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.

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.

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

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.

As a result of sharing a single placenta, the blood supplies of monochorionic twin fetuses can become connected, so that they share blood circulation: although each fetus uses its own portion of the placenta, the connecting blood vessels within the placenta allow blood to pass from one twin to the other. It is thought that most monochorionic placentae have these "shared connections" that cross the placenta, with the net flow volumes being equal between them. This state is sometimes referred to as "flow balance". Depending on the number, type and direction of the interconnecting blood vessels (anastomoses), blood can be transferred disproportionately from one twin (the "donor") to the other (the "recipient"), due to a state of "flow imbalance" imparted by new blood vessel growth across the placental "equator", the line that divides each baby's proportion of the shared placenta. This state of transfusion causes the donor twin to have decreased blood volume, retarding the donor's development and growth, and also decreased urinary output, leading to a lower than normal level of amniotic fluid (becoming oligohydramnios). The blood volume of the recipient twin is increased, which can strain the fetus's heart and eventually lead to heart failure, and also higher than normal urinary output, which can lead to excess amniotic fluid (becoming polyhydramnios).

TTTS usually develops during the period of peak placental growth, starting in week 16 and proceeding through week 25; after this point, the placenta's growth decelerates, essentially stopping just after week 30. While TTTS has occasionally been detected beyond this timepoint, it is thought that its occurrence beyond week 30 may be due to a placental embolism that upsets the flow balance of the shared connections between the babies. TTTS is potentially lethal to either or both twins, no matter when it is detected. However, when detected past week 25, emergency delivery may be considered to rescue the babies if the TTTS is severe.

Other than requiring a monochorionic twin (or higher multiple) pregnancy, the underlying causes of TTTS are not known. It is not known to be hereditary or genetic.

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.

Signs and symptoms of CTLN1 in infants are caused by increasing levels of ammonia in the blood and cerebrospinal fluid and include excessive vomiting, anorexia, refusal to eat, irritability, increased intracranial pressure, and worsening lethargy, seizures, hypotonia, respiratory distress, hepatomegaly, and cerebral edema. These symptoms appear within days of birth in the more severe forms of the disease with complete deficiency of the enzyme. As ammonia accumulates further, the affected infant may enter a hyperammonemic coma, which indicates neurological damage and can cause developmental delays, cognitive disabilities, cerebral palsy, hypertonia, spasticity, ankle clonus, seizures, and liver failure.

Milder forms of the disease are caused by partial arginosuccinate synthetase deficiency and may manifest in childhood or in adulthood. Symptoms of mild CTLN1 include failure to thrive, avoidance of high-protein foods, ataxia, worsening lethargy, and vomiting. Hyperammonemic coma can still develop in these people. CTLN1 can also develop in the perinatal period.

In neonates born at or beyond 35 weeks, neonatal encephalopathy may present itself as the following symptoms:

- Reduced level of consciousness

- Seizures (which peak at 48 hours)

- Difficulty initiating and maintaining respiration

- Depression of tone and reflexes

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.

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

Neonatal encephalopathy (NE), also known as neonatal hypoxic-ischemic encephalopathy (neonatal HIE or NHIE), is defined by signs and symptoms of abnormal neurological function in the first few days of life in an infant born at term. In this condition there is difficulty initiating and maintaining respirations, a subnormal level of consciousness, and associated depression of tone, reflexes, and possibly seizures. Encephalopathy is a nonspecific response of the brain to injury which may occur via multiple methods, but is commonly caused by birth asphyxia.

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.

LCCS1 is characterized by total lack of the movements of the fetus, and is detectable at 13th week of pregnancy. It is accompanied by oedema, small chin, small lungs, crooked joints and occasional skin webs of the neck and elbows. The fetus has characteristic pattern of malpositions recognizable even in severely macerated fetuses with club feet and hyperextension of the knees but the elbows and wrists showing flexion contractures.

Neuropathological analysis shows lack of anterior horn motoneurons and severe atrophy of the ventral spinal cord. The skeletal muscles are severely hypoplastic.

Infantile hypophosphatasia presents in the first 6 months of life, with the onset of poor feeding and inadequate weight gain. Clinical manifestations of rickets often appear at this time. Although cranial sutures appear to be wide, this reflects hypomineralization of the skull, and there is often “functional” craniosynostosis. If the patient survives infancy, these sutures can permanently fuse. Defects in the chest, such as flail chest resulting from rib fractures, lead to respiratory compromise and pneumonia. Elevated calcium in the blood (hypercalcemia) and urine (hypercalcenuria) are also common, and may explain the renal problems and recurrent vomiting seen is this disease.

Radiographic features in infants are generally less severe than those seen in perinatal hypophosphatasia. In the long bones, there is an abrupt change from a normal appearance in the shaft (diaphysis) to uncalcified regions near the ends (metaphysis), which suggests the occurrence of an abrupt metabolic change. In addition, serial radiography studies suggest that defects in skeletal mineralization (i.e. rickets) persist and become more generalized. Mortality is estimated to be 50% in the first year of life.

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.

Hypophosphatasia in childhood has variable clinical expression. As a result of defects in the development of the dental cementum, the deciduous teeth (baby teeth) are often lost fore the age of 5. Frequently, the incisors are lost first; occasionally all of the teeth are lost prematurely. Dental radiographs can show the enlarged pulp chambers and root canals that are characteristic of rickets.

