of adhering to a vegetarian diet during pregnancy .  Vegetarianism  is "the principle or practice of excluding all meat and fish, and sometimes, in the case of vegans, all  animal products  (such as eggs, milk, cheese, etc) from one's diet." [ 1 ]  Although some people frown upon pregnant women practicing vegetarianism, there is no evidence that vegetarianism—practiced properly—is unhealthful during pregnancy. There are millions of healthy babies born each year from vegetarian households. [ 2 ]


Most opponents of  pregnancy  vegetarianism are concerned about the pregnant woman's  protein  intake because vegetarians do not eat  chicken , fish, or beef. It is recommended, for example, that a pregnant woman should aim to have something from the four main food groups every day. [ 3 ]  These include fruit and vegetables,  carbohydrates , protein-rich foods and dairy foods. [ 4 ]  There are several vegetarian sources of protein: soy, cooked dried beans or peas, tofu, nuts or seeds, peanut butter, and eggs. Vegetarians focus on foods that are normally left out of most non-meat pregnancy diets such as include beans, fresh dark green vegetables, and whole grains which are good sources of protein. [ 5 ]  The risks associated with vegetarianism, that is to say the problems vegetarians face, can generally be lessened by a careful diet. These problems that many associate with vegetarianism, such as  anaemia , are in fact not due to the vegetarian diet alone, but more so to the fact that the subject in question has failed to supplement their body with the nutrition they require. When cutting out meats, some vegetarians fail to intake any other kinds of protein. [ citation needed ]  To intake protein is very important during pregnancy as one of the cause of the anaemia is iron deficiency and it varies by region. [ 6 ]  The iron-deficiency anaemia increases the risk of low weight in birth and transmits the iron-deficiency to infants. [ 7 ]


One benefit of adopting pregnancy vegetarianism, is the possibility of minimizing pregnancy weight gain. Because being a vegetarian is a choice less often chosen, many have described this control of weight as due to them being more conscious of their diet. [ 8 ]  A 2009 study showed that over 52 percent of pregnant women gain more weight than the recommended, 23-35 pounds. [ 9 ]  During the second and third trimester, the average diet needs only to be increased by 300 calories, and it may be argued that pregnancy vegetarianism may be a way of monitoring diet and calorie intake. [ 10 ]


According to dietitian Sarah Schenker, being a vegetarian during pregnancy is perfectly safe so long as a strict diet is being followed. By this she means that one must know exactly what their body needs and make sure that they are taking in these nutrients. A healthy diet is very important when pregnant as a vegetarian. Seeing a dietitian could be beneficial to one as they could provide guidelines which should be followed for a healthy lifestyle. [ 11 ]


Pregnant woman should get enough  omega-3s ,  vitamin B 12 , and calcium. All these elements could be found in vegetarian meals and products. Omega-3s are found in dark leafy green vegetables, flax seed, walnuts, kidney and pinto beans, broccoli and squash. Calcium is found in cottage cheese and fortified plant-based drinks. Moreover, pregnant woman should get enough zinc, protein, and iron. These elements are found in peas and beans. Vegetables and fruits should be eaten every day more than five times in order to get enough vitamins. [ 12 ] [ unreliable source? ]


However, as vegetarians have a greater exposure to  phytoestrogens  than omnivores, there are studies [ 13 ]  which support the possibility of negative effect on the developing  male reproductive system  and can increase the risk of the baby developing  birth defects  such as  hypospadias . [ 14 ]


Pregnancy-related anxiety  is a distinct  anxiety  contextualized by  pregnancy  specific fears, worries, and concerns. [ 1 ] [ 2 ]  Pregnancy-related anxiety is characterized by increased concerns or excessive fears and worries about their unborn baby,  childbirth ,  body image , and impending motherhood. [ 3 ] [ 4 ]  This anxiety is also known as pregnancy-specific anxiety, pregnancy anxiety, pregnancy distress, or pregnancy concerns  [ 5 ]  and was first identified in 1956 when women were observed to be anxious about different aspects of their pregnancy. [ 6 ]  However, it was not until conventional measures of anxiety and depression were shown to not adequately capture this anxiety that the first empirical evidence was provided. [ 7 ]  Subsequent studies have provided further support for the distinctiveness of pregnancy-related anxiety from state and trait anxiety, depression and anxiety disorder symptomology.  [ 8 ] [ 2 ] [ 9 ]


Several adverse outcomes are regularly associated with pregnancy-related anxiety. This anxiety is a risk factor for negative fetal/child outcomes, including  preterm birth ,  low birth weight ,  developmental delays , and behavioral problems. [ 10 ] [ 11 ] [ 12 ]  Pregnancy-related anxiety is also linked to negative affectivity and poorer child and infant cognitive development. [ 13 ]  Health risk behaviors such as  alcohol consumption  and continued  smoking during pregnancy  have also been associated with pregnancy-related anxiety. [ 14 ] [ 15 ] [ 16 ]  This is particularly concerning given that these behaviors introduce harmful  teratogens  into the baby's environment during critical developmental periods. [ 17 ]


Several instruments assess pregnancy-related anxiety. These include unidimensional scales such as Levin's Pregnancy Anxiety Scale, [ 18 ]  Cote-Arsenault's Pregnancy Anxiety Scale, [ 19 ]  the Pregnancy Related Thoughts Scale, [ 20 ]  and the Pregnancy Specific Anxiety Scale. [ 21 ]  In addition, the Pregnancy Related Anxiety Questionnaire (PRAQ-R) is a multidimensional scale that assesses core concerns of pregnant women (i.e., childbirth, appearance, and the unborn baby). [ 2 ]  The PRAQ-R2 is the revised version applicable for women of any parity. [ 22 ]


The reported prevalence of pregnancy-related anxiety varies depending on the country and timing of the assessment. For example, in  high-income countries , the prevalence is around 10%, [ 23 ] [ 24 ]  whereas, in low-income or  less developed countries , it is as high as 56%. [ 25 ]  Also, the prevalence of this anxiety type can fluctuate across the duration of pregnancy, with higher prevalence noted in the earlier and later stages of pregnancy consistent with a u-shaped course. [ 26 ]  This u-shaped curve is consistent with worries and concerns in early pregnancy for the unborn child being more salient in the first  trimester  and fears about childbirth more salient in late pregnancy. [ 27 ] [ 28 ]


Pregnant women  have historically been excluded from  clinical research  due to ethical concerns about harming the  fetus  or the perception of increased risk to the woman. Excluding pregnant women from research has also been called unethical, as it results in a scarcity of data about how therapies affect pregnant women and their fetuses. Despite consensus from bioethicists, researchers, and regulators that pregnant women should be included in clinical research, up to 95% of Phase IV clinical trials that could have included pregnant women did not, according to a 2013 review.


There are several points of concern regarding clinical research with pregnant women. Some concern is related to the idea that the  fetus  cannot give consent to participate in the research. [ 1 ]  Some clinical research could also result in unexpected harm to the fetus. [ 2 ]  Other concerns are that pregnant women are potentially more vulnerable to negative side effects than other populations. It has also been hypothesized that pregnant women could be more susceptible to coercion than non-pregnant adults. There is insufficient data to support either of these two latter concerns, according to a 2020 review. [ 3 ]


Conversely, the exclusion of pregnant women from clinical research has also been called unethical. The data regarding drug use and pregnancy is scarce and of poor quality. Therefore, pregnant women do not necessarily have the same access to informed, effective healthcare as other populations. [ 2 ]


Due to complications from the drugs  thalidomide  and  diethylstilbestrol  in women in the 1960s and 1970s, the US  Food and Drug Administration  (FDA) enacted protections to limit reproductive-age women's exposure to  substances that may cause birth defects . However, the guidelines were interpreted to exclude pregnant women from any clinical trial. [ 1 ]  Despite a 1994  National Academy of Medicine  Report  Ethical and Legal Issues of Including Women in Clinical Studies  concluding that "pregnant women should be presumed to be eligible for participation in biomedical research", a 2013 publication noted that about 95% of  Phase IV  clinical trials that could have included pregnant women instead excluded them. [ 3 ]  note that this “review” is not linked to in this article and that [3] is a study about testing during an Ebola outbreak.


