Calcium Disorders In Pregnancy

Calcium metabolism is dramatically altered by pregnancy and lactation. The normal fetal skeleton accumulates approximately 30g of calcium by term, proportional to the fetal weight. The largest proportion (80%) of that accretion occurs in the third trimester, at a rate of about 250-300 mg/day (181).

Total serum calcium levels fall early in pregnancy, due to hemodilution and the consequent decline in serum albumin (Figure 4). Ionized calcium levels and phosphate levels remain normal throughout pregnancy (181-5). PTH levels fall to 10-30% of the mean nonpregnant range in the first trimester but increase again to the midnormal range by term (185-7). Serum calcitonin levels increase during gestation (184,188), partly due to extrathyroidal synthesis in the placenta and breast. While PTH levels decline, total and free 1,25-dihydroxyvitamin D levels increase 2-fold in the first trimester, then remain constant until term (187,188). The maternal kidneys are the primary source for this increase in vitamin D secondary to up-regulation of the renal 1a-hydroxylase by PTHrP, with possibly small contributions from the maternal deciduas (189). PTHrP appears to increase early during pregnancy (190,191). The role of PTHrP is manifold. The amino-terminal portion stimulates renal 1a-hydroxylase and skeletal calcium resorption (189). It can also inhibit acetylcholine-induced uterine contractions in the rat and is decreased acutely in the amnion and myometrium at the onset of labor in humans (192). The carboxy-terminal portion inhibits osteoclastic bone resorption (“osteostatin”), while the mid-portion stimulates placental calcium transfer (189). The roles of estradiol, progestins, prolactin, chorionic somatomammotropin, and IGF-1 are still under investigation.

Figure 4. Schematic illustration of the longitudinal changes in calcium, phosphate, and calcitropic hormone levels that occur during human pregnancy. Normal adults ranges are indicated by the shaded areas. The progression in PTHrP levels has been depicted by a dashed line to reflect that the data are less complete. (From Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocrine Revs 1997;18:832.)

With the increase in 1,25-dihydroxyvitamin D, there is increased intestinal expression of the vitamin D-dependent calcium binding protein calbindin9K-D (189). This leads to a doubling in intestinal calcium absorption by 12 weeks of gestation (187), and appears to be the major maternal adaptation to supply the fetal calcium requirements. Prolactin and somatomammotropin may also play roles in this increased calcium absorption (189). Animal models suggest that this increased calcium intake is stored in the maternal skeleton until required in the third trimester, but this has not been assessed in humans.

Urinary calcium excretion increases early in gestation secondary to an increased calcium load filtered by the kidneys and the increased glomerular filtration rate of pregnancy. The elevation of calcitonin levels may also contribute. Renal calcium excretion is low or normal in the fasted state (190).

In pregnant rat models, bone turnover is increased but bone mineral content is unchanged. Bone biopsies of women who underwent an elective termination of pregnancy in the first trimester revealed increased bone resorption, with increased resorption surface, increased number of resorption cavities, and decreased osteoid (193). This is not seen at term.

Most of the investigations of skeletal metabolism in pregnancy use bone markers and have a number of confounding variables including lack of prepregnancy baseline values, alterations in renal clearance, contributions from the gravid uterus, clearance by the placenta and hemodilution. Alkaline phosphatase is secreted by the placenta, and is not useful as a marker of bone formation in pregnancy. Urinary deoxypyridinoline, pyridinoline, and hydroxyproline increase in early to mid-pregnancy, suggesting bone resorption at that time (181). Bone formation markers osteocalcin and bone-specific alkaline phosphatase are decreased in early pregnancy and rise to normal or above by term (181). These findings suggest an increase in bone turnover in the first trimester but do not demonstrate a dramatic increase in the third trimester when most of the maternal-fetal calcium transfer occurs.

Studies of bone mineral density in pregnancy are limited because of the concerns regarding fetal radiation exposure and the confounding effects of altered maternal body composition and weight. Conflicting results have been obtained according to the method of bone density measurement used, the site examined, and the timing during gestation and postpartum. Ultrasonography at the os calcis suggests a decline in bone mineral density through gestation (194,195). Numerous studies of osteoporotic women do not demonstrate a significant association with parity (196), suggesting that any effect on bone metabolism is transient.

Osteoporosis

Transient, focal osteoporosis of the hip is a rare self-limited form of osteoporosis usually found in the third trimester or early postpartum. It generally presents as unilateral or bilateral hip pain, limp, and possible hip fracture. Bone mineral density is diminished at the femoral neck and head, with increased water content in the bone and the marrow. It generally resolves spontaneously within 2 to 6 months. There is no apparent association with the calcitropic hormones. Theories to explain this focal condition include femoral venous stasis secondary to compression by the gravid uterus, fetal pressure on the obturator nerve, marrow hypertrophy, immobilization, viral infection, trauma, and reflex sympathetic dystrophy (181).

Fragility fractures in pregnancy and the puerperium may also be due to preconception osteoporosis and increased bone turnover in pregnancy and lactation. Chronic therapy with heparin, corticosteroids, and anticonvulsants may cause secondary osteoporosis. Low dietary intake of calcium and vitamin D may cause excessive skeletal calcium resorption. Adequate calcium and vitamin D intake and exercise should be instituted when needed. Specific treatment with bisphosphonates or calcitonin is contraindicated because of possible adverse effects on the developing fetus.

Hypercalcemia

Hypercalcemia is generally mild and asymptomatic in pregnancy and is usually found on routine screening or on investigation of hypocalcemia in the neonate (197). Hypercalcemia occurs in 0.1-0.6% of the general population. In the child-bearing years, the most common etiology is hyperparathyroidism.

The diagnosis of mild hyperparathyroidism may be obscured by the pregnancy-induced fall in total calcium, the fall in intact PTH, and the rise in the 24-hour urinary excretion of calcium. In more severe forms of this condition, the risk of adverse pregnancy outcomes rises dramatically. Severe hypercalcemia may cause rapidly progressive anorexia, nausea, vomiting, weakness, fatigue, dehydration, and stupor. This requires emergency treatment as it may be fatal. Acute pancreatitis (182,197-9) may occur at rates 6 times that of the nonpregnant population, with significant risks for both mother and fetus. Patients with persistent vomiting must be hydrated rapidly to prevent worsening of the hypercalcemia from dehydration. As pregnancy tends to ameliorate hypercalcemia with the placental transfer of calcium to the fetus, maternal hypercalcemia may dramatically worsen postpartum (197-9).

Infants of mothers with severe hypercalcemia are at risk for spontaneous abortion (8%), premature birth (10%), stillbirth (2%), severe hypocalcemia with or without tetany (15-25%), and neonatal death (2%) (182,197-9). PTH does not cross the placenta, and the neonatal hypocalcemia is secondary to suppression of the fetal parathyroid glands by the placental transfer of elevated calcium levels, which stops at birth. The parathyroid gland suppression and hypocalcemia is transient, lasting up to 3-5 months, and can be managed with calcium and vitamin D supplements (182,197-9).

Because of the potential hazards to mother and child, all patients with known primary hyperparathyroidism should undergo surgery before conceiving. When hyperparathyroidism is diagnosed during pregnancy, parathyroidectomy is generally well-tolerated by mother and fetus. Of those pregnancies in which the hyperparathyroid mothers were treated expectantly or with oral phosphates, 40% of the neonates developed hypocalcemia. Hypercalcemia discovered late in gestation may be managed with oral phosphate (Fleet’s Phospho-Soda, 15-50 cc/day in divided doses) (182,197-9). Calcium levels should be monitored every 2-4 weeks.

Initial therapy for patients with severe hypercalcemia (calcium > 14 mg/dl) includes rehydration with saline. Forced diuresis with furosemide may further increase urinary calcium excretion. However, loop diuretics readily cross the placenta and cause increased fetal urine production and polyhydramnios. Glucocorticoids and calcitonin may also be used, but the safety of bisphosphonates and other agents has not been established in pregnancy.

Hypocalcemia

The most common cause of hypocalcemia is hypoparathyroidism secondary to surgery for thyroid or parathyroid disease. Autoimmune, infiltrative, and idiopathic causes are uncommon. Vitamin D deficiency is very rare. During pregnancy, women with hypoparathyroidism generally have fewer hypocalcemic symptoms, with decreased dependence on supplemental calcitriol to maintain a normal serum calcium (189,200,201). This likely occurs because 1,25-dihydroxyvitamin D levels are less dependent on PTH production in pregnancy, but are also regulated by PTHrP, and possibly prolactin and chorionic somatomammotropin. In late pregnancy, hypercalcemia may occur unless the calcitriol dose is decreased below the prepregnancy level (200,201) This is more pronounced during breastfeeding, likely due to the large secretion of PTHrP at that time (see below).

