Neuropathol. 13 : 277-284, 1993

Workshop Developmen ta 1 Neuropa thology - 5

Intrauterine Embolism Syndrome : Multiple Infarction of Co-Twin of Dead Counterpart in Utero

Masahiro Nakayama

Department of Pathology, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka

(Accepted January 4, 1994)

Twenty-two cases of delivery of twins following the antepartum death of one twin a r e presented. Serious complications were noted in 12 of the live-born twins. Nine live-born twins were delivered more than 1 week after the antepartum death of their counterpart. Two who were delivered 2 days and 5 days, respectively, there- after showed f a t a l cerebral and/or renal necrosis caused by multiple infarction. I n one case the course from the death of the counterpar t t o delivery was unclear. I n all of these cases monochorionic placenta with superficial vascular anastomosis was noted. The remaining 10 twins had good outcomes. Monochronic placenta was noted in 7 cases and placental superficial vascular anas- tomosis in 4. I n these cases, the surviving twin was delivered within 4 d a y s of the antepartum death of the counterpart. I n 3 cases in which the dichorionic placenta lacked vascular anastomoses, the surviving twin also showed excellent prognosis even though the duration after demise of t h e counterpart was prolonged. T h e incidence of venous anastomosis of the placental vessels and the type of anastomosis apparently is very important in determining the live-born twin survives. T h e autopsies revealed no definite evidence of intrauter ine disseminated intravascular coagulation but intrauter ine fetal embolism was considered t o be the pathogenetic factor in multi-organ infarction.

Key words: Twins, Intrautei i i ie dea th of twin fetus, Antepartum dea th of one twin, In t rau ter - ine embolism syndrome

I n t r o d u c t i o n

When one of a pair of twins dies antepartum and both remain for a prolonged period in utero, the live-born twin may frequently show serious infarction in multiple organs including the kidney, spleen, liver and brain. In most studies of such cases, no statistical analysis not detailed placental pathological results are usually presented. We discuss 22 cases of live birth

following the antepartum death of one twin, including autopsy findings for seven and neuropathological findings in five. The relationship of the clinical and pathological fiindings in these cases to the clinical condition and pathogenetic factors is discussed.

P l a c e n t a l findings

Of 613 pairs of twins delivered at our perinatal center between October 1981 and December 1992, in 22 cases one twin had died in utero. The clinical and pathological findings in these cases are shown in Table 1. Twelve neonates showed unfavorable outcome ; seven died in the neonatal period and one at 8 months, and four showed severe growth retardation with mal- formed cerebrum. Patient 5 died soon after birth, Patients 2 and 4 on the third day after birth, Patient 1 on the 19th day, and Patient 3 on the 25th day. Renal insufficiency and intracranial hemorrhage were seen clinically in most of the patients with unfavorable outcomes. An autopsy was conducted on six patients of neonatal death and one of infantile death. Infarc- tion of the brain was seen in five, and, infarction or massive cortical necrosis of the kidneys in five. Splenic infarction and hepatic necrosis were observed in four cases. In all of the patientt with unfavorable outcome, monochorionic diamniotic placenta with marked superficial vascular anastomosis was observed. Placental vein-to-vein (V-V) anastomosis or a complex anastomosis pattern was more frequently seen in this group than in those with favorable outcome. In the patients with unfavorable outcome, the duration from the antepartum death of their counterpart until deliv- ery was more than 7 days. Ten neonates remain alive and well at this time. For four of these patients, monochorionic diamniotic placenta with superficial vascular anastomosis was noted. In three, the dura-

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Anasto- mosis

Neuropathol. 13, 1993

Placental pathology

Table 1 Poor prognosis group

died soon after birth

Case

25

Outcome

died on 3rd day 31

died at 8 months 31

13

14

15

A-A

v-v A-A

v-v

normal 35 w 2,470 (2,322) g 2 day Mono-di +

normal 33 w 1,550 (1,050) g 4 day Mono-di + Torsion

normal 31 w 1,518 (1,448)g 2day Mono-di (-) Fibrin Hypoplastic RV

17 A-A

v-v normal 36 w 2,798 (2,350) g I day ? Mono-di + Ischemia

18

19

normal 34 w 1,680 (1,170) g a few days Mono-di (-1 normal 32 w 1,650 (1,450) g I day Mono-di (-1

20 j normal 1 36 w VSD, PA 2,204 (1,336) g 1 day Di-di ( - ) SUA, VUE

Chrorion, Amnion

Pathorogy of neonates

B.W. Live (Dead)

1,946 (1,035) g

From death to deliv. ,, 19th day 1 2 w Mono-di A-A+V-V I Fibrin No autopsy

1,260 ( 634) g Mono-di V-V ~ Fibrosis I n f a r c t i o n o f b r a i n , k i d n e y , spleen

died on 3rdday I 30w over 2 w

25th died day On I 31 1,578 (1,000) g 1-2 w Mono-di Infarction of liver, brain A-A : Infarction

4 died 3rd day On I 36 1,940 (2,550) g 2 day Mono-di Necrosis of chorion A-A ~

Hepatic necrosis, renal infarction

5 A-A + 1 RPH (1VFD) v-v

Infarction of brain, spleen 680 ( 146) g over 2 w Mono-di

6 died 1st day On 1 2 4 w 846 ( 390) g over 2 w Infarction of liver, spleen and kidney

