A number of studies have shown that tobacco use is a significant factor in miscarriages among pregnant smokers, and that it contributes to a number of other threats to the health of the fetus. Smoking and pregnancy, combined, cause twice the risk of premature rupture of membranes, placental abruption and placenta previa. Also, it causes 30% higher odds of the baby being born prematurely.

DES (diethylstilbestrol) is a drug that mimics estrogen, a female hormone. From 1938 until 1971 doctors prescribed this drug to help some pregnant women who had had miscarriages or premature deliveries on the theory that miscarriages and premature births occurred because some pregnant women did not produce enough estrogen naturally to sustain the pregnancy for full term . An estimated 5-10 million pregnant women and the children born during this period were exposed to DES. Currently, DES is known to increase the risk of breast cancer, and cause a variety of birth-related adverse outcomes exposed female offsprings such as spontaneous abortion, second-trimester pregnancy loss, preterm delivery, stillbirth, neonatal death, sub/infertility and cancer of reproductive tissues . DES is an important developmental toxicant which links the fetal basis of adult disease.

Methylmercury and inorganic mercury is excreted in human breast milk and infants are particularly susceptible to toxicity due to this compound. The fetus and infant are especially vulnerable to mercury exposures with special interest in the development of the CNS since it can easily cross across the placental barrier, accumulate within the placenta and fetus as the fetus cannot eliminate mercury and have a negative effect on the fetus even if the mother does not show symptoms. Mercury causes damage to the nervous system resulting from prenatal or early postnatal exposure and is very likely to be permanent.

Prenatal cocaine exposure is associated with, for example, premature birth, birth defects and attention deficit disorder.

A recent study on cocaine in Prenatal Drug Exposure(2008) explores how the differences between children who were exposed to drugs prenatal and those with non-drug prenatal exposure differ at the age of five.

Many of the side effects from the children who were exposed to the recreational drug being cocaine had side effects including the following; lack in school readiness, slower impulse control and lack in visual attention.

Studies have found after controlling for other factors that some effects are present in pregnancies involving cocaine: abruptio placenta, prematurity, low birth weight, and small size compared to babies of the same gestational time. PCE newborns have smaller heads and shorter bodies. PCE effects are more severe when the amounts of cocaine are greater. As many as 17–27% of cocaine-using pregnant women deliver prematurely. In association with prematurity, growth in the womb is reduced, and low birth weight is connected to PCE. There are also data showing that spontaneous abortion is associated with cocaine use. Cocaine reduces the appetite and has been linked with reduced maternal weight gain during pregnancy; in addition, constriction of the blood vessels may further limit supply of nutrients to the fetus. Using cocaine while pregnant also heightens the chances of maternal and fetal vitamin deficiencies,

respiratory distress syndrome for the baby, and infarction of the bowels. Early reports found that cocaine-exposed babies were at high risk for sudden infant death syndrome; however, by itself, cocaine exposure during fetal development has not subsequently been identified as a risk factor for the syndrome. Some, but not all, PCE children experience hypertonia (excessive muscle tone), and reduced reflexes and motor function have been found in babies four to six weeks old.

While newborns who were exposed prenatally to drugs such as barbiturates or heroin frequently have symptoms of drug withdrawal (neonatal abstinence syndrome), this does not happen with babies exposed to crack "in utero"; at least, such symptoms are difficult to separate in the context of other factors such as prematurity or prenatal exposure to other drugs.

A number of the effects that had been thought after early studies to be attributable to prenatal exposure to cocaine are actually due partially or wholly to other factors, such as exposure to other substances (including tobacco, alcohol, or marijuana) or to the environment in which the child is raised.

PCE is very difficult to study because of a variety of factors that may confound the results: pre- and postnatal care may be poor; the pregnant mother and child may be malnourished; the amount of cocaine a mother takes can vary; she may take a variety of drugs during pregnancy in addition to cocaine; measurements for detecting deficits may not be sensitive enough; and results that are found may only last a short time. Studies differ in how they define heavy or light cocaine use during pregnancy, and the time period of exposure during pregnancy on which they focus (e.g. first, second, or third trimester. Drug use by mothers puts children at high risk for exposure to toxic or otherwise dangerous environments, and PCE does not present much risk beyond these risk factors. PCE is clustered with other risk factors to the child, such as physical abuse and neglect, domestic violence, and prenatal exposure to other substances. Such environmental factors are known to adversely affect children in the same areas being studied with respect to PCE.