Maternal hypocalcemia causes fetal hypocalcemia because of an inadequate transfer of calcium to the fetus. This results in fetal hyperparathyroidism with attendant skeletal demineralization, subperiostial bone resorption, osteitis fibrosa cystica and, rarely, death (202). 1,25-dihydroxyvitamin D is the preferred therapy because its rapid action allows precise modulation of serum calcium levels.

Lactation

Breast feeding causes a daily maternal calcium loss of 280-400 mg/day (196). This calcium seems to come primarily from the skeleton, with bone density losses of 1-3% per month, secondary to declining estrogen levels and high PTHrP. Ionized calcium levels increase to the high normal range (203). Phosphate levels may rise above the normal range, with increased renal reabsorption and skeletal resorption (184). PTH is reduced 50% in the first several months postpartum, and rises to above normal after weaning (187,189). Total and free levels of 1,25-dihydroxyvitamin D levels fall to normal within days postpartum (186). As 1,25-dihydroxyvitamin D levels fall to normal, intestinal calcium absorption decreases to the non-pregnant level. PTHrP levels are higher in lactating women than in nonpregnant controls, with a rise after suckling (203,204). PTHrP levels in breast milk may exceed 10,000 times that found in the serum of nonpregnant controls (205,206). PTHrP may regulate mammary development and mammary blood flow (189). It may also contribute to maternal skeletal calcium resorption, renal tubular reabsorption of calcium, and suppression of PTH. PTHrP levels correlate negatively with PTH levels and positively with the ionized calcium levels (181,203) and loss of bone mineral density in lactating women (207). The lactation influence on calcium homeostasis does not occur in women with pseudohypoparathyroidism who have resistance to the amino-terminal actions of PTH and PTHrP. Renal calcium excretion falls to 50 mg/24 hours with the decline in GFR to below prepregnant levels, and with increased tubular reabsorption of calcium.

Rat models reveal increased bone turnover with a 35% loss of bone mineral in 2-3 weeks of lactation. Urinary markers of bone resorption are higher than during pregnancy, and 2- to 3-fold higher than in nonpregnant controls. Bone formation markers are also higher than in pregnancy or the nonpregnant state (189). Bone density at trabecular sites declines at a rate of 1-3% per month, for a total of 3-10% lost within 2-6 months of lactation, with smaller losses at cortical sites (196). This loss correlates with the calcium lost in breast milk (208), and is not prevented by increasing calcium supplementation (209-12). The duration of amenorrhea, which corresponds to reduced estrogen levels and increased intensity of lactation and breast milk calcium losses, correlates positively with bone loss during lactation (207,210-12). The decline in bone density is greater than that seen in women with lower estrogen levels, increased urinary calcium excretion, and suppressed 1,25-dihydroxyvitamin D and PTH, induced by GnRH agonist therapy, who lose 1-4% of their trabecular bone density in 6 months (213). Lactating women have higher estrogen levels, reduced calcium excretion, and normal 1,25-dihydroxyvitamin D levels. PTHrP may be the added mechanism contributing to their higher bone loss at both cortical and trabecular sites. Postweaning, bone density increases by 0.5-2% per month, returning to normal in 3-6 months (196,211). PTH and 1,25-dihydroxyvitamin D levels increase after weaning (214), but the exact mechanism for rapid bone accretion is unstudied.

ADRENAL DISORDERS IN PREGNANCY

Pregnancy modifies adrenal steroid metabolism substantially. In contract to the effects on the hypothalamic-pituitary-adrenal axis, glucocorticoid levels provide a positive feedback on the placental corticosteroid axis. Placental CRH rises several hundred-fold during pregnancy, is extensively protein bound until term, and modulates both maternal and fetal pituitary-adrenal axes and may regulate parturition (215). Both maternal and placental ACTH levels rise dramatically after 16-20 weeks’ gestation (216)(Figure 5), with a final surge in ACTH and plasma cortisol during labor. Despite the increase in the placental hormones, the normal maternal circadian rhythm of ACTH secretion persists throughout pregnancy.

Figure 5. Plasma concentrations of adrenocortiotropic hormone (ACTH) and cortisol during normal pregnancy. Blood samples were obtained from five normal pregnant women weekly at 8:00 to 9:00 AM and from three women during labor and on the second postpartum day. In addition, umbilical cord plasma was obtained from the newborn infants of three of these subjects. The mean plasma concentrations for ACTH are denoted by the solid circles, whereas plasma cortisol levels are denoted by open circles. The vertical bars correspond to the magnitude of the standard error of the mean. (From Carr BR, Parker Jr CT, Madden JD, et al. Maternal plasma adrenocortiotropin and cortisol relationships throughout human pregnancy. AM J Obstet Gynecol 1981;139:416)

The fetoplacental unit has a marked capacity for steroidogenesis. At the same time, maternal cortisol levels increase 2- to 3-fold throughout pregnancy (217,218) with an increase in the size of the maternal zona fasciculate (219). There is an estrogen-stimulated increase in circulating cortisol binding globulin levels, resulting in an increase in total cortisol levels and a decreased rate of cortisol clearance (220). With displacement of cortisol from CBG by progesterone, free cortisol levels also increase (217). Urine free cortisol levels rise 2-3 fold during gestation.

Numerous changes occur in the renin-angiotensin-aldosterone system as well. Plasma renin activity increases 4-fold and plateaus at 20 weeks’ gestational age, despite the increase in plasma volume with pregnancy. Angiotensin II levels increase approximately 3-fold by term, although there is resistance to its pressor effects. Plasma mineralocorticoid levels increase 5- to 7-fold during gestation (218,221), but aldosterone secretion continues to respond normally to physiologic stimuli and varies inversely to changes in volume or dietary salt (222). The increase in aldosterone correlates with the pregnancy increase in GFR and in progesterone (223), which competitively inhibits sodium retention by aldosterone at the distal renal tubules. Progesterone also demonstrates an anti-kaliuretic effect (222), with a report of amelioration of hypokalemia during pregnancy in a woman with primary aldosteronism (224).

Cushing’s Syndrome During Pregnancy

Cushing’s syndrome is uncommon, with an incidence of 2 in 1,000,000. Just over 100 cases have been reported in pregnancy to date, as fertility is generally reduced by altered gonadotropin secretion in pituitary disease, and increased adrenal androgen secretion in adrenal disease. Approximately 44% are secondary to a pituitary adenoma vs. an 80% rate expected in the nonpregnant woman. Of the remaining, 44% are adrenal adenomas, 11% adrenal carcinomas (225-31), and the remainer a mix of adrenonodular hyperplasia and ectopic ACTH (227). Recently, several cases of pregnancy-dependent Cushing’s syndrome have been described, with no intrapartum adrenal steroid abnormalities noted (232,233). The increase in placental CRH rise apparently caused a pregnancy-induced exacerbation and recognition of the hypercortisolism in many cases, with occasional improvement in the symptoms postpartum (226,227).

It may be difficult to diagnose Cushing’s syndrome during pregnancy because the typical symptoms of weight gain, fatigue, emotional lability, glucose intolerance, hypertension, and edema are also common accompaniments of pregnancy. Pigmentation of striae and development of hirsutism or acne may suggest the hyperandrogenemia of Cushing’s syndrome, and proximal myopathy may also help to distinguish Cushing’s syndrome from normal pregnancy symptoms. The laboratory evaluation is confounded by the normal pregnancy rise in ACTH and cortisol levels. Normal pregnancy is also associated with “inadequate” suppression during the overnight dexamethasone suppression test (228). The elevated cortisol levels may be suppressed by the high dose dexamethasone suppression test, suggesting Cushing’s disease (226). For all forms of Cushing’s syndrome, ACTH levels are normal or high, likely from placental ACTH production or from the CRH-stimulated pituitary ACTH production (225-31). Thus, ACTH levels can not be used to distinguish between pituitary and adrenal etiologies.

The hypercortisolism of pregnancy continues to exhibit a normal circadian rhythm. This is absent in all forms of Cushing’s syndrome (234). Petrosal sinus sampling has been performed during pregnancy with no ill effects (235), and patients with Cushing’s disease apparently have the typical exaggerated ACTH response to CRH (229). CT or MRI are necessary for further characterization of pituitary or adrenal lesions.

Maternal complications of Cushing’s syndrome include hypertension, diabetes, myopathy, postoperative wound infection and dehiscence. Fetal mortality of 25% from spontaneous abortion, stillbirth, and prematurity has been observed (225-31). Premature labor is common. The maternal hypercortisolemia may occasionally lead to fetal adrenal suppression (236), and the neonate should be tested for this and treated prophylactically until the results are known.

Rates of fetal loss and premature labor decrease, though are still increased, in patients who are treated during pregnancy (225,228). Medical therapy is generally ineffective (227,228,231), though metyrapone has proved efficacious in a few patients. Adrenal surgery may be performed through a flank incision or by laparoscopy. Because of the high rate of adrenal carcinoma, early surgery may improve the poor prognosis. Transsphenoidal surgery has also been used successfully (226). The risks of surgery to both mother and fetus are outweighed by the benefits of appropriately treating the Cushing’s syndrome.