I n f a r c t i o n o f brain, spleen kidney, lung

Microcephalus, Infarction of kid- ney, liver

Hydranencephal y

Mono-di

Mono-di

Mono-di

Mono-di

A-A + v-v

7 1,866 ( 830) g 2 w

4 A-A + v-v

8 1,474 ( 190) g 2 w

alive 1 34w 9 1,700 ( 374) g 6 w Ischemia

Infarction 10 1,180 ( 140) g 6 w -

Mono-di alive

alive

Infarction

2,954 (2,276) g unknown Mono-di + A-A v-v ~

MCA occlusion 11

jj_ alive 2,210 (2,096) g 5 day Mono-di + Villitis A-A v-v I Infarction

12

16 I normal 1 38 w I 1,920 (1.666) g I 4 d a y 1 Mono-di 1 A-A I VUE, Infarc. I

22 1 normal 1 35w 1 2,112 ( 154)g I 11 w I Di-di I ( - ) I SUA, Aneurysm I

M. Nakuyama : Intrauterine embolism syndrome 279

tion from the antepartum death of the conterpart until delivery was 4 days or less. For one, the duration was 7days, but the fetal umbilical cord was abnormally tightly twisted at the base adjacent to the placental insertion. For three patients with favorable outcome, monochorionic diamniot ic placenta wi thout superficial anastomosis was noted. The duration of exposure for the patients with favorable outcore was much shorter than that for those with unfavorabl outcome. The duration in the three cases in which dichorinic placenta lacked vascular anastomosis was longer than that in the four cases in which vascular anastomosis was present.

Clinical summary and autopsy findings for the poor prognosis group.

Autopsy findings

Autopsies were performed in Cases 2, 3,4, 5,6, 7, and 8.

Case2. The co-twin had died more than 10days before the birth of the live twin. Twin A, the severely macerated stillborn fetus, weighed 634 g, and the placenta demonstrated velamentous insertion of the umbilical cord. Monochorionic diamniotic mem- branes and vein-to-vein (V-V) anastomoses were seen on the placental surface. The autopsy findings for Twin A revealed no anomalies. Twin B weighed 1,260g at birth, and the Apgar score was 6/7. No external anomalies were seen. The live-born twin had

generalized edema after birth and persistent oliguria. Chest X-ray revealed typical reticulo-granular patterns consistent with respiratory distress syndrome. On the 2nd day, intraventricular hemorrhage was detected using ultrasound examination. Blood exchange trans- fusion and dialysis therapy were instituted, but were not effective. The patient died on the 3rd day. The autopsy findings for Twin B revealed yellow hyaline membrane disease with atelectatic lungs, bilateral renal atrophy (weight 6.4 g ; average normal weight, 13 g) with necrosis of the cortex and medulla, massive splenic infarcts with hemorrhage, and massive necrosis of the brain which was marked at the bilateral parietal lobes, as is consistent with occlusion of the middle cerebral arteries (Fig. 1). The left cerebral lesion was more marked than that on the right. Thrombus was detected at both middle cerebral arteries (Fig. 2). Left intraventricular hemorrhage and right subependymal hemorrhage were also seen (Fig. 3). The cerebellum, pons, medulla oblongata, and spinal cord showed no definite infarctions. The brain weight was 125 g (nor- mal range, 189+68 g).

Case3. The co-twin had died more than 5 days before the birth of the live twin. Both neonates were delivered by cesarean section at 31.2 weeks gestation. Twin B, the macerated stillborn fetus, presented nor- mal physical appearance and weighed 1,000 g, and the placenta demonstrated a velamentous insertion of the u m b i l i c a l c o r d . T h e membranes had a monochorionic-diamniotic configuration, and artery-

Fig. 1 External view of cerebrum of Case 2. Infarction is observed at the parietal lobe.

280 Neuropathol. 13, 1993

Fig. 2 Thrombus is detected in the middle cerebral artery of Case 2 .

Fig. 3 Cut surface of cerebrum of Case 2. Infarction and intraventricular hemorrhage are observed.

to-artery (A-A) anastomoses were seen on the placental ductus arteriosus (PDA). Rupture of the gastro- surface. Twin A, in cephalic presentation, weighed intestinal tract was noted on the 17th day after birth, 1,578 g at delivery, and the Apgar score was 8/8. No and she died 8 days later. The autopsy findings for external anomalies were seen. After birth, hydroce- this twin were PDA, anemic lungs with focal phalus and ischemic change of the brain were detected atelectasis and hemorrhage, ulcerated stomach due to at ultrasound examination. Twin A demonstrated submucosal degenerative necrosis of one vessel area, persistent congestive heart failure due to a large patent liver cirrhosis with massive necrosis of Glisson’s triad,

M. Nukuyuma : Intrauterine embolism syndrome 281

Fig. 4 External view of cerebrum of Case 3. Cerebral parenchyma is replaced by fluid

firm and fibrotic kidneys with pelvic enlargement due to parenchymal atrophy, and complete destruction of the brain excluding only small residual portions of the lateral and occipital lobes. Most of the cerebral parenchyme had been replated by fluid (Fig. 4). The brain stem was well preserved. No intracranial hem- orrhage was seen. The brain weight was only 54g (normal range, 189k68 g).

The co-twin had died 2days before the birth of the live twin. Autospy of Twin A, the still- born fetus, was conducted at another hospital, and revealed no anomalies or definite causes of fetal death. Twin B, the live-born neonate weighed 1,940 g at birth, and the Apgar score was 0/1. Brain edema and renal failure developed, followed by convulsion and dis- seminated intravascular coagulation (DIC). Blood exchange transfusion therapy was performed twice, but she died on the 4th day after birth. The autopsy findings of this twin indicated marked edema of the lungs, dark greyish-yellow liver with coarsely and finely granular surface associated with severe hemorr- hagic necrosis, ascites containing stool, pneumoper- itoneum and pneumore t roper i toneum, large pneