Twin-to-twin transfusion syndrome (TTTS), also known as feto-fetal transfusion syndrome (FFTS) and twin oligohydramnios-polyhydramnios sequence (TOPS) is a complication of disproportionate blood supply, resulting in high morbidity and mortality. It can affect monochorionic multiples, that is, multiple pregnancies where two or more fetuses share a chorion and hence a single placenta. Severe TTTS has a 60–100% mortality rate.

Intrauterine hypoxia occurs when the fetus is deprived of an adequate supply of oxygen. It may be due to a variety of reasons such as prolapse or occlusion of the umbilical cord, placental infarction and maternal smoking. Intrauterine growth restriction (IUGR) may cause or be the result of hypoxia. Intrauterine hypoxia can cause cellular damage that occurs within the central nervous system (the brain and spinal cord). This results in an increased mortality rate, including an increased risk of sudden infant death syndrome (SIDS). Oxygen deprivation in the fetus and neonate have been implicated as either a primary or as a contributing risk factor in numerous neurological and neuropsychiatric disorders such as epilepsy, ADHD, eating disorders and cerebral palsy.

Perinatal mortality (PNM), also perinatal death, refers to the death of a fetus or neonate and is the basis to calculate the perinatal mortality rate. Variations in the precise definition of the perinatal mortality exist specifically concerning the issue of inclusion or exclusion of early fetal and late neonatal fatalities. The World Health Organization defines perinatal mortality as the "number of stillbirths and deaths in the first week of life per 1,000 total births, the perinatal period commences at 22 completed weeks (154 days) of gestation and ends seven completed days after birth", but other definitions have been used.

The UK figure is about 8 per 1,000 and varies markedly by social class with the highest rates seen in Asian women. Globally about 2.6 million neonates died in 2013 before the first month of age down from 4.5 million in 1990.

Perinatal asphyxia, neonatal asphyxia or birth asphyxia is the medical condition resulting from deprivation of oxygen to a newborn infant that lasts long enough during the birth process to cause physical harm, usually to the brain. Hypoxic damage can occur to most of the infant's organs (heart, lungs, liver, gut, kidneys), but brain damage is of most concern and perhaps the least likely to quickly or completely heal. In more pronounced cases, an infant will survive, but with damage to the brain manifested as either mental, such as developmental delay or intellectual disability, or physical, such as spasticity.

It results most commonly from a drop in maternal blood pressure or some other substantial interference with blood flow to the infant's brain during delivery. This can occur due to inadequate circulation or perfusion, impaired respiratory effort, or inadequate ventilation. Perinatal asphyxia happens in 2 to 10 per 1000 newborns that are born at term, and more for those that are born prematurely. WHO estimates that 4 million neonatal deaths occur yearly due to birth asphyxia, representing 38% of deaths of children under 5 years of age.

Perinatal asphyxia can be the cause of hypoxic ischemic encephalopathy or intraventricular hemorrhage, especially in preterm births. An infant suffering severe perinatal asphyxia usually has poor color (cyanosis), perfusion, responsiveness, muscle tone, and respiratory effort, as reflected in a low 5 minute Apgar score. Extreme degrees of asphyxia can cause cardiac arrest and death. If resuscitation is successful, the infant is usually transferred to a neonatal intensive care unit.

There has long been a scientific debate over whether newborn infants with asphyxia should be resuscitated with 100% oxygen or normal air. It has been demonstrated that high concentrations of oxygen lead to generation of oxygen free radicals, which have a role in reperfusion injury after asphyxia. Research by Ola Didrik Saugstad and others led to new international guidelines on newborn resuscitation in 2010, recommending the use of normal air instead of 100% oxygen.

There is considerable controversy over the diagnosis of birth asphyxia due to medicolegal reasons. Because of its lack of precision, the term is eschewed in modern obstetrics.

A staging system proposed by fetal surgeon Dr. Ruben Quintero is commonly used to classify the severity of TTTS.

Stage I: A small amount of amniotic fluid (oligohydramnios) is found around the donor twin and a large amount of amniotic fluid (polyhydramnios) is found around the recipient twin.

Stage II: In addition to the description above, the ultrasound is not able to identify the bladder in the donor twin.

Stage III: In addition to the characteristics of Stages I and II, there is abnormal blood flow in the umbilical cords of the twins.

Stage IV: In addition to all of the above findings, the recipient twin has swelling under the skin and appears to be experiencing heart failure (fetal hydrops).

Stage V: In addition to all of the above findings, one of the twins has died. This can happen to either twin. The risk to either the donor or the recipient is roughly equal & is quite high in Stage II or higher TTTS.