Adrenal Insufficiency

Primary adrenal insufficiency rarely presents in pregnancy (237). Secondary adrenal insufficiency, from pituitary neoplasms or glucocorticoid supression of the hypothalamic-pituitary-adrenal axis, is more common.

Recognition of adrenal insufficiency may be difficult in the first trimester as many of the clinical features are found in normal pregnancies, including weakness, lightheadedness, syncope, nausea, vomiting, and increased pigmentation. Addisonian hyperpigmentation may be distinguished from chloasma of pregnancy by its presence on the mucous membranes, on extensor surfaces, and over non-exposed areas. Weight loss together with these symptoms should prompt a clinical evaluation. If unrecognized, adrenal crisis may ensue at times of stress, such as a urinary tract infection or during labor (237). Fetal cortisol production may be protective, shielding the mother from severe adrenal insufficiency until postpartum (238).

The fetoplacental unit largely controls its own steroid milieu, so maternal adrenal insufficiency generally causes no problems with fetal development. Maternal antiadrenal autoantibodies may cross the placenta, but usually not in sufficient quantities to cause fetal or neonatal adrenal insufficiency (239). Although Osler observed intrauterine fetal growth restriction in offspring of women with Addison’s disease (240), this observation has not been supported in most subsequent case series.

Adrenal insufficiency is associated with laboratory findings of hyponatremia, hyperkalemia, hypoglycemia, eosinophilia, and lymphocytosis. Plasma cortisol levels may fall in the normal “nonpregnant” range due to the increase in CBG concentrations, but will not be appropriately elevated for the stage of pregnancy. With primary adrenal insufficiency, ACTH levels will be elevated. However, ACTH will not be low with secondary forms because of the placental production of this hormone, which is nevertheless insufficient to maintain normal maternal adrenal function.

Despite the normal increase in plasma cortisol during pregnancy, maternal replacement doses of corticosteroids usually are not different from those required in the non-pregnant state. Higher doses are needed at times of stress, such as during the course of “morning sickness” or during labor and delivery. Mineralocorticoid replacement requirements usually do not change during gestation, though some clinicians have decreased fludrocortisone intake in the third trimester in an attempt to treat Addisonian patients who develop preeclampsia (241).

Patients who have received glucocorticoids as antiinflammatory therapy are presumed to have adrenal axis suppression for at least one year (242). These patients should be treated with “stress” doses of glucocorticoids during labor and delivery. They are at risk for postoperative wound infection and dehiscence as are patients with endogenous Cushing’s syndrome, and their offspring are at risk for transient adrenal insufficiency. Although prednisone readily crosses the placenta (243), the maternal:fetal gradient is higher than with other available agents (244,245). Corticosteroid therapy during pregnancy is generally safe and suppression of neonatal adrenal function is uncommon (246). Glucocorticoid therapy during lactation is also safe, as minimal amounts of these medications are passed into breast milk.

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia is a family of monogenic inherited enzymatic defects of adrenal steroid biosynthesis, with manifestations secondary to an accumulation of precursors proximal to the enzymatic deficiency. The most common form of CAH in the population is 21-hydroxylase deficiency, seen in more than 90% of the CAH cases in pregnancy (247,248). Classic, severe 21-hydroxylase deficiency is associated with ambiguous genitalia, an inadequate vaginal introitis, and progressive postnatal virilization including precocious adrenarche, advanced somatic development, central precocious puberty, menstrual irregularity, a reduced fertility rate, and possibly salt wasting (248-50). The spontaneous abortion rate is twice that in the normal population (251), and congenital anomalies are more frequent. Cephalopelvic disproportion from an android pelvis may occur, sometimes complicated by the previous reconstructive surgery (252,253). Conception requires adequate glucocorticoid therapy, which then continues at stable rates during gestation, except at labor and delivery. Nonclassic (late-onset) 21-hydroxylase deficiency patients present with pubertal and postpubertal hirsutism and menstrual irregularity and may have improved fertility with glucocorticoid therapy (251). Often, however, ovulation induction is required to enable these patients to conceive children.

Fetal risk depends on the carrier status of the father. Unfortunately, ACTH stimulation testing to measure 17-OH progesterone demonstrates overlap between heterozygotes for CAH and the normal population (254). Virilization is not seen in the female fetus with nonclassic 21-hydroxylase deficiency (255), but occurs in a fetus with classic 21-hydroxylase deficiency unless fetal adrenal androgen production is adequately suppressed. Dexamethasone most readily crosses the placenta as it is not bound to CBG and is not metabolized by placental 11 b-hydroxysteroid dehydrogenase. It is commonly used at doses of 20 mg/kg maternal body weight per day to a maximum of 1.5 mg daily in 3 divided doses beginning before the 9th week of gestation (248,249). Maternal plasma and/or urinary estriol levels reflect fetal adrenal synthesis and are monitored to assess efficacy. Maternal cortisol and DHEA-S will determine maternal adrenal suppression. There is little effect on maternal 17-OH progesterone with therapy. As only 25% of female fetuses are affected in a family with CAH, it is important to discontinue therapy as soon as possible in the male fetus and unaffected female fetus. Chorionic villus sampling at 9-11 weeks’ gestation may be used for gender determination and direct DNA analysis for the 21-hydroxylase gene CYP21.(247,249,256) The test itself is associated with a 1-4% risk of miscarriage and 2% risk of limb defects. An alternative is karyotyping and DNA analysis or measuring androstenedione and 17-OH progesterone levels in amniotic fluid at 16-18 weeks of gestation after dexamethasone has been withheld for 5 days.(256) Side effects of dexamethasone therapy are potentially significant, including excessive weight gain, severe striae with scarring, edema, irritability, gestational diabetes mellitus, hypertension, and gastrointestinal intolerance (249,257). In affected pregnancies, dexamethasone may be lowered to 0.75 to 1.0 mg/day in the second half of pregnancy to decrease maternal side effects while avoiding fetal virilization (257). Treatment by the 9th week of gestation is very effective in reducing the risk of virilization in the affected female fetus (249).

Primary Hyperaldosteronism During Pregnancy

Primary hyperaldosteronism rarely has been reported in pregnancy (258-61), and is most often caused by an adrenal adenoma. The elevated aldosterone levels found in patients are similar to those in normal pregnant women, but the plasma renin activity is suppressed (258-61).

Salt loading tests may be used to diagnose hyperaldosteronism. If baseline and suppression testing are equivocal, or radiologic scanning does not suggest unilateral disease, patients may be treated medically until delivery to allow more definitive investigations (260). Spironolactone, the usual nonpregnant therapy, is contraindicated in pregnancy as it crosses the placenta and is a potent antiandrogen which can cause ambiguous genitalia in a male fetus (261). Surgical therapy may be delayed until postpartum if hypertension can be controlled with agents safe in pregnancy, such as methyldopa, labetolol, and amiloride. As noted above, the hypokalemia may ameliorate in pregnancy because of the antikaliuretic effect of progesterone. Both hypertension and hypokalemia may exacerbate postpartum due to removal of the progesterone effect (262,263).

Pheochromocytoma in Pregnancy

Exacerbation of hypertension is a typical presentation of pheochromocytoma in nonpregnant patients, but during pregnancy is frequently mistaken for pregnancy-induced hypertension or preeclampsia (264). As the uterus enlarges and an actively moving fetus compresses the neoplasm, maternal complications such as severe hypertension, hemorrhage into the neoplasm, hemodynamic collapse, myocardial infarction, cardiac arrhythmias, congestive heart failure, and cerebral hemorrhage may occur. Extra-adrenal tumors which occur in 10%, such as in the organ of Zuckerkandl at the aortic bifucation, are particularly prone to hypertensive episodes with changes in position, uterine contractions, fetal movement, and Valsalva maneuvers (265). Unrecognized pheochromocytoma is associated with a maternal mortality rate of 50% at induction of anesthesia or during labor (266,267).

There is minimal placental transfer of catecholamines (268,269), likely due to high placental concentrations of catechol-O-methyltransferase and monoamine oxidase (268,270). Adverse fetal effects such as hypoxia are a result of catecholamine-induced uteroplacental vasoconstriction and placental insufficiency (271-3), and of maternal hypertension, hypotension, or vascular collapse.

As always, diagnosis of pheochromocytoma requires an index of suspicion. Preconception screening of families known to have MEN 2 with RET proto-oncogene is essential. Patients with MEN 2A are more likely to have paroxysmal hypertension and have higher rates of bilateral neoplasms than those with sporadic pheochromocytoma (274). Examination for associated evidence for MEN2 may be difficult in pregnancy, with the expected pregnancy alterations in calcium, PTH, and calcitonin. Clinical thyroid examination should be done, with fine needle aspiration of any nodules so that overt medullary carcinoma can be treated immediately. Individuals with neurofibromatosis (275), von Hipple-Lindau disease (276), or retinal angiomatosis should also be screened for pheochromocytomas prior to pregnancy.