As a result of excluding pregnant women from clinical trials, the safety and efficacy of therapies cannot be evaluated for them. Over 80% of pregnant women are regularly prescribed therapies that are untested in pregnant populations. [ 1 ]  A study of medications approved by the FDA from 1980 to 2010 showed that 91% of medications for adults lacked data about the safety and efficacy for pregnant women, or determinations of risk to the fetus. [ 2 ]  In the case of highly lethal illnesses like Ebola and HIV/AIDS before the development of effective therapies, the exclusion of pregnant women from potentially life-saving clinical therapies results in them being "protected to death". [ 3 ]


Regulators, researchers, and  bioethicists  generally agree that clinical trials should include pregnant women. Because pregnancy changes the way the body metabolizes drugs, it is otherwise difficult to predict how drugs tested in non-pregnant adults will affect pregnant women. In order to treat illness in pregnant women, clinical research must involve them. [ 2 ]


Several projects and coalitions have formed to promote the inclusion of pregnant women in clinical research. These include the Coalition to Advance Maternal Therapeutics, which consists of twenty member organizations, [ 4 ]  and the Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT), a project that sought to increase the inclusion of pregnant women in vaccine trials during  epidemics . [ 3 ]


Preimplantation factor   (PIF)  is a  peptide  secreted by  trophoblast cells  prior to  placenta formation  in early  embryonic development . [ 1 ]  Human  embryos  begin to express PIF at the  4-cell stage , with expression increasing by the  morula  stage and continuing to do so throughout the first trimester. [ 2 ] [ 1 ] [ 3 ]  Expression of preimplantation factor in  the blastocyst  was discovered as an early correlate of the viability of the eventual  pregnancy . [ 1 ] [ 4 ]  Preimplantation factor was identified in 1994 by a lymphocyte platelet-binding assay, where it was thought to be an early biomarker of pregnancy. [ 5 ]  It has a simple  primary structure  with a short sequence of fifteen amino acids without any known quaternary  structure . [ 6 ]  A synthetic analogue of preimplantation factor (commonly abbreviated in studies as sPIF or PIF*) that has an identical amino acid sequence and mimics the normal  biological activity  of PIF has been developed and is commonly used in research studies, particularly those that aim to study potential adult therapeutics. [ 7 ] [ 8 ] [ 9 ]


Preimplantation factor acts by  paracrine signaling ; that is to say trophoblast cells, which collectively form extra-embryonic tissues, secrete it onto the surface of the endometrium. PIF is known to influence many events in the  implantation process , the process by which an early embryo implants into the uterine wall. A crucial event in human implantation is when trophoblast cells expressing preimplantation factor invade  the uterine wall  and found the placenta, an organ that connects maternal blood supply, and along with it, nutrients, to the growing fetus. This requires changes to the  histology  of the endometrium; a process called  decidualisation . Upregulated expression of PIF increases the presence of  integrins  on the endometrium wall, promoting the embryo's  adhesion  to the uterine wall. [ 10 ]  PIF is thought to modulate and facilitate the depth of the trophoblast's invasion into the uterus at physiological doses. [ 1 ]


Maternal  immune system  regulation is also a critical event in implantation as the early embryo is essentially a partial  allograft , that is a tissue that is recognised as fully identical to that of the mother. [ 11 ] [ 12 ]  Consequently, the embryo may be  rejected  and attacked if it is not recognised, an event that normally causes  spontaneous miscarriage . [ 11 ] [ 12 ]  Preimplantation factor regionally modulates the mother's immune system, decreasing the activity of peripheral maternal  leukocytes , reducing inflammation and consequently also increasing the chance that the embryo will be  tolerated . [ 13 ]  Preimplantation factor is also an  anti-apoptotic effector , maintaining the trophoblast cell integrity through the intrinsic  p53 signalling pathway . [ 14 ]  Moreover, preimplantation factor protects the  central nervous system  by  downregulating  pathways that promote neurone death and promoting neurogenesis. [ 7 ] [ 9 ]  PIF is also known to signal against neonatal prematurity and rescues embryos from toxic uterine environments. [ 7 ] [ 11 ] [ 15 ]


Due to its multiple  autoimmune  and  neuroprotective  effects in the embryonic environment, preimplantation factor has been studied in clinical environments as a potential novel  therapy  for reproductive, autoimmune and neurodegenerative diseases. PIF has been successfully studied as a therapy for  recurrent pregnancy loss , as it is able to rescue non-viable embryos from a hostile maternal environment. [ 16 ]  It has also been shown to prevent  diabetes mellitus type 1  in mice due to its ability to modulate  immunological tolerance  in the pancreas. [ 8 ]  Finally, it reverses  paralysis  and  neuroinflammation  whilst promoting  neurogenesis  in adult patients with  neurodegenerative diseases . [ 11 ] [ 17 ]  It also may be able to decrease the severity of brain injuries by modulating the behaviour of supporting cells in the nervous system. [ 9 ]


Preimplantation factor has a simple primary peptide structure with a 15 amino acid sequence (MVRIKPGSANKPSDD). [ 18 ]