Most women who use cocaine while pregnant use other drugs too; one study found that 93% of those who use cocaine or opiates also use tobacco, marijuana, or alcohol. When researchers control for use of other drugs, many of the seeming effects of cocaine on head size, birth weight, Apgar scores, and prematurity disappear.

Addiction to any substance, including crack, may be a risk factor for child abuse or neglect. Crack addiction, like other addictions, distracts parents from the child and leads to inattentive parenting. Mothers who continue to use drugs once their babies are born have trouble forming the normal parental bonds, more often interacting with their babies with a detached, unenthusiastic, flat demeanor. Conversely, low-stress environments and responsive caregiving may provide a protective effect on the child's brain, potentially compensating for negative effects of PCE.

Many drug users do not get prenatal care, for a variety of reasons including that they may not know they are pregnant. Many crack addicts get no medical care at all and have extremely poor diets, and children who live around crack smoking are at risk of inhaling secondary smoke. Cocaine using mothers also have a higher rate of sexually transmitted infections such as HIV and hepatitis.

In some cases, it is not clear whether direct results of PCE lead to behavioral problems, or whether environmental factors are at fault. For example, children who have caregiver instability may have more behavioral problems as a result, or it may be that behavioral problems manifested by PCE children lead to greater turnover in caregivers. Other factors that make studying PCE difficult include unwillingness of mothers to tell the truth about drug history, uncertainty of dosages of street drugs and high rates of attrition (loss of participants) from studies.

Factors increasing the risk (to either the woman, the fetus/es, or both) of pregnancy complications beyond the normal level of risk may be present in a woman's medical profile either before she becomes pregnant or during the pregnancy. These pre-existing factors may relate to physical and/or mental health, and/or to social issues, or a combination.

Some common risk factors include:

- Age of either parent

- Adolescent parents

- Older parents

- Exposure to environmental toxins in pregnancy

- Exposure to recreational drugs in pregnancy:

- Ethanol during pregnancy can cause fetal alcohol syndrome and fetal alcohol spectrum disorder.

- Tobacco smoking and pregnancy, when combined, causes twice the risk of premature rupture of membranes, placental abruption and placenta previa. Also, it causes 30% higher odds of the baby being born prematurely.

- Prenatal cocaine exposure is associated with, for example, premature birth, birth defects and attention deficit disorder.

- Prenatal methamphetamine exposure can cause premature birth and congenital abnormalities. Other investigations have revealed short-term neonatal outcomes to include small deficits in infant neurobehavioral function and growth restriction when compared to control infants. Also, prenatal methamphetamine use is believed to have long-term effects in terms of brain development, which may last for many years.

- Cannabis in pregnancy is possibly associated with adverse effects on the child later in life.

- Exposure to Pharmaceutical drugs in pregnancy. Anti-depressants, for example, may increase risks of such outcomes as preterm delivery.

- Ionizing radiation

- Risks arising from previous pregnancies:

- Complications experienced during a previous pregnancy are more likely to recur.

- Many previous pregnancies. Women who have had five previous pregnancies face increased risks of very rapid labor and excessive bleeding after delivery.

- Multiple previous fetuses. Women who have had more than one fetus in a previous pregnancy face increased risk of mislocated placenta.

- Multiple pregnancy, that is, having more than one fetus in a single pregnancy.

- Social and socioeconomic factors. Generally speaking, unmarried women and those in lower socioeconomic groups experience an increased level of risk in pregnancy, due at least in part to lack of access to appropriate prenatal care.

- Unintended pregnancy. Unintended pregnancies preclude preconception care and delays prenatal care. They preclude other preventive care, may disrupt life plans and on average have worse health and psychological outcomes for the mother and, if birth occurs, the child.

- Height. Pregnancy in women whose height is less than 1.5 meters (5 feet) correlates with higher incidences of preterm birth and underweight babies. Also, these women are more likely to have a small pelvis, which can result in such complications during childbirth as shoulder dystocia.

- Weight

- Low weight: Women whose pre-pregnancy weight is less than 45.5 kilograms (100 pounds) are more likely to have underweight babies.