The diagnosis should be considered in pregnant women with severe or paroxysmal hypertension, particularly in the first half of pregnancy or in association with orthostatic hypotension or episodic symptoms of anxiety, headaches, palpitations, or diaphoresis. Symptoms may occur or worsen during pregnancy because of the increased vascularity of the tumor and mechanical factors such as pressure from the expanding uterus or fetal movement (272).

Laboratory diagnosis of pheochromocytoma is unchanged from the nonpregnant state as calecholamine metabolism is not altered by pregnancy per se (277). If possible, methyldopa and labetolol should be discontinued prior to the investigation as these agents may interfere with the quantification of the catecholamines and VMA (278). Provocative testing should be avoided because of the increased risk of maternal and fetal mortality. Tumor localization with MRI, with high intensity signals noted on T2-weighted images, provides the best sensitivity without fetal exposure to ionizing radiation. Metaiodobenzylguanidine scans are contraindicated in pregnancy, but may be necessary if other tumor localization methods fail.

Differentiation from preeclampsia is generally simple. The edema, proteinuria, and hyperuricemia found in preeclampsia are absent in pheochromocytoma. Plasma and urinary catecholamines may be modestly elevated in preeclampsia and other serious pregnancy complications requiring hospitalization, though they remain normal in mild preeclampsia and pregnancy-induced hypertension (279). Catecholamine levels are 2- to 4-times normal after an eclamptic seizure (280).

Initial medical management involves a-blockade with phenoxybenzamine, phentolamine, prazocin, or labetolol. All of these agents are well-tolerated by the fetus, but phenoxybenzamine is considered the preferred agent as it provides long-acting, stable, non-competitive blockade (272). Placental transfer of phenoxybenzamine occurs (281), but is generally safe (282,283). If hypertension remains inadequately controlled, metyrosine has also been used successfully to reduce catecholamine synthesis in a pregnancy complicated by malignant pheochromocytoma (284), but may potentially adversely affect the fetus. Beta blockade is reserved for treating maternal tachycardia or arrhythmias which persists after full a-blockade and volume repletion. Beta blockers may be associated with fetal bradycardia and with intrauterine fetal growth restriction, when used early in pregnancy (277,285). All of these potential fetal risks are small compared to the risk of fetal wastage from unblocked high maternal levels of catecholamines. Hypertensive emergencies should be treated with phentolamine or nitroprusside, although the latter should be limited because of fetal cyanide toxicity.

The timing of surgical excision of the neoplasm is controversial and may depend on the success of the medical management and the location of the tumor. As noted above, pressure from the uterus, motion of the fetus, and labor contractions are all stimuli that may cause an acute crisis, particularly in patients with a tumor at the organ of Zuckerkandl. In the first half of pregnancy, surgical excision may proceed once adequate a-blockade is established, although there is a higher risk of miscarriage with first trimester surgery. In the early 2nd trimester, abortion is less likely and the size of the uterus will not make excision difficult. If the pheochromocytoma is not recognized until the second half of gestation, increasing uterine size makes surgical exploration difficult. Successful laparoscopic excision of a pheochromocytoma has been described in the 2nd trimester of pregnancy (286). Other options include combined cesarean delivery and tumor resection or delivery followed by tumor resection at a later date. Delivery is generally delayed until the fetus reaches sufficient maturity to reduce postpartum morbidity, providing successful medical management exists.

Although successful vaginal delivery has been reported (287), it has been associated with higher rates of maternal mortality than cesarean section. Labor may result in uncontrolled release of catecholamines secondary to pain and uterine contractions (288). Severe maternal hypertension may lead to placental ischemia and fetal hypoxia. However in the well-blocked patient, vaginal delivery may be possible with intensive pain management with epidural anesthesia and avoidance of mechanical compression, employing techniques of passive descent and instrumental delivery.

There is no available information regarding the impact of maternal use of phenoxybenzamine on the nursing neonate.

Another Perspective On Metaphyseal Fractures

Another perspective on the cause of metaphyseal fractures

Marvin Miller

Received: 13 December 2007 / Accepted: 5 January 2008 / Published online: 12 February 2008
# Springer-Verlag 2008

Sir,
I read with interest the article by O’Connell and Donoghue [1] that describes three newborn infants with classic metaphyseal fractures (CMLs) following cesarean delivery. All of the CMLs were diagnosed radiographically or by clinical features on day 2 of life. Two of the infants were in the breech presentation, and in the third case the mother had poorly controlled gestational diabetes. While the authors attribute these fractures to twisting and pulling of the
extremities during delivery, and possibly to large size (all three infants weighed >3.45 kg), there are many such
infants born in a similar fashion who never show any evidence of bone fractures. The critical issue is whether these three infants may be predisposed to having lower newborn bone strength, and I would suggest that fetal immobilization is likely the common thread to understanding such a predisposition in these three infants. Application of the Utah paradigm to the in utero development of fetal bone strength would suggest that bone loading through fetal movement is critical to the realization of normal bone strength at the time of birth [2]. Situations that diminish fetal movement will decrease bone strength and include the following: cephalopelvic disproportion, malpresentation (including breech presentation), twin pregnancy, prematurity, oligohydramnios, large maternal fibroids, and maternal use of medications that can cause decreased fetal movement [3, 4]. Since two of the three infants were in the breech presentation, it is likely that they may have been confined and moved less than normal while in utero.
It is known that infants of diabetic mothers have a lower bone mineral content at birth compared to controls as a
result of increased bone resorption [5, 6]. It is also known that infants of diabetic mothers have decreased cyclic
movements compared to normal controls, and this relative fetal immobilization would explain the osteoclast-mediated osteopenia in infants of diabetic mothers [7]. Case reports such as those in the article by O’Connell and Donoghue support the existence of a transient brittle bone state from fetal immobilization that can lead to the same types of fractures as seen in child abuse [1, 8]. CMLs associated with physical therapy in the treatment of clubfeet
have also been described in this journal, and it has also been noted that some of these cases were also associated
with fetal immobilization [9, 10]. The idea of decreased fetal bone loading leading to decreased bone strength has a
scientific foundation based on experimental observations and is in accord with contemporary thinking of bone
physiology [2, 8, 11, 12].

The authors imply that CMLs are specific for abuse unless there is a prior history of accidental injury. I disagree with this position. In the cases they present, what would have happened if the swelling and leg abnormalities were not noted until after the newborn infants had been discharged from the hospital and were in the care of the parents? Child abuse would have been alleged against the parents. There is a differential diagnosis for metaphyseal fractures that includes copper deficiency, Menkes disease, scurvy, hyperparathyroidism, osteogenesis imperfecta, temporary brittle bone disease from fetal immobilization, physical therapy for clubfoot, breech presentation with/ without external version, the bone disease of prematurity, fetal exposure to magnesium, and child abuse [1, 13, 14].

Pediatr Radiol (2008) 38:598–599
DOI 10.1007/s00247-008-0758-4
DO00758; No of Pages
M. Miller
Department of Pediatrics,
Wright State University Boonshoft School of Medicine,
Children’s Medical Center, 1 Children’s Plaza,
Dayton, OH 45404, USA
e-mail: millerme@childrensdayton.org

Source:

http://www.springerlink.com/content/an4lg43v94900x15/fulltext.pdf?page=1

Liability For Removal Errors

Circuit Mulls Liability of City Caseworkers for Removal Errors

Mark Hamblett

10-08-2009
Whether New York City social workers and agency officials should face liability for wrongfully or mistakenly removing children from allegedly abusive homes was at the center of oral arguments yesterday at the U.S. Court of Appeals for the Second Circuit.
Judges Jose A. Cabranes and Roger Miner, and Southern District Judge Jed S. Rakoff, sitting by designation, heard argument in four cases concerning the proper degree of legal exposure for the city and employees of its Administration for Children’s Services (ACS).
Carolyn Kubitschek of Lansner Kubitschek Schaffer & Zuccardy in Manhattan, arguing for parents, foster parents and children who have been wrongfully removed from their homes, called the city agency “out of control.” She contended that agency officials should be liable under federal civil rights law for relying on a doctor criticized for over-reporting child abuse, and that caseworkers should be held liable for prematurely removing a child or failing to act quickly in returning them once the parent or foster parent has been cleared of responsibility for the child’s injury.
But in arguing for immunity, Deborah Brenner of the New York City Law Department told the court that caseworkers should not be held liable for decisions they make under pressure. “Caseworkers walk a very fine line every day,” she said. “They have to balance the right of the parent to family integrity” versus the safety of the children. New York City was represented by four senior counsels with the Law Department’s Appeals Division: Tahirih Sadrieh argued Green v. Mattingly, 08-4636-cv; Ms. Brenner argued V.S. v. Mattingly, 08-5157-cv; Drake Colley argued Graham v. Mattingly, 08- 5271-cv; and Janet Zaleon argued Cornejo v. Bell, 08-3069-cv.

The panel was openly skeptical about Ms. Zaleon’s argument in Cornejo that caseworkers and ACS lawyers should have absolute immunity for their actions. In Cornejo, caseworkers removed a baby who later died from injuries that included a fractured rib allegedly suffered when the mother was not home. It was later revealed the child died of a birth defect. Agency lawyers stuck by the removal in Family Court even after some staff said it should drop the case. The attorneys continued, the court was told, because there remained a belief the father may have shaken the baby.
“That’s a novel theory we don’t have any support for,” Judge Cabranes said. Judge Miner said, “Absolute immunity is a pretty heavy concept.” He also wanted to know if there is “any historical or common law basis for this assertion?” Ms. Zaleon said the situation with caseworkers and lawyers at ACS was unique because, unlike police officers and prosecutors, they work for the same agency and are supposed to assist the court in determining what is in the best interests of the child on an ongoing basis. But Ms. Kubitschek said the attorneys in Cornejo “stepped out of that function when they resisted their clients’ efforts” to drop the case, she said. “They were acting contrary to the
instructions as given” by caseworkers and supervisory staff.

Agency’s Responsibilities

A central figure in the arguments was Dr. Deborah Esernio-Jenssen of Long Island Jewish Hospital, who has been criticized by Family Court judges for incorrect diagnoses of Shaken Baby Syndrome. The issue is whether ACS workers, knowing about Dr. Esernio-Jenssen’s reputation, could be held liable for relying on her opinion in what turned out to be the mistaken removal of a child. Ms. Brenner said it “can’t be the correct constitutional standard” to require “that ACS has to look into a history of over-reporting.” “The plaintiffs would ask this court to place the onus on the ACS” and demand that caseworkers in a situation of likely child abuse look into a doctor’s history, she said. But Ms. Kubitschek said Dr. Esernio-Jenssen “has a long history of giving incorrect diagnoses,” and the agency should have gotten a second opinion. Simply because a doctor has a medical degree, she said, “does not entitle caseworkers whose duty is to do what’s best for children to rely on a doctor who is biased.”

Ms. Brenner countered that it was enough that Dr. Esernio-Jenssen “was qualified by the state of New York and she has given ACS a list of injuries and a diagnosis.” Judge Miner asked, “Suppose she had been wrong on a number of cases and ACS knew it,” would that be enough? “Yes,” Ms. Brenner responded. “ACS has some very serious responsibilities here. ACS simply as a matter of policy can’t be required to check on a doctor’s reputation.” In the Graham case, a woman unsuccessfully sued the city after she had three grandchildren and five children removed from her home. The woman had been asleep two floors away while a friend of a relative attacked one of the children, an 11 year-old girl, and Ms. Kubitschek said the agency removed all the children even though the person the girl “accused of abusing her had been arrested and the other children weren’t in danger.”
This ran contrary to the holding in another case Ms. Kubitschek and partner David Lansner had handled, Nicholson v. Scopetta, 344 F.3d 154 (2003), where the circuit, with guidance from the New York Court of Appeals, held in part that ACS should not insist on keeping the child out of the home once the danger had been removed. She also told the judges that ACS has a number of practices and policies that conflict with court holdings on due process and other violations.
She said the agency does not provide pre-deprivation hearings before removal, the agency “resolves any ambiguity in favor of removing the children,” officials make it “acceptable to misrepresent facts” in Family Court, and the “parent is required to explain how a child was injured even if the parent wasn’t present during the injury and someone else was caring for the child.” The law department’s Mr. Colley countered that, in the Graham case, a jury had correctly found that “the defendants’ lawful actions were shown not to violate procedural due process rights” and the Fourth Amendment claim brought by the grandmother “was rightfully dismissed.”
Mr. Colley said the grandmother missed the 11-year-old’s injuries, which were only discovered by school officials the following day. Ms. Kubitschek responded that the grandmother “could not have been expected to anticipate this would happen” and the 11 year-old child “said it hadn’t happened to her before.”
@|Mark Hamblett can be reached at mhamblett@alm.com.

Source:

http://familyrightsassociation.com/news/archive/2009/oct/CAK_NYLJ.pdf

Challenging An Assumption Response

Letters to the Editor

In our August 2009 issue, we published the article “Challenging an Assumption” (p. 29), which
was a profile of Dr. John Plunkett, a Minnesota pathologist who questions the validity of the
shaken baby syndrome diagnosis. In January, we received and published a letter critical of our
article and of Dr. Plunkett’s views (p. 5). That letter was signed by members of the international
advisory board of the National Center on Shaken Baby Syndrome. Since then, we have received
numerous letters taking issue with their letter and the views of its signers. Clearly, we have
touched a nerve in writing about this issue. Our intent for the story about Dr. Plunkett was
neither to validate nor to denigrate his work. We merely wanted to highlight the fact that a
Minnesota physician is taking part in a highly controversial debate that has ramifications for
medicine and the legal system. Below are some of the letters we have received recently on this
topic. Others can be viewed online at http://www.minneotamedicine.com.
—the editors

Growing Body of Contrary Evidence

In your January 2010 issue, nine doctors, a prosecutor, and a police detective—all of whom are
associated with the National Center on Shaken Baby Syndrome, an advocacy group devoted to
the promotion of “shaken baby” theory—attacked Dr. John Plunkett, who was featured in the
August 2009 issue of Minnesota Medicine. Dr. Plunkett has spent his recent career applying
basic biomechanical and medical principles to shaken baby syndrome (SBS) and testifying, if
needed, when accused parents or caretakers are confronted with unproven or demonstrably
incorrect medical claims. Because of his work and research by others, the literature on SBS has
changed substantially since 2000, forcing major changes in the SBS position papers of the major
medical organizations. In their 2010 letter, the representatives of the National Center on Shaken
Baby Syndrome claim that Dr. Plunkett’s findings are based on “belief” rather than “evidence.”
In fact, doctors have been diagnosing SBS for nearly 40 years without an adequate scientific
basis—and in the face of a growing body of contrary evidence.
In the 1970s, “shaking” was advanced as a theory to explain a triad of findings (subdural
hemorrhage, retinal hemorrhage, and/or brain swelling) that is sometimes seen in infants or
children who have no signs of trauma. The theory was that shaking caused these findings by
rupturing bridging veins and tearing the axons within the brain. In 1987, Dr. Ann-Christine
Duhaime, a neurosurgeon working with biomechanical engineers at the University of
Pennsylvania, attempted to prove that shaking could cause these injuries. However, her study
showed the opposite: The forces of shaking fell well below established injury thresholds and
were 1/50th the force of impact, including impact on soft surfaces.1
Despite these findings, many doctors continued to testify that shaking was the primary or sole
cause for the triad of symptoms and that it would take a fall from a multistory building to cause
these findings. In 2001, Dr. Plunkett disproved this premise in an article that included a
videotaped fall of a toddler from a 28-inch plastic indoor play structure that resulted in subdural
hemorrhage, retinal hemorrhage, and death.2 This videotape proved definitively that short falls
can cause the triad and are sometimes fatal. Although SBS proponents initially suggested that
the videotape had been altered, Dr. Case (one of the signatories to the attack on Dr. Plunkett) has
acknowledged the validity of the videotape, which has been shown in courtrooms and at teaching
seminars in the United States and England.3 Numerous biomechanical studies have further
confirmed that the force from short falls meets the injury thresholds, while shaking does not.4-6
Short falls are not the only cause of medical findings previously attributed to shaking. Studies
by Dr. Jennian Geddes published in Brain, England’s leading neurology journal, from 2001 and
2003 found that the brain injuries of allegedly shaken children were generally hypoxic rather
than traumatic in origin, and that subdural hemorrhages are also found in natural deaths.7,8 In
2002, Drs. Hymel, Jenny, and Block (two of whom signed the attack on Dr. Plunkett) listed the
alternative causes for findings previously attributed to shaking or inflicted head trauma as
accidental trauma; medical or surgical interventions; prenatal, perinatal, and pregnancy-related
conditions; birth trauma; metabolic, genetic, oncologic, or infectious diseases; congenital
malformations; autoimmune disorders; clotting disorders; the effects of drugs, poisons, or toxins;
and other miscellaneous conditions.9 A 2006 text on abusive head trauma in infants and children
(co-edited by Dr. Alexander, another signatory to the attack on Dr. Plunkett) and a 2007 review
article by Patrick Barnes, professor of radiology at Stanford University and chief of pediatric
neuroradiology at Lucile Salter Packard Children’s Hospital, are in accord.10 Despite this
consensus, hundreds to thousands of parents and caretakers have been imprisoned based on
testimony by doctors that subdural hemorrhages, retinal hemorrhages, and/or brain swelling are
diagnostic of abuse, with little or no regard to the alternatives, including short falls and natural
causes.
At the same time, many doctors and academics have recognized that the real problem lies in the
lack of an evidence base for shaken baby theory. In 2003, a review article by Dr. Mark Donohoe
found that “[T]he evidence for SBS appears analogous to an inverted pyramid, with a small data
base (most of it poor-quality original research, retrospective in nature, and without appropriate
control groups) spreading to a broad body of somewhat divergent opinions.” 12 In 2006, the
National Association of Medical Examiners withdrew its position paper on shaking, and its
annual conference included presentations with titles such as “‘Where’s the Shaking?’: Dragons,
Elves, the Shaking Baby Syndrome, and Other Mythical Entities” and “Use of the Triad of Scant
Subdural Hemorrhage, Brain Swelling, and Retinal Hemorrhages to Diagnose Non-Accidental
Injury is Not Scientifically Valid.” In subsequent publications, Dr. Waney Squier of Oxford
University, one of England’s leading neuropathologists, and Dr. Jan Leestma, author of the
textbook Forensic Neuropathology, similarly concluded that the evidence base for shaken baby
syndrome is lacking.13,14 None of this material is addressed or cited in the attack on Dr. Plunkett.
The problem, in short, is not that Dr. Plunkett was wrong; the problem is that he was right. Over
the past decades, hundreds to thousands of caretakers—many of whom are innocent—have been
convicted based on theories that lack a scientific basis. These convictions must now be revisited.
Of course children are abused. But there are many ways to abuse children, one of which is
ripping them from their families and imprisoning their parents and caretakers based on
misdiagnoses of abuse. We therefore urge the medical profession to join us in developing a
calm, rational and evidence-based approach to pediatric head injury and child death.