As the regulation of the maternal immune system is a requisite for successful implantation, the immune system shows different characteristics in pregnant women and non-pregnant women. In 1994, preimplantation factor was isolated by a lymphocyte platelet-binding assay that compared immune responses and proteins found in pregnant women and non-pregnant women. [ 5 ]  The assay also compared immune responses with men to verify if the proteins were specific to female reproductive tissues. [ 5 ]  Results generated in the preliminary study showed that "a preimplantation factor" was being expressed exclusively in pregnant women. [ 5 ]  On the fourth day after  embryo transfer  in women who had undergone successful  in-vitro fertilisation , this protein was also found, suggesting that it had a role in the determination of the viability of the embryo. [ 5 ]  Subsequent studies, most seminally including a 1996 study that partially characterised the biological activity of PIF, adopted and established the current term "preimplantation factor" as the name for this novel peptide. [ 6 ]


Trophoblast cells form the outer lining of the blastocyst in preimplantation development, eventually forming more differentiated  extra-embryonic tissues  including the placenta. [ 19 ]  Before this differentiation can occur the embryo's invasion and infiltration into the uterine wall must be tightly regulated by both maternal and foetal signals, including secretion of PIF by trophoblast cells. [ 20 ]  In particular, preimplantation factor is thought to have a  paracrine  effect on the decidualisation process, which ultimately primes trophoblast cells to invade appropriately into the endometrium. [ 1 ]  When compared to non-functional short peptides at the same concentration, application of PIF to the endometrium at the implantation stage promoted deeper invasion of the embryo. [ 1 ]  This effect was not observed to occur indefinitely with successive increases of concentration and any artificial increases of PIF above the human physiological concentration (approximately 50  nmol/L ) did not meaningfully increase the invasion of the embryo. [ 1 ]  Consequently, it is thought that PIF is limited in its promotion of trophoblast invasion by maternal signals. [ 1 ] [ 12 ]


The outermost layer of the uterine wall is an  epithelial  tissue called the endometrium that requires  cell surface adhesion molecules  called integrins to adhere the embryo. This additional paracrine effect of PIF has been shown to increase the expression of the integrin molecule α2β3 on  the cell membranes  of cells in the endometrium. [ 10 ]  Integrins are a broad class of cell adhesion molecules that allow cells to bind to  extracellular matrix . [ 10 ]  In this way, they assist the entire embryo in binding to the uterine wall, an important event in successfully generating a placenta. [ 10 ]


The embryo is immunologically characterised as a partial allograft as it is not a maternal tissue. [ 3 ] [ 11 ]  During  fertilisation , a paternal  spermatozoon  fuses with a maternal  oocyte  producing a  zygote . Phenotypically, the zygote expresses certain  epitopes  that are controlled by genes inherited from the father, making the embryo a foreign material. In order for successful implantation to occur, the maternal immune system must tolerate the presence of the embryo while not completely inactivating its innate responsiveness to foreign  pathogens.  This process is not always successful; indeed maternal immune rejection of the embryo is a common and well-characterised cause of recurrent pregnancy loss. [ 16 ]


Preimplantation factor has a significant role in signalling this grafting behaviour; it has been, for instance shown to signal an  anti-inflammatory response  in a broad range of  peripheral blood mononuclear cells . [ 3 ]  PIF also impacts similar  cytoskeletal proteins  in  CD14+ ,  CD8+  and  CD4+  cells suggesting that they have a broad and integrative role in modulating the immune system of the mother. [ 21 ]  In particular, PIF inhibits the process of platelet aggregation in helper T lymphocytes and skeletal proteins in cytotoxic T cells. [ 21 ]   While PIF attenuates or modulates the immune system, it does not effect the response to other pathogens or foreign material. [ 11 ]  This modulatory effect on immunological tolerance is responsible for a strong correlation between PIF expression and the viability of pregnancy. [ 4 ]


The expression of preimplantation factor in the embryo is strongly correlated with the likelihood of a  live birth . [ 4 ] [ 21 ]  This observed viability is not solely due to PIF's ability to mediate the implantation and allografting process but also due to its ability to promote the upregulation and integrity of certain intracellular targets that are positively associated with normal developmental processes. [ 21 ]  For instance, PIF is known to target the enzyme disulfide  isomerase , which reduces intracellular  oxidative stress  and also  heat-shock proteins , which are  molecular chaperones  that ensure proteins produced by a cell will fold into the correct conformation for their function. [ 22 ]  Additionally, PIF is known to promote the production of vital cytoskeletal proteins including  actin  and  tubulin  that are required for the current morphological development of nerve  axons  and the  viscera  of vital organs. [ 15 ]  Axons use circular tubulin polymers called  microtubules  to transport intracellular material between the  cell body  and the  axon terminal  and require actin to form  synapses . [ 23 ]  They are hence important for the organisation and function of the growing immune system.