- Obese women are more likely to have very large babies, potentially increasing difficulties in childbirth. Obesity also increases the chances of developing gestational diabetes, high blood pressure, preeclampsia, experiencing postterm pregnancy and/or requiring a cesarean delivery.

- Intercurrent disease in pregnancy, that is, a disease and condition not necessarily directly caused by the pregnancy, such as diabetes mellitus in pregnancy, SLE in pregnancy or thyroid disease in pregnancy.

Drug and alcohol use during pregnancy can lead to many health problems in the baby besides NAS. These may include:

- Birth defects

- Low birth weight

- Premature birth

- Small head circumference

- Sudden infant death syndrome (SIDS)

- Problems with development and behavior

Neonatal abstinence syndrome treatment can last from 1 week to 6 months. Even after medical treatment for NAS is over and babies leave the hospital, they may need continued treatment for weeks or months.

A 2012 study from the University of Michigan and the University of Pittsburgh published in the "Journal of the American Medical Association" analyzed information on 7.4 million discharges from 4,121 hospitals in 44 states, to measure trends and costs associated with NAS over the past decade. The study indicated that between 2000 and 2009, the number of mothers using opiates increased from 1.19 to 5.63 per 1,000 hospital births per year. Newborns with NAS were 19% more likely than all other hospital births to have low birthweight and 30% more like to have respiratory complications. Between 2000 and 2009, total hospital charges for NAS cases, adjusted for inflation, are estimated to have increased from $190 million to $720 million.

Neonatal abstinence syndrome in Canada are significant.

Tobacco (cigarette) smokers have an increased risk of miscarriage. There is an increased risk regardless of which parent smokes, though the risk is higher when the gestational mother smokes.

Several intercurrent diseases in pregnancy can potentially increase the risk of miscarriage, including diabetes, polycystic ovary syndrome (PCOS), hypothyroidism, certain infectious diseases, and autoimmune diseases. PCOS may increases the risk of miscarriage. Two studies suggested treatment with the drug metformin significantly lowers the rate of miscarriage in women with PCOS, but the quality of these studies has been questioned. The use metformin treatment in pregnancy has not been shown to be safe. In 2007 the Royal College of Obstetricians and Gynaecologists also recommended against use of the drug to prevent miscarriage. Thrombophilias or defects in coagulation and bleeding were once thought to be a risk in miscarriage but have been subsequently questioned.

Severe cases of hypothyroidism increase the risk of miscarriage. The effect of milder cases of hypothyroidism on miscarriage rates has not been established. A condition called luteal phase defect (LPD) is a failure of the uterine lining to be fully prepared for pregnancy. This can keep a fertilized egg from implanting or result in miscarriage.

"Mycoplasma genitalium" infection is associated with increased risk of preterm birth and miscarriage.

Infections can increase the risk of a miscarriage: rubella (German measles), cytomegalovirus, bacterial vaginosis, HIV, chlamydia, gonorrhoea, syphilis, and malaria.

Strong evidence links pesticide exposure to birth defects, fetal death and altered fetal growth. Agent Orange, a 50:50 mixture of 2,4,5-T and 2,4-D, has been associated with bad health and genetic effects in Malaya and Vietnam. It was also found that offspring that were at some point exposed to pesticides had a low birth weight and had developmental defects.

Some disorders and conditions can mean that pregnancy is considered high-risk (about 6-8% of pregnancies in the USA) and in extreme cases may be contraindicated. High-risk pregnancies are the main focus of doctors specialising in maternal-fetal medicine.

Serious pre-existing disorders which can reduce a woman's physical ability to survive pregnancy include a range of congenital defects (that is, conditions with which the woman herself was born, for example, those of the heart or , some of which are listed above) and diseases acquired at any time during the woman's life.

While active maternal tobacco smoking has well established adverse perinatal outcomes such as LBW, that mothers who smoke during pregnancy are twice as likely to give birth to low-birth weight infants. Review on the effects of passive maternal smoking, also called environmental tobacco exposure (ETS), demonstrated that increased risks of infants with LBW were more likely to be expected in ETS-exposed mothers.

Regarding environmental toxins in pregnancy, elevated blood lead levels in pregnant women, even those well below 10 ug/dL can cause miscarriage, premature birth, and LBW in the offspring. With 10 ug/dL as the Centers for Disease Control and Prevention's “level of concern”, this cut-off value really needs to arise more attentions and implementations in the future.