The Quintero staging does not provide information about prognosis, and other staging systems have been proposed.

Preterm birth is the most common cause of perinatal mortality, causing almost 30 percent of neonatal deaths. Infant respiratory distress syndrome, in turn, is the leading cause of death in preterm infants, affecting about 1% of newborn infants. Birth defects cause about 21 percent of neonatal death.

There are several pathologic conditions that can predispose a pregnancy to polyhydramnios. These include a maternal history of diabetes mellitus, Rh incompatibility between the fetus and mother, intrauterine infection, and multiple pregnancies.

During the pregnancy, certain clinical signs may suggest polyhydramnios. In the mother, the physician may observe increased abdominal size out of proportion for her weight gain and gestation age, uterine size that outpaces gestational age, shiny skin with stria (seen mostly in severe polyhydramnios), dyspnea, and chest heaviness. When examining the fetus, faint fetal heart sounds are also an important clinical sign of this condition.

There are various causes for intrauterine hypoxia (IH). The most preventable cause is maternal smoking. Cigarette smoking by expectant mothers has been shown to have a wide variety of deleterious effects on the developing fetus. Among the negative effects are carbon monoxide induced tissue hypoxia and placental insufficiency which causes a reduction in blood flow from the uterus to the placenta thereby reducing the availability of oxygenated blood to the fetus. Placental insufficiency as a result of smoking has been shown to have a causal effect in the development of pre-eclampsia. While some previous studies have suggested that carbon monoxide from cigarette smoke may have a protective effect against preeclampsia, a recent study conducted by the Genetics of Pre-Eclampsia Consortium (GOPEC) in the United Kingdom found that smokers were five times more likely to develop pre-eclampsia.

Nicotine alone has been shown to be a teratogen which affects the autonomic nervous system, leading to increased susceptibility to hypoxia-induced brain damage.

Maternal anemia in which smoking has also been implicated is another factor associated with IH/BA. Smoking by expectant mothers causes a decrease in maternal nucleated red blood cells (NRBC), thereby reducing the amount of red blood cells available for oxygen transport.

The perinatal brain injury occurring as a result of birth asphyxia, manifesting within 48 hours of birth, is a form of hypoxic ischemic encephalopathy.

In most cases, the exact cause cannot be identified. A single case may have one or more causes, including intrauterine infection (TORCH), rh-isoimmunisation, or chorioangioma of the placenta. In a multiple gestation pregnancy, the cause of polyhydramnios usually is twin-to-twin transfusion syndrome. Maternal causes include cardiac problems, kidney problems, and maternal diabetes mellitus, which causes fetal hyperglycemia and resulting polyuria (fetal urine is a major source of amniotic fluid).

A recent study distinguishes between mild and severe polyhydramnios and showed that Apgar score of less than 7, perinatal death and structural malformations only occurred in women with severe polyhydramnios.

In another study, all patients with polyhydramnios, that had a sonographically normal fetus, showed no chromosomal anomalies.

but these anomalies include:

- gastrointestinal abnormalities such as esophageal atresia & duodenal atresia (causing inability to swallow amniotic fluid), anencephaly, facial cleft, neck masses, tracheoesophageal fistula, and diaphragmatic hernias. An annular pancreas causing obstruction may also be the cause.

- Bochdalek's hernia, in which the pleuro-peritoneal membranes (especially the left) will fail to develop & seal the pericardio- peritoneal canals. This results in the stomach protrusion up into the thoracic cavity, and the fetus is unable to swallow sufficient amounts of amniotic fluid.

- fetal renal disorders that result in increased urine production during pregnancy, such as in antenatal Bartter syndrome. Molecular diagnosis is available for these conditions.

- neurological abnormalities such as anencephaly, which impair the swallowing reflex. Anencephaly is failure of close of the rostral neuropore (rostral neural tube defect). If the rostral neuropore fails to close there will be no neural mechanism for swallowing.

- chromosomal abnormalities such as Down syndrome and Edwards syndrome (which is itself often associated with GI abnormalities)

- Skeletal dysplasia, or dwarfism. There is a possibility of the chest cavity not being large enough to house all of the baby's organs causing the trachea and esophagus to be restricted, not allowing the baby to swallow the appropriate amount of amniotic fluid.

- sacrococcygeal teratoma

Hyperemesis gravidarum is the presence of severe and persistent vomiting, causing dehydration and weight loss. It is more severe than the more common morning sickness and is estimated to affect 0.5–2.0% of pregnant women.