Additionally, when uterine serum from patients with recurrent pregnancy loss is applied to embryos that are positive for PIF, they display the capacity to resist the toxin and are able to survive. [ 22 ]  Combined, these observations and combination of intracellular effects suggest that PIF has multifaceted impacts directed towards viable pregnancy.


In the  prenatal  environment, PIF has neuroprotective impacts. It protects the growing fetus against  neonatal prematurity , preventing the fetus from being delivered before adequate neural development has taken place. [ 7 ] [ 11 ]  The neurogenic effects of PIF are not isolated to the prenatal environment; in fact PIF is thought to have impacts throughout life. In adult models, PIF has multiple neurogenic effects: it promotes the growth of neurons and reduces neuroinflammation. [ 7 ] [ 11 ] [ 17 ]  It is thought to have these impacts by modulating signalling through the ubiquitous  protein kinase A  and  protein kinase C  intracellular signalling pathways. [ 7 ]  PIF also inhibits  microRNA  let-7, a sequence that is highly upregulated in the central nervous system. The Let-7 system has been associated with cell death in neurons, and PIF is known to inhibit this process from occurring. [ 9 ]  In rats that were induced to have a  hypoxic-ischemic  brain injury, PIF was able to promote neuron growth, reduced detrimental responses by  neuroglia  and was able to generate a significant  cerebral cortex  volume, suggesting it could rescue rats from side effects of brain damage. [ 9 ]


PIF also has a series of anti-apoptotic impacts in human extravillous trophoblasts, mediated by the  TP53 gene . [ 14 ]  Apoptosis is a controlled cell death process that must not occur if a cell is to proliferate. PIF has specific anti-apoptotic impacts by reducing the  phosphorylation  of the p53 protein at the serine-15 residue. Without phosphorylation p53 is unstable and undergoes  ubiquitylation , signalling the trophoblast and endometrial cells to degrade it in  proteasomes  and attenuating downstream apoptotic effects. PIF, in particular, has been correlated with increasing the expression of anti-apoptotic effector  BCL2  and decreasing the expression of pro-apoptotic effector  BAX . [ 14 ]  BCL2, which is upregulated by PIF, ensures that  cytochrome c  remains within  the inner mitochondrial membrane  and hence does not trigger the production of an  apoptosome  in the cell cytosol. BAX, which is downregulated by PIF, produces  transmembrane transport channels  that liberate cytochrome c, triggering apoptosis. Collectively, these biochemical effects show that PIF signals against the internal mechanisms of apoptosis in extravillous trophoblast cells, allowing them to proliferate before they implant into the uterine wall.


Given its multifaceted functionality, including autoimmune, neuroprotective and anti-apoptotic effects, preimplantation factor has been extensively studied as a potential therapeutic agent in both reproductive and non-reproductive medical contexts. PIF is also advantageous because of its easily replicable biochemical structure. [ 6 ]  In reproductive contexts, PIF has been studied as a treatment for  infertility . In women with recurrent pregnancy loss, treatment with PIF is able to rescue a non-viable embryo and promotes a successful implantation and pregnancy. [ 16 ]  It does this by mitigating the toxic influence of certain factors that naturally occur in the uterus, such as acidity. [ 16 ]


PIF has also been studied in a range of other non-reproductive contexts. Due to the ability of PIF to attenuate the attack mechanisms of mononuclear immune cells, it has been implicated as a successful treatment for autoimmune diseases including diabetes mellitus type 1 in mice studies. Diabetes mellitus type 1 is characterised by the misrecognition of pancreatic beta islet cells as foreign material. [ 8 ]  These studies show that PIF is able to preserve the pancreatic beta islet cell's integrity, rescuing them from the autoimmune attacks which cause diabetes. [ 8 ]  In adult models, PIF also reverses the pathological neuroinflammation caused by autoimmune diseases such as  multiple sclerosis . [ 17 ]  It also reverses paralysis and promotes growth of neurons in patients with neurodegeneration. [ 11 ]