Heather Kirkwood, J.D.

Seattle, Washington

Barry S. Scheck, J.D.

Co-director, Innocence Project
Benjamin N. Cardozo School of Law
New York City

Keith Findley, J.D.

President, Innocence Network
Co-director, Wisconsin Innocence Project
University of Wisconsin Law School
Madison, Wisconsin

Bridget McCormack, J.D.

Co-director, Michigan Innocence Clinic
University of Michigan Law School
Ann Arbor, Michigan

Julie Jonas, J.D.

University of Minnesota Innocence Clinic
Managing Attorney, Innocence Project of Minnesota
Minneapolis, Minnesota

Jacqueline McMurtrie, J.D.

Director, Innocence Project Northwest Clinic
University of Washington School of Law Seattle, Washington

References

1. Duhaime AC, Gennarelli TA, Thibault LE, Bruce DA, Margulies SS, Wiser R. The shaken baby syndrome. A clinical,
pathological, and biomechanical study. J Neurosurg 1987;66(3):409-15.
2. Plunkett J. Fatal pediatric head injuries caused by short-distance falls. Am J Forensic Med Pathol 2001;22(1):1-12.
3. Seventh North American Conference on Shaken Baby Syndrome (Abusive Head Trauma), Vancouver, B.C. October
2008.
4. Ommaya AK, Goldsmith W, Thibault L. Biomechanics and neuropathology of adult and paediatric head injury. Br J
Neurosurg 2002;16(3):220-42.
5. Prange MT, Coats B, Duhaime AC, Margulies SS. Anthropomorphic simulations of falls, shakes, and inflicted impacts
in infants. J Neurosurg 2003;99(1):143-50.
6. Goldsmith W, Plunkett J. A biomechanical analysis of the causes of traumatic brain injury in infants and children. Am
J Forensic Med Pathology 2004;25(2):89-100.
7. Geddes JF, Hackshaw AK, Vowles GH, Nickols CD, Whitwell HL. Neuropathology of inflicted head injury in children,
I and II. Brain. 2001;124(part 7):1290-8.
8. Geddes J, Tasker RC, Hackshaw AK, et al. Dural haemorrhage in non-traumatic infant deaths: does it explain the
bleeding in ‘shaken baby syndrome’? Neuropathol Appl Neurobiol 2003;29:114-22.
9. Hymel KP, Jenny C, Block RW. Intracranial hemorrhage and rebleeding in suspected victims of abusive head trauma:
addressing the forensic controversies. Child Maltreat 2002:7(4):329-48.
10. Frasier L, Rauth-Farley K, Alexander R, Parrish R. Abusive Head Trauma in Infants and Children: A Medical,
Legal, and Forensic Reference. G.W. Medical Publishing, Inc.; St. Louis, MO: 2006.
11. Barnes PD, Krasnokutsky M. Imaging of the central nervous system in suspected or alleged nonaccidental injury,
including the mimics. Top Magn Reson Imaging 2007;18:53-74.
12. Donohoe M. Evidence-based medicine and shaken baby syndrome part I: literature review, 1966-1998. Am J Forensic
Med Pathol 2003;24(3):239-42.
13. Squier W. Shaken baby syndrome: the quest for evidence. Dev Med Child Neurol 2008;50(1):10-4.
14. Leestma J. Forensic Neuropathology, Second ed. CRC Press; Chicago: 2009.

Circular Reasoning

We read with interest Kate Ledger’s article “Challenging an Assumption: A pathologist
questions shaken baby syndrome” (Minnesota Medicine, August 2009) and the response of Drs.
Alexander, Barr, Block, et al. (January 2010).
Dr. Block and his cosigners complain that Ms. Ledger ignored the enormous body of
international peer-reviewed medical literature about shaken baby syndrome. Much of this
literature exhibits circular reasoning, selection bias, or misrepresents the data. Of the 14
references they cite, six are unsystematic reviews or consensus statements that mingle opinion
with fact and add no original supporting evidence. Two are based on data described by the
authors as “explorative.” Those authors suggest that “further surveillance … and modelling will
be required.” Two are invalidated by insufficiently robust criteria to reliably diagnose abuse and
one by failure to address the fundamental methods on which the study was based.
Dr. Block and his cosigners suggest that this literature “consistently and repeatedly supports the
concept of shaken baby syndrome.” We do not disagree with this but would point out, as Ms.
Ledger clearly did, that supporting a concept is far from demonstrating the scientific basis for it.
Just as disturbing as the literature Block and his cosigners cite is the indignation they expressed
that someone should challenge their opinions as medical “experts” in a court of law—as if they
are somehow exempt from the human tendency for cognitive errors in medical decision making.
What scientist is afraid of debate that is crucial to our understanding of evolving ideas?
Fortunately, medicine has never been static. There is much to learn about the pathophysiology of
infant brain trauma. We cannot make up for this lack of knowledge by reiterating opinion and
poor data: Ignoring new evidence and failing to question and engage in debate is a dereliction of
our duties to our patients and their families.

Waney Squier, FRCP FRCPath

Consultant neuropathologist
John Radcliffe Hospital
Oxford, United Kingdom

Julie Mack, M.D.

Assistant professor of radiology
Penn State Hershey Medical Center
Hershey, Pennsylvania

Patrick E. Lantz, M.D.

Professor of pathology
Wake Forest University
Winston-Salem, North Carolina

Patrick D. Barnes, M.D.

Chief of pediatric neuroradiology
Lucile Packard Children’s Hospital
Stanford University Medical Center
Stanford, California

Irene Scheimberg, M.D.

Paediatric and perinatal pathologist
The Royal London Hospital
London, England

James T. Eastman, M.D.

Clinical professor of pathology and laboratory medicine
University of Wisconsin
Madison, Wisconsin

Marta Cohen, M.D.

Sheffield Children’s Hospital NHS Foundation Trust
Sheffield, United Kingdom

Peter J. Stephens, M.D., FCAP

Forensic pathologist
Burnsville, North Carolina

Darinka Mileusnic-Polchan, M.D., Ph.D.

Medical Examiner for Knox and Anderson Counties
Regional Forensic Center
University of Tennessee Medical Center Knoxville, Tennessee

Persuasive Evidence and a Theory

I serve on occasion as an expert witness for the defense in shaken baby syndrome (SBS) cases.
That is a matter I disclose as a potential conflict of interest. I wish the writers of the letter in your
January 2010 issue had done the same.
When I cast doubt on the validity of SBS, I cite the original literature. In my judgment, SBS is so
lacking in evidence, it is hard to understand how the hypothesis ever gained traction.1,2
I cite a review of seminal SBS literature up to 1998. It concluded the evidence was inadequate.3 I
cite Ommaya, et al., who did the original work on whiplash biomechanics that debunks the SBS
hypothesis.4 I cite experimental work that indicates forces generated by manual shaking are an
order of magnitude less than forces of impact, and less than the threshold for injury.5 I cite an
article that states the neck should be destroyed if manual shaking were capable of producing
brain damage.6 I have seen no case in which neck injury was observed.
Finally, I cite my own hypothesis. It is untested, just as the SBS hypothesis is untested. If the
forces of shaking are sufficient to cause brain damage, the thumbs of the shaker and the places
where the thumbs are applied on the victim should be conspicuously injured. They are not.