The combustion products of solid fuel in developing countries can cause many adverse health issues in people. Because a majority of pregnant women in developing countries, where rate of LBW is high, are heavily exposed to indoor air pollution, increased relative risk translates into substantial population attributable risk of 21% of LBW.

One environmental exposure which has been found to increase the risk of low birth weight is particulate matter, a component of ambient air pollution. Because particulate matter is composed of extremely small particles, even nonvisible levels can be inhaled and present harm to the fetus. Particulate matter exposure can cause inflammation, oxidative stress, endocrine disruption, and impaired oxygen transport access to the placenta, all of which are mechanisms for heightening the risk of low birth weight. To reduce exposure to particulate matter, pregnant women can monitor the EPA’s Air Quality Index and take personal precautionary measures such as reducing outdoor activity on low quality days, avoiding high-traffic roads/intersections, and/or wearing personal protective equipment (i.e., facial mask of industrial design). Indoor exposure to particulate matter can also be reduced through adequate ventilation, as well as use of clean heating and cooking methods.

A correlation between maternal exposure to CO and low birth weight has been reported that the effect on birth weight of increased ambient CO was as large as the effect of the mother smoking a pack of cigarettes per day during pregnancy.

It has been revealed that adverse reproductive effects (e.g., risk for LBW) were correlated with maternal exposure to air pollution combustion emissions in Eastern Europe and North America.

Mercury is a known toxic heavy metal that can harm fetal growth and health, and there has been evidence showing that exposure to mercury (via consumption of large oily fish) during pregnancy may be related to higher risks of LBW in the offspring.

It was revealed that, exposure of pregnant women to airplane noise was found to be associated with low birth weight. Aircraft noise exposure caused adverse effects on fetal growth leading to low birth weight and preterm infants.

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

- Ethanol during pregnancy can cause fetal alcohol syndrome and fetal alcohol spectrum disorder. Studies have shown that light to moderate drinking during pregnancy might not pose a risk to the fetus, although no amount of alcohol during pregnancy can be guaranteed to be absolutely safe.

- Tobacco smoking during pregnancy can cause a wide range of behavioral, neurological, and physical difficulties. Smoking during pregnancy causes twice the risk of premature rupture of membranes, placental abruption and placenta previa. Smoking is associated with 30% higher odds of preterm birth.

- Prenatal cocaine exposure is associated with premature birth, birth defects and attention deficit disorder.

- Prenatal methamphetamine exposure can cause premature birth and congenital abnormalities. Short-term neonatal outcomes show small deficits in infant neurobehavioral function and growth restriction. Long-term effects in terms of impaired brain development may also be caused by methamphetamine use.

- Cannabis in pregnancy has been shown to be teratogenic in large doses in animals, but has not shown any teratogenic effects in humans.

A study by the Agency for Healthcare Research and Quality (AHRQ) found that of the 3.8 million births that occurred in the United States in 2011, approximately 6.1% (231,900) were diagnosed with low birth weight (<2,500 g). Approximately 49,300 newborns (1.3%) weighed less than 1,500 grams (VLBW). Infants born at low birth weight are at a higher risk for developing neonatal infection.

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

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

A number of pesticides including dibromochlorophane and 2,4-D has been associated with impaired fertility in males.

Pesticide exposure resulted in reduced fertility in males, genetic alterations in sperm, a reduced number of sperm, damage to germinal epithelium and altered hormone function.

For many adopted or adults and children in foster care, records or other reliable sources may not be available for review. Reporting alcohol use during pregnancy can also be stigmatizing to birth mothers, especially if alcohol use is ongoing. In these cases, all diagnostic systems use an unknown prenatal alcohol exposure designation. A diagnosis of FAS is still possible with an unknown exposure level if other key features of FASD are present at clinical levels.

Amount, frequency, and timing of prenatal alcohol use can dramatically impact the other three key features of FASD. While consensus exists that alcohol is a teratogen, there is no clear consensus as to what level of exposure is toxic. The CDC guidelines are silent on these elements diagnostically. The IOM and Canadian guidelines explore this further, acknowledging the importance of significant alcohol exposure from regular or heavy episodic alcohol consumption in determining, but offer no standard for diagnosis. Canadian guidelines discuss this lack of clarity and parenthetically point out that "heavy alcohol use" is defined by the National Institute on Alcohol Abuse and Alcoholism as five or more drinks per episode on five or more days during a 30-day period.