Several terms are used to describe congenital abnormalities. (Some of these are also used to describe noncongenital conditions, and more than one term may apply in an individual condition.)

Gestational diabetes is when a woman without diabetes develops high blood sugar levels during pregnancy.

Much of the language used for describing congenital conditions predates genomic mapping, and structural conditions are often considered separately from other congenital conditions. It is now known that many metabolic conditions may have subtle structural expression, and structural conditions often have genetic links. Still, congenital conditions are often classified in a structural basis, organized when possible by primary organ system affected.

TTN is a diagnosis of exclusion as it is a benign condition that can have symptoms and signs similar to more serious conditions, such as respiratory distress syndrome. A chest X-ray may show a radiopaque line - fluid - in the horizontal fissure of the right lung, fluid infiltrate throughout alveoli or fluid in individual lung lobes. The lungs may also appear hyperinflated.

Transient tachypnea of the newborn (TTN, TTNB, or "transitory tachypnea of newborn") is a respiratory problem that can be seen in the newborn shortly after delivery. Amongst causes of respiratory distress in term neonates, it is the most common. It consists of a period of rapid breathing (higher than the normal range of 30-60 times per minute). It is likely due to amniotic fluid remaining in the lungs after birth. Usually, this condition resolves over 24–48 hours. Treatment is supportive and may include supplemental oxygen and antibiotics. The chest x-ray shows hyperinflation of the lungs including prominent pulmonary vascular markings, flattening of the diaphragm, and fluid in the horizontal fissure of the right lung.

The main symptoms of AIE include:

- Diarrhea (frequent loss of fluids)

- Intestinal inflammation

- Vomiting

- Intestinal bleeding

- Difficulty or inability to gain weight

- Rapid weight loss

- Decreased urine output from dehydration

Neonatal hypocalcemia is an abnormal clinical and laboratory hypocalcemia condition that is frequently observed in infants.[1]

Healthy term infants go through a physiological nadir of serum calcium levels at 7.5 - 8.5 mg/dL by day 2 of life. Hypocalcemia is a low blood calcium level. A total serum calcium of less than 8 mg/dL (2mmol/L) or ionized calcium less than 1.2 mmol/L in term neonates is defined as hypocalcemia. In preterm infants, it is defined as less than 7mg/dL (1.75 mmol/L) total serum calcium or less than 4mg/dL (1 mmol/L) ionized calcium. [2]

Both early onset hypocalcemia (presents within 72h of birth) and late onset hypocalcemia (presents in 3-7 days after birth) require calcium supplementation treatment.

Circumvallate placenta is a placental morphological abnormalitiy, a subtype of placenta extrachorialis in which the fetal membranes (chorion and amnion) "double back" on the fetal side around the edge of the placenta. After delivery, a circumvallate placenta has a thick ring of membranes on its fetal surface.

The fetal surface is divided into a central depressed zone surrounded by a thickened white ring which is incomplete the ring is situated at varying distance from the margin of the placenta. The ring is composed of a double fold of amnion and chorion with degenerated decidua vera and fibrin in between. Vessels radiate from the cord insertion as far as the ring and then disappear from the view.

Complete circumvallate placenta occurs in approximately 1% of pregnancies. It is diagnosed prenatally by medical ultrasonography, although one 1997 study of prenatal ultrasounds found that "of the normal placentas, 35% were graded as probably or definitely circumvallate by at least one sonologist," and "all sonologists misgraded the case of complete circumvallation as normal." The condition is associated with perinatal complications such as placental abruption, oligohydramnios, abnormal cardiotocography, preterm birth, and miscarriage.

There are 3 types of autoimmune enteropathy:

Type 1: IPEX syndrome: Immune dysregulation, Polyendocrinopathy, Enteropathy, X – linked

Type 2: IPEX-like, which manifests similarly to IPEX syndrome but without recognizable mutations in the FOXP3 gene. This can affect both genders and includes a variety of manifestations of varying severity.

Type 3: Autoimmune manifestations primarily limited to the GI tract. This can affect both genders and may also be considered IPEX-like.

There is considerable overlap in these disorders, and it is often unclear how to properly distinguish between them as the responsible genes are generally poorly understood at this time.

Some of the possible symptoms that can occur with metabolic disorders are: lethargy, weight loss, jaundice, seizures, to name a few. The symptoms expressed would vary with the type of metabolic disorder. There are four categories of symptoms: acute symptoms, late-onset acute symptoms, progressive general symptoms and permanent symptoms.

Often AGID is a symptom of other problems, including colon cancer, lupus, lung, breast, or ovarian carcinoma or thymoma. or other diseases. Irritable bowel syndrome (IBS) is the most recognized form of AGID.