Patients may experience delayed walking, a characteristic waddling gait, stiffness and pain, and muscle weakness (especially in the thighs) consistent with nonprogressive myopathy. Typically, radiographs show defects in calcification and characteristic bony defects near the ends of major long bones. Growth retardation, frequent fractures, and low bone density (osteopenia) are common. In severely-affected infants and young children, cranial bones can fuse prematurely, despite the appearance of open fontanels on radiographic studies. The illusion of open fontanels results from hypomineralization of large areas of the calvarium. Premature bony fusion of the cranial sutures may elevate intracranial pressure.

Citrullinemia type I (CTLN1), also known as arginosuccinate synthetase deficiency, is a rare disease caused by a deficiency in argininosuccinate synthetase, an enzyme involved in excreting excess nitrogen from the body. There are mild and severe forms of the disease, which is one of the urea cycle disorders.

Prenatal and neonatal diagnosis of boomerang dysplasia includes several prominent features found in other osteochondrodysplasias, though the "boomerang" malformation seen in the long bones is the delineating factor.

Featured symptoms of boomerang dysplasia include: dwarfism (a lethal type of infantile dwarfism caused by systemic bone deformities), underossification (lack of bone formation) in the limbs, spine and ilium (pelvis); proliferation of multinucleated giant-cell chondrocytes (cells that produce cartilage and play a role in skeletal development - chondrocytes of this type are rarely found in osteochondrodysplasias), brachydactyly (shortened fingers) and (undersized, shortened bones).

The characteristic "boomerang" malformation presents intermittently among random absences of long bones throughout the skeleton, in affected individuals. For example, one individual may have an absent radius and fibula, with the "boomerang" formation found in both ulnas and tibias. Another patient may present "boomerang" femora, and an absent tibia.

Lethal congenital contracture syndrome 1 (LCCS1), also called Multiple contracture syndrome, Finnish type, is an autosomal recessive genetic disorder characterized by total immobility of a fetus, detectable at around the 13th week of pregnancy. LCCS1 invariably leads to prenatal death before the 32nd gestational week. LCCS1 is one of 40 Finnish heritage diseases. It was first described in 1985 and since then, approximately 70 cases have been diagnosed.

Low birth weight (LBW) is defined by the World Health Organization as a birth weight of a

infant of 2,499 g or less, regardless of gestational age. Subcategories include very low birth weight (VLBW), which is less than 1500 g (3 pounds 5 ounces), and extremely low birth weight (ELBW), which is less than 1000 g (2 pounds 3 ounces). Normal weight at term delivery is 2500–4200 g (5 pounds 8 ounces – 9 pounds 4 ounces).

HELLP usually begins during the third trimester; rare cases have been reported as early as 21 weeks gestation. Often, a woman who develops HELLP syndrome has already been followed up for pregnancy-induced hypertension (gestational hypertension), or is suspected to develop pre-eclampsia (high blood pressure and proteinuria). Up to 8% of all cases occur after delivery.

Women with HELLP syndrome often appear non-toxic. Early symptoms can include:

- In 90% of cases, either epigastric pain described as "heartburn" or right upper quadrant pain develops.

- In 90% of cases, malaise occurs.

- In 50% of cases, nausea or vomiting happen.

Gradual but marked onset of headaches (30%), blurred vision, and paresthesia (tingling in the extremities) can occur. Edema may occur, but its absence does not exclude HELLP syndrome. Arterial hypertension is a diagnostic requirement, but may be mild. Rupture of the liver capsule and a resultant hematoma may occur. If a woman has a seizure or coma, the condition has progressed into full-blown eclampsia.

Disseminated intravascular coagulation is also seen in about 20% of all women with HELLP syndrome, and in 84% when HELLP is complicated by acute renal failure. Pulmonary edema is found in 6% of all women with HELLP syndrome, and when HELLP is complicated by acute renal failure, pulmonary edema is found in 44% of women with the syndrome.

A woman with symptoms of HELLP can be misdiagnosed in the early stages, increasing the risk of liver failure and morbidity. Rarely, after a caesarean section surgery, a woman may have signs and symptoms of a shock condition mimicking either pulmonary embolism or reactionary haemorrhage.

Fibrochondrogenesis is a congenital disorder presenting several features and radiological findings, some which distinguish it from other osteochondrodysplasias. These include: fibroblastic dysplasia and fibrosis of chondrocytes (cells which form cartilage); and flared, widened

long bone metaphyses (the portion of bone that grows during childhood).

Other prominent features include dwarfism, shortened ribs that have a appearance, micrognathism (severely underdeveloped jaw), macrocephaly (enlarged head), thoracic hypoplasia (underdeveloped chest), enlarged stomach, platyspondyly (flattened spine), and the somewhat uncommon deformity of tongue (in which the tongue appears split, resembling that of a reptile).

GRACILE syndrome is a very rare autosomal recessive genetic disorder, one of the Finnish heritage diseases. It is caused by mutation in BCS1L gene that occurs in at least 1 out of 47,000 live births in Finnish people.

GRACILE is an acronym for growth retardation, amino aciduria (amino acids in the urine), cholestasis, iron overload, lactic acidosis, and early death. Other names for this syndrome include Finnish lethal neonatal metabolic syndrome (FLNMS); lactic acidosis, Finnish, with hepatic hemosiderosis; and Fellman syndrome.

Boomerang dysplasia is a lethal form of osteochondrodysplasia known for a characteristic congenital feature in which bones of the arms and legs are malformed into the shape of a boomerang. Death usually occurs in early infancy due to complications arising from overwhelming systemic bone malformations.

Osteochondrodysplasias are skeletal disorders that cause malformations of both bone and cartilage.