"The 4-Digit Diagnostic Code" ranking system distinguishes between levels of prenatal alcohol exposure as "high risk" and "some risk". It operationalizes high risk exposure as a blood alcohol concentration (BAC) greater than 100 mg/dL delivered at least weekly in early pregnancy. This BAC level is typically reached by a 55 kg female drinking six to eight beers in one sitting.

Cannabis consumption in pregnancy might be associated with restrictions in growth of the fetus, miscarriage, and cognitive deficits. The American Congress of Obstetricians and Gynecologists recommended that cannabis use be stopped before and during pregnancy, Cannabis is the most commonly used illicit substance

among pregnant women.

Although it is difficult to draw firm conclusions, there is some evidence that prenatal exposure to marijuana may be associated with deficits in language, attention, cognitive performance, and delinquent behaviors. THC exposure in rats during the prenatal developmental phase may cause epigenetic changes in gene expression, but there is limited knowledge about the risk for psychiatric disorders because of ethical barriers to studying the developing human brain. While animal studies cannot take into account factors that could influence the effects of cannabis on human maternal exposure, such as environmental and social factors, a 2011 review of rodent studies by Campolongo "et al." said there was "... increasing evidence from animal studies showing that cannabinoid drugs ... induce enduring neurobehavioral abnormalities in the exposed offspring ..." Campolongo "et al." added that "clinical studies report hyperactivity, cognitive impairments and altered emotionality in humans exposed in utero to cannabis". Martin "et al." investigated recent trends in substance abuse treatment admissions for cannabis use in pregnancy in the US, based on Treatment Episodes Data Set (TEDS) from 1992 to 2012, and discovered that, while the proportion of treatment admissions for pregnant women was stable (about 4%), the admissions for women who were pregnant and reported any marijuana use grew from 29% to 43%. A 2015 review found that cannabis use by pregnant mothers impaired brain maturation in their children, and that it also predisposed their children to neurodevelopmental disorders.

A longitudinal study done on prenatal stress and gender roles showed that prenatal stress only plays a small part in the gender roles the offspring takes on and mentions it has more to do with older siblings, maternal use of alcohol and/or tobacco, maternal education, and the observance or teaching of “traditional sex roles” from the parents.

The role of the endocannabinoid system (ECS) in female fertility has long been suspected and studied. Most studies through 2013 linking development of the fetus and cannabis show effects of consumption during the gestational period, but abnormalities in the endocannabinoid system during the phase of placental development are also linked with problems in pregnancy. According to Sun and Dey (2012), endocannabinoid signaling plays a role in "female reproductive events, including preimplantation embryo development, oviductal embryo transport, embryo implantation, placentation, and parturition". Karusu "et al" (2011) said that a "clear correlation ... in the actual reproductive tissues of miscarrying versus healthy women has yet to be established. However, the adverse effects of marijuana smoke and THC on reproductive functions point to processes that are modulated by ECS."

Keimpema and colleagues (2011) said, "Prenatal cannabis exposure can lead to growth defects during formation of the nervous system"; "[c]annabis impacts the formation and functions of neuronal circuitries by targeting cannabinoid receptors ... By indiscriminately prolonging the "switched-on" period of cannabinoid receptors, cannabis can hijack endocannabinoid signals to evoke molecular rearrangements, leading to the erroneous wiring of neuronal networks". A report prepared for the Australian National Council on Drugs concluded cannabis and other cannabinoids are contraindicated in pregnancy as they may interact with the endocannabinoid system.

Most pregnancies that are diagnosed with confined placental mosaicism continue to term with no complications and the children develop normally.

However, some pregnancies with CPM experience prenatal or perinatal complications. The pregnancy loss rate in pregnancies with confined placental mosaicism, diagnosed by chorionic villus sampling, is higher than among pregnancies without placental mosaicism. It may be that sometimes the presence of significant numbers of abnormal cells in the placenta interferes with proper placental function. An impaired placenta cannot support the pregnancy and this may lead to the loss of a chromosomally normal baby. On the other hand, an apparently normal diploid fetus may experience problems with growth or development due to the effects of uniparental disomy (UPD). Intrauterine growth restriction (IUGR) has been reported in a number of CPM cases. In follow-up studies adequate postnatal catch-up growth has been demonstrated, which may suggest a placental cause of the IUGR.

When predicting the likely effects (if any) of CPM detected in the first trimester, several potentially interactive factors may be playing a role, including:

- "Origin of error:" Somatic errors are associated with lower levels of trisomy in the placenta and are expected usually to involve only one cell line (i.e.: the trophoblast cells or the villus stroma cells). Somatic errors are thus less likely than meiotic errors to be associated with either ultrasound abnormalities, growth problems or detectable levels of trisomy in small samples of prenatal CVS. Currently, there is no evidence that somatic errors, which lead to confined placental trisomy, are of any clinical consequence. Errors of meiotic origin are correlated with higher levels of trisomy in placental tissues and may be associated with adverse pregnancy outcome. The cell type in which the abnormality is seen is also an important factor in determining the risk of fetal involvement. The villus stroma or mesenchymal core is more likely than the cytotrophoblast to be reflective of the fetal genotype.

- "Level of mosaicism:" There is a correlation between a high number of aneuploid cells detected at CVS with poor pregnancy progress. This includes an association between high levels of abnormal cells in placental tissue and concerns with the growth of the baby. However, it is not accurate to use these associations to try to predict pregnancy outcome based on the percent of trisomic cells in a first trimester CVS result.

- "Specific chromosomes:" The influence of CPM on fetal growth is chromosome specific. Certain chromosomes carry imprinted genes involved in growth or placental function, which may contribute to impaired pregnancy progress when CPM is detected. Different chromosomes are observed at different frequencies depending on the type of CPM observed. The pregnancy outcome is strongly chromosome specific. The most frequently seen trisomic cells in confined placental mosaicism involve chromosomes 2, 3, 7, 8 and 16. The next frequently involved are 9, 13, 15, 18, 20 and 22. It has been observed that CPM involving the sex chromosomes usually has no adverse effects on fetal development. The common autosomal trisomies (21, 18, 13) made up a smaller number of cases of mosaicism detected on CVS, but were more often confirmed in fetal tissue (19%). On the other hand, the uncommon autosomal trisomies accounted for a greater number of placental mosaicism cases, but were less often confirmed in fetal tissue (3.2%). When CPM is detected on CVS involving certain chromosomes which are known or suspected to carry imprinted genes, molecular investigations should be performed to exclude fetal UPD. We will explore chromosome specific cases in the chromosome specific section.

- "Type of chromosome abnormality:" The factor that had the highest predictive value as to whether the fetus was affected or not was the type of chromosome abnormality. Marker chromosomes were more often confirmed in the fetus than trisomies. For example, of 28 cases of mosaic polyploidy detected on CVS, fetal mosaicism was confirmed in only one case. This is compared to marker chromosomes detected on CVS, in which mosaicism was confirmed in 1/4 of the fetuses.

Prenatal stress (or prenatal maternal stress) is exposure of an expectant mother to stress, which can be caused by stressful life events or by environmental hardships. The resulting changes to the mother's hormonal and immune system may harm the fetus's (and after birth, the infant's) immune function and brain development.

Prenatal stress is shown to have several affects in fetal brain development. In the hippocampus of adult male rats, prenatal stress has shown to decrease the rate of proliferation and cell death in the hypothalamus-pituitary axis. Prenatal stressed animals have prolonged corticosterone response. Removing the adrenal glands of the mother eliminates the effect of the pup's corticosterone response. Supplementing the adrenalectamized mother with corticosterone, rescued the hypothalamic-pituitary-axis response to maternal stress for prenatally stressed offspring. Prenatal stress caused high glucocorticoids, which in turn affects the hypothalamic-pituitary-axis negative feedback.

A study by García-Cáceres et al. showed that prenatal stress decreases cell turnover and proliferation in the hypothalamus of adult rats, which reduces structural plasticity and reduces the response to stress in adulthood. This study also showed that when prenatally stressed rats were stressed in adulthood the females showed an increase in corticotropin-releasing hormone suggesting it to be an up-regulation in the hypothalamic-pituitary adrenal axis. Males showed no elevation of corticosterone levels. Increase in adrenocorticotropic hormone with no effect of adult stress and a decrease in the corticotropin-releasing hormone mRNA in the hypothalamus showed a down-regulation. The author concludes that this makes prenatally stressed females less reactive to later life stressors than males.