Edward N. Willey, M.D.

St. Petersburg, Florida

References

1. Guthkelch AN. Infantile subdural haematoma and its relationship to whiplash injuries. Br Med J 1971;2(5759):430-1.
2. Caffey J. On the theory and practice of shaking infants. Its potential residual effects of permanent brain damage and
mental retardation. Am J Dis Child 1972;124(2):161-9.
3. Donohoe M. Evidence-based medicine and shaken baby syndrome: part I: literature review, 1966-1998. Am J Forensic
Med Pathol 2003;24(3):239-42.
4. Ommaya AK, Goldsmith W, Thibault L. Biomechanics and neuropathology of adult and paediatric head injury. Br J
Neurosurg 2002;16(3): 220-42.
5. Duhaime, AC, Gennarelli TA, Thibault LE, et al. The shaken baby syndrome. A clinical, pathological, and
biomechanical study. J Neurosurg 1987;66(3): 409-15.
6. Bandak FA. Shaken baby syndrome: a biomechanics analysis of injury mechanisms. Forensic Sci Int 2005;151(1):71-9

Source:

http://www.edwilleymd.com/mn-medicine.pdf

Gender And Macrocephaly Question SBS

Overrepresentation of Males in Traumatic Brain Injury of Infancy and in Infants With Macrocephaly: Further Evidence That Questions the Existence of Shaken Baby Syndrome

Miller, Rubin BA; Miller, Marvin MD

Abstract

Shaken baby syndrome (SBS) has been thought to be caused by violent shaking of an infant and is characterized by the triad of findings: subdural hematoma (SDH), retinal hemorrhages, and neurologic abnormalities. The triad is not specific for SBS and can be seen in accidental trauma and in certain medical conditions. Recent observations, however, question whether SBS exists. Herein, we review the gender differences in 3 groups of infants with traumatic brain injury:

(1) neonates with SDH from birth trauma,

(2) infants with SDH from accidental trauma, and

(3) infants with SDH from SBS.

Gender differences are also presented in a fourth group of infants with macrocephaly related to increased extra-axial fluid spaces (IEAFS). Compared with the expected male frequency of 51.4% in newborns, there was a statistically significant overrepresentation of males in each of the 4 groups-65.3%, 62.2%, 62.6%, and 68.8%, respectively. We believe that the most likely explanation for these findings relates to the larger head size of the male compared with the female which has several relevant consequences. First, the larger head circumference of a male newborn compared with a female newborn may increase the likelihood that a male newborn will incur a small SDH from the minor trauma of the birthing process that can later rebleed and present with a symptomatic SDH that could be misdiagnosed as SBS and child abuse. Second, a short fall would have a greater likelihood of causing a SDH in a male infant than a female infant who could subsequently become symptomatic from hours to weeks later and could thus present as an unexplained SDH. Third, infants with macrocephaly related to IEAFS may be at increased risk for developing a SDH from the larger head size and greater tautness of the bridging vessels in the extra-axial fluid spaces. We believe that many infants who have been diagnosed with SBS have been given incorrect diagnoses of child abuse. Rather, their SDH may occur as a result of a small SDH from the birthing process that enlarges during early infancy, a short fall, or from macrocephaly with IEAFS.

Source:

http://journals.lww.com/amjforensicmedicine/Abstract/publishahead/Overrepresentation_of_Males_in_Traumatic_Brain.99904.aspx

Unexplained Fractures And Bone Fragility

Unexplained fractures in infancy: looking for fragile bones

Nick Bishop   Alan Sprigg    Ann Dalton

Author Affiliations

¹Academic Unit of Child Health, University of Sheffield, Sheffield Children’s Hospital, Sheffield, UK

²Sheffield Children’s NHS Foundation Trust, Sheffield Children’s Hospital, Sheffield, UK

³Sheffield Molecular Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield Children’s Hospital, Sheffield, UK

Correspondence to:

Dr N Bishop,  Academic Unit of Child Health, University of Sheffield, Sheffield Children’s Hospital, Sheffield S10 2TH, UK; n.j.bishop@sheffield.ac.uk

• Accepted 13 October 2006

A fracture occurs when the force exerted on a bone exceeds the ability of the bone to absorb the force by deforming. Fractures in children are common—approximately one third of children will have a fracture by 16 years of age, with more boys experiencing fracture than girls.1 This differentiation in fracture risk is apparent from 2 years of age. Before the age of 2 years, fracture incidence is equal and occurs at a rate of approximately 80/10 000 person years. For the UK, therefore, approximately 4800 infants will have a clinically evident fracture before their first birthday each year.

Some long-bone fractures may occur at birth2 in association with events such as shoulder dystocia3; skull fractures may occur during forceps4 and ventouse delivery.5 Some may (uncommonly) occur as a result of clearly defined trauma such as road accidents.6 Most, however, fall into the “unexplained” category. This article reviews our current approach to identifying bone disease in the infant presenting with more than one unexplained fractures, and discusses the recognised disease processes that result in increased bone fragility.

The history should include inquiry into specific areas as listed in the box. The two most frequently recognised underlying disease processes causing bone fragility in infancy are metabolic bone disease of prematurity7 and osteogenesis imperfecta, and directed questioning is appropriate for these conditions. For premature infants, the features commonly associated with fracture are delivery at <28 weeks of gestation, necrotising enterocolitis, late (>30 days) establishment of full enteral feeds, conjugated hyperbilirubinaemia, chronic lung disease, and use of furosemide.8,9 For a proportion of infants with osteogenesis imperfecta, there will be a family history either of osteogenesis imperfecta itself or of features that suggest osteogenesis imperfecta. The other elements of the history relating to the …

Source:

http://adc.bmj.com/content/92/3/251.extract

Reply

Differentiating osteopenia of prematurity from child abuse

• Chandan Gupta, Senior House Officer Neonates

Mayday University Hospital, Croydon CR7 7YE, United Kingdom

Dear Editor,

The review on fractures in infancy is brilliant and very informative. I would like to take this opportunity to stress the sensitive issue of fractures due to osteopenia of prematurity that many a times needs differentiating from child abuse.

Reports of osteopenia/rickets of prematurity are on the increase because of improved survival rates of low birthweight infants.2 The incidence of osteopenia among infants born before 28 weeks of gestational age are as high as 30%. 1 The contributory factors are prematurity, lack of activity, chronic lung disease, use of diuretics, prolonged parenteral nutrition and iatrogenic factors that are unavoidable in neonatal intensive care. Iatrogenic injuries are frequently the result of physiologic or anatomical response to proper and lifesaving treatment. The most serious of these are found in the premature infant, who may suffer chronic lung disease or, more seriously, brain damage.3

The diagnosis of osteopenia of prematurity remains difficult as there is no screening test which is both sensitive and specific.5 Such infants sometimes go undiagnosed of fractures from the neonatal unit and when they come back with reasons like excessive crying and the x-rays show multiple healing fractures, the differential of child abuse, unfortunately, tends to take the top position. Due to the obvious reasons and the sensitivity of the issue, clinicians have shown concerns about the mistaken diagnosis of child abuse.4

I agree with the authors that the plain film radiography is not the final arbiter of bone fragility in infancy; as with the other forms of investigation discussed in the article, it is a part of the overall approach to discriminating between a diagnosis of bone fragility and one of non-accidental injury.Dual energy X-ray absorptiometry and quantitative ultrasound has been employed by some neonatal units to determine the mineral density of the bone but it is still not universal due to the issues like ionising radiation and the difficulty to interpret data.5

As a result, the clinicians, especially the junior doctors who happen to be the first contact with the carers need to keep osteopenia of prematurity high on their list of differentials especially when a NICU graduate presents without an official diagnosis of it.

References

1. Kocsis I, Kis E, Szabó A, et al. Osteopenia of Prematurity. Orv Hetil. 2005; 146:2491-7.

2. Caksen H, Oztürk A, Kurtoðlu S, et al .Reports of osteopenia/rickets of prematurity are on the increase because of improved survival rates of low birthweight infants. J Emerg Med 2002; 23:305-6.