Usually associated with diaphragmatic hernia,

pulmonary hypoplasia,

imperforate anus,

micropenis,

bilateral cryptorchidism,

cerebral ventricular dilation,

camptodactyly,

agenesis of sacrum,

low-set ear.

- Fryns et al. (1979) reported 2 stillborn sisters with a multiple congenital anomaly syndrome characterized by coarse facies with cloudy corneae, diaphragmatic defects, absence of lung lobulation, and distal limb deformities. A sporadic case was reported by Goddeeris et al. (1980). Fitch (1988) claimed that she and her colleagues were the first to describe this disorder. In 1978 they reported a single infant, born of second-cousin parents, who had absent left hemidiaphragm, hydrocephalus, arhinencephaly, and cardiovascular anomalies.

- Lubinsky et al. (1983) reported a brother and sister with Fryns syndrome who both died in the neonatal period. Facial anomalies included broad nasal bridge, microretrognathia, abnormal helices, and cleft palate. Other features included distal digital hypoplasia, lung hypoplasia, and urogenital abnormalities, including shawl scrotum, uterus bicornis, and renal cysts. They were discordant for diaphragmatic hernia, cleft lip, and Dandy–Walker anomaly.

- Meinecke and Fryns (1985) reported an affected child; consanguinity of the parents supported recessive inheritance. They noted that a diaphragmatic defect had been described in 4 of the 5 reported cases and lung hypoplasia in all. Young et al. (1986) reported a sixth case. The male infant survived for 12 days. These authors listed corneal clouding, camptodactyly with hypoplastic nails, and abnormalities of the diaphragm as cardinal features.

- Samueloff et al. (1987) described a family in which all 4 children had Fryns syndrome and neonatal mortality. Features included hypoplastic lungs, cleft palate, retrognathia, micrognathism, small thorax, diaphragmatic hernia, distal limb hypoplasia, and early onset of polyhydramnios with premature delivery. Schwyzer et al. (1987) described an affected infant whose parents were second cousins.

- Moerman et al. (1988) described infant brother and sister with the syndrome of diaphragmatic hernia, abnormal face, and distal limb anomalies. Both died shortly after birth with severe respiratory distress. Ultrasonography demonstrated fetal hydrops, diaphragmatic hernia, and striking dilatation of the cerebral ventricles in both infants. Post-mortem examination showed Dandy–Walker malformation, ventricular septal defect, and renal cystic dysplasia.

- Cunniff et al. (1990) described affected brothers and 3 other cases, bringing the total reported cases of Fryns syndrome to 25. One of the affected brothers was still alive at the age of 24 months. Bilateral diaphragmatic hernias had been repaired on the first day of life. He required extracorporeal membrane oxygenation therapy for 5 days and oscillatory therapy for 3 months. Ventriculoperitoneal shunt was required because of slowly progressive hydrocephalus. Scoliosis was associated with extranumerary vertebral bodies and 13 ribs. Because of delayed gastric emptying, a gastrostomy tube was inserted. In addition, because of persistent chylothorax, he underwent decortication of the right lung and oversewing of the thoracic duct.

- Kershisnik et al. (1991) suggested that osteochondrodysplasia is a feature of Fryns syndrome.

- Willems et al. (1991) suggested that a diaphragmatic hernia is not a necessary feature of Fryns syndrome. They described a child with all the usual features except for diaphragmatic hernia; the diaphragm was reduced to a fibrous web with little muscular component. Bartsch et al. (1995) presented 2 unrelated cases with a typical picture of Fryns syndrome but without diaphragmatic hernia. One of these patients was alive at the age of 14 months, but was severely retarded. Bamforth et al. (1987) and Hanssen et al. (1992) also described patients with this syndrome who survived the neonatal period. In the report of Hanssen et al. (1992), 2 older sibs had died in utero. The reports suggested that survival beyond the neonatal period is possible when the diaphragmatic defect and lung hypoplasia are not present. However, mental retardation has been present in all surviving patients.

- Vargas et al. (2000) reported a pair of monozygotic twins with Fryns syndrome discordant for severity of diaphragmatic defect. Both twins had macrocephaly, coarse facial appearance, hypoplasia of distal phalanges, and an extra pair of ribs. Twin A lacked an apparent diaphragmatic defect, and at 1 year of age had mild developmental delay. Twin B had a left congenital diaphragmatic hernia and died neonatally. The authors suggested that absence of diaphragmatic defect in Fryns syndrome may represent a subpopulation of more mildly affected patients.

- Aymé, "et al." (1989) described 8 cases of Fryns syndrome in France. The most frequent anomalies were diaphragmatic defects, lung hypoplasia, cleft lip and palate, cardiac defects, including septal defects and aortic arch anomalies, renal cysts, urinary tract malformations, and distal limb hypoplasia. Most patients also had hypoplastic external genitalia and anomalies of internal genitalia, including bifid or hypoplastic uterus or immature testes. The digestive tract was also often abnormal; duodenal atresia, pyloric hyperplasia, malrotation and common mesentery were present in about half of the patients. When the brain was examined, more than half were found to have Dandy–Walker anomaly and/or agenesis of the corpus callosum. A few patients demonstrated cloudy cornea. Histologically, 2 of 3 patients showed retinal dysplasia with rosettes and gliosis of the retina, thickness of the posterior capsule of the lens, and irregularities of Bowman membrane.

- Alessandri et al. (2005) reported a newborn from the Comores Islands with clinical features of Fryns syndrome without diaphragmatic hernia. They noted that diaphragmatic hernia is found in more than 80% of cases and that at least 13 other cases had been reported with an intact diaphragm.

- In a postneonatal survivor of Fryns syndrome, Riela et al. (1995) described myoclonus appearing shortly after birth, which was well controlled on valproate. Progressive cerebral and brainstem atrophy was noted on serial MRIs made at 3 months and after 6 months of age.

- Van Hove et al. (1995) described a boy with Fryns syndrome who survived to age 3 years and reviewed the outcome of other reported survivors (approximately 14% of reported cases). Survivors tended to have less frequent diaphragmatic hernia, milder lung hypoplasia, absence of complex cardiac malformation, and severe neurologic impairment. Their patient had malformations of gyration and sulcation, particularly around the central sulcus, and hypoplastic optic tracts beyond the optic chiasm associated with profound mental retardation.

- Fryns and Moerman (1998) reported a second-trimester male fetus with Fryns syndrome and midline scalp defects. The authors stated that the finding of a scalp defect in Fryns syndrome confirms that it is a true malformation syndrome with major involvement of the midline structures.

- Ramsing et al. (2000) described 2 sibships with 4 fetuses and 1 preterm baby of 31 weeks' gestation affected by a multiple congenital disorder suggestive of Fryns syndrome. In addition to the diaphragmatic defects and distal limb anomalies, they presented with fetal hydrops, cystic hygroma, and multiple pterygias. Two affected fetuses in 1 family showed severe craniofacial abnormalities with bilateral cleft lip and palate and cardiovascular malformation.

- Arnold et al. (2003) reported a male fetus with Fryns syndrome and additional abnormalities, in particular, multiple midline developmental defects including gastroschisis, central nervous system defects with left arrhinencephaly and cerebellar hypoplasia, midline cleft of the upper lip, alveolar ridge, and maxillary bone, and cleft nose with bilateral choanal atresia.

- Pierson et al. (2004) reviewed 77 reported patients with Fryns syndrome and summarized the abnormal eye findings identified in 12 of them. They also described 3 new patients with Fryns syndrome, 1 of whom demonstrated unilateral microphthalmia and cloudy cornea.

- Slavotinek et al. (2005) noted that Fryns syndrome may be the most common autosomal recessive syndrome in which congenital diaphragmatic hernia (see DIH2, 222400) is a cardinal feature. The autosomal recessive inheritance in Fryns syndrome contrasts with the sporadic inheritance for most patients with DIH.

Risk factors of early neonatal hypocalcemia

- Prematurity

- Perinatal asphyxia

- Diabetes mellitus in the mother

- Maternal hyperparathyroidism

- Intrauterine growth retardation (IUGR)

- Iatrogenic

Risk factors of late neonatal hypocalcemia

- Exogenous phosphate load

- Use of gentamicin

- Gender and ethnic: late neonatal hypocalcemia occurred more often in male infants and Hispanic infants

- Others

Since primordial dwarfism disorders are extremely rare, misdiagnosis is common. Because children with PD do not grow like other children, poor nutrition, a metabolic disorder, or a digestive disorder may be diagnosed initially. The correct diagnosis of PD may not be made until the child is 5 years old and it becomes apparent that the child has severe dwarfism.

AIDS dysmorphic syndrome, also called HIV embryopathy, is a cluster of facial malformations seen in children with perinatal HIV infection. Its status as a syndrome is disputed by the research community. Common symptoms of perinatal HIV infection include candidiasis, lymphocytic interstitial pneumonitis, hepatosplenomegaly, and lymphadenopathy.