3. Singleton EB. Intentional and unintentional abuse of infants and children. Curr Probl Diagn Radiol 1986; 15:277-330

4. Blumenthal I. Osteogenesis imperfecta, non-accidental injury, and temporary brittle bone disease. Arch Dis Child 1996; 74:91

5. McDevitt H, Ahmed SF. Quantitative ultrasound assessment of bone health in the neonate. Neonatology 2007; 91:2-11.

Source:

http://adc.bmj.com/content/92/3/251.extract/reply#archdischild_el_3269

Understanding The Fragility Of Children`s Bones

Toddler fracture question

Question:

My son is a very active 3 and 7 months. After spending the morning running, jumping and saving the world, he started limping. The limping quickly progressed to pain when touching the leg. I took him to the ER where x-rays showed a small line on the tibia. They put him in a cast and told me it was a toddlers fracture”. There was never a moment when he fell or yelled in pain. Is this common? I always thought bone breaks were after a trauma. There is no bruising or swelling either and is it common for bones to just break in young healthy kids?

Answer:

Children differ from adults in many ways. Compared to adults, children’s bones are more porous than are adult bones, which are well calcified and hard. Children’s bones are more prone to fractures because of their porosity and because their ligaments are stronger than their bones. It is the reverse in adults. Adults suffer sprains while children suffer fractures.

Children also have different types of fractures than do adults because of these bony differences. Children experience greenstick fractures, which are a partial crack through the bone rather than a full separation of the bone segments. They also have buckle fractures where the more porous bone is basically compressed downwards in one area but the bone is not broken through. They also have bend fractures where a long bone is clearly bent but not cracked through.

Unlike adults, children also have growth plates that actively lengthen bones throughout life. Adults have no active growth plates in their bones. Fractures through these growth plates are called Salter-Harris fractures. These are particularly difficult fractures because a child may lose all or part of their bone’s growth plate causing uneven growth of the bone as well as a difference in bone length from one side of the body to the other. This results in obvious problems in movement and appearance that are difficult to correct.

Happily your son saw a good pediatric doctor who recognized his fracture and casted him. Even when the bone is not separated, a fracture is still very painful and feels a lot better when it is immobilized in a cast. As a young child, he will also heal quickly.

While it is possible that your son could have an underlying problem with his bones, that is unlikely. If he has more fractures after little impact or malformed teeth, then it is worth discussing a possible problem with his doctor. Otherwise, he is just a normal, active little boy with a normal child’s more fracture-prone bones.

I hope he heals quickly and uneventfully!

McMillan et al. (Eds.) (2006). Oski’s Pediatrics: Principles and Practice (4th Edition). Philadelphia: Lippincort, Williams, and Wilkins.

Source:

http://www.netwellness.org/question.cfm/69642.htm

Response by:

Mary M. Gottesman, PhD, RN, CPNP, FAAN Associate Professor, Specialty Program Director Pediatric Nurse Practitioner Program College of Nursing The Ohio State University

Coup-Contrecoup Skull Fracture From Car Accident

Child skull fracture

Question:

My daughter is 3 1/2 years old, and we were involved in an accident where the impact was on the front passenger side of the vehicle. She had a bruise on her right eye which led me to believe that her car seat may have shifted towards the impact of the wreck. However, she was taken to the hospital 4 days later when she developed black eyes and it was found that she had a skull fracture and some bleeding. The skull fracture was on her left side of her head, which is very puzzling. Is this possible? If so are there documented medical cases, and where could I find such cases or articles?

Answer:

Yes, it is possible as a result of what is called the coup-contrecoup type of closed head injury. In this situation the brain suffers damage directly under the area of impact, but a second injury of equal or greater magnitude occurs directly opposite the point of contact. This occurs because the brain is suspended in the cranium or skull in cerebral spinal fluid with long nerve tracts extending from deep within the brain down into the spinal cord. When the head suffers a blow, the brain is first injured directly beneath the point of impact and then secondarily on the opposite side as the brain hurtles across the skull and slams into the  bony plates opposite the point of impact,  bouncing back yet again to the original site of injury. Children’s bones are much more porous than adult bones and hence are far more likely to fracture than are adult bones.

In addition to the direct injury and secondary injury, such a severe blow also results in what is called diffuse axonal injury from the stretching and shearing of nerves in the brain as they move to the contrecoup injury site across the skull. This may result in abnormal brain function for sometimes lengthy periods as the nerves swell in response to the injury and then eventually heal. It is not possible to know what the exact outcomes of any injury will be, particularly for children, since their brains have more flexibility in healing (plasticity) and in the transfer of skills to other neurons than do the brains of adults. There is no way to predict how many cells are affected or their degree of recovery.

Your daughter’s injury highlights the critical importance of using optimal restraint systems for children precisely in order to protect their brains, the most likely body part to be injured in a motor vehicle accident. Because children’s heads are so large and heavy compared to the rest of their bodies, their heads function like bullets in an accident, pulling the child forward toward impact. Children should be in approved and properly installed car seats and booster seats until they are 80 pounds in weight AND 4 feet 9 inches in height. Research shows that up to 80% of child restraint systems are installed or used incorrectly.

If you are interested in reading more, enter coup-contrecoup injury or diffuse axonal injury or closed head injury into a search engine – these terms should lead you to additional information. I hope this information is helpful.

Source:

http://www.netwellness.org/question.cfm/46710.htm

Child skull fracture

Question:

my child and I were involved in a car accident. As far as I know, she may have hit her head on her right side as she had a bruise on her right eye. However, she sustained a skull fracture on her left side. Is this possible?

Answer:

Yes, it is absolutely possible because of a phenomenon known as rebound injury, wherein the brain opposite the injury is also damaged. When the force that directly impacts the skull is significant, it causes the brain, it’s blood vessels, nerves, and cushioning fluid to move swiftly across the space inside the skull and literally smash up against the other side of the bony skull. This applies shearing or tearing forces to all of these tissues as they move at high velocity to slam into a the bony skull barrier and then rebound again to inflict more damage at the original site of impact.

I don’t know how old your child is, but the bony plates that make up the skull do not fuse completely with one another until sometime after 10 years of age. This allows for the rapid growth of brain tissue that occurs in the first decade of life that is necessary for normal development and learning. In younger children bones are also more likely to fracture than they are in adults because they are less calcified.

Your experience highlights the critical need for the proper restraint of all children in appropriate car seats and booster seats until they meet the weight AND the height criteria for moving into standard seatbelt usage. These milestones are 80 pounds and four feet nine inches. Use of booster seats and car seats reduces serious injury by 60-80%. Regular seat belts used on smaller individuals result in cutting across the trachea or windpipe,potentially collapsing it or the esophagus as the windpipe is driven back into the esophagus or food pipe, making swallowing and eating painful and difficult. They also can inflict significant bruising injury on the abdominal organs leading to internal bleeding as well as painful bruising over bony areas.

I hope both you and your daughter heal quickly and consistently use good restraint practices when back out on the road.

Source:

http://www.netwellness.org/question.cfm/46432.htm

Responses by:

Mary M. Gottesman, PhD, RN, CPNP, FAAN
Associate Professor, Specialty Program Director
Pediatric Nurse Practitioner Program
College of Nursing
The Ohio State University

Predilection Sites For Skull Fractures In Infants

Predilection sites of infantile skull fractures following blunt force

Weber W.

Abstract

Previous investigations on calvarial fractures in infants have shown that the flexibility and displacement of the infant calvarial are not sufficient to avoid fractures as a result of fall. From a table height onto hard ground – and in special cases, fractures cannot be avoided even after falls onto softly cushioned ground. The skull fractures are located in paper-thin, transparent, single-layer bone areas without diploe. The results of previous literature were compared with investigations of the skulls of 82 infants (from neonates up to infants 14 months of age). Congenital fissures, cranioschisis, locally retarded ossification in the cranium and craniotabes are all weak points where fracture has a tendency to occur even if the impact is minor. These ossification defects are increased in the ossa parietalia, but can also be found in the os frontale or in the os occipitale. The location is not always the same but can be detected by locating the skull transparency using diaphanoscopy.

Source:

http://www.ncbi.nlm.nih.gov/pubmed/3111120

Fragility Of The Infant Skull

Biomechanical fragility of the infant skull

Weber W.

Abstract

Following previous experiments on postmortem skull fractures of infants, falls from 82-cm heights onto stone (A), carpet (B) and foam-backed linoleum (C), 35 further falling tests were carried out onto softly cushioned ground. In 10 cases a 2-cm thick foam rubber mat (D) was chosen and in 25 further cases a double-folded (8-cm-thick) camel hair blanket (E). Hence the results of altogether 50 tests could be evaluated. In test groups A-C on a relatively hard surface, skull fractures of the parietale were observed in every case; in test group D this fracture was seen in one case and in test group E in four cases. Measurements along the fracture fissures showed bone thickness of 0.1-0.4 mm. The fracture injuries originated in paper-thin single-layer bone areas without diploe, which can also be considered the preferred regions for skull fractures of older infants following falls from low heights. These results indicate that it is no longer possible to assume that the skull of infants is not damaged after falls from table height.

Source:

http://www.ncbi.nlm.nih.gov/pubmed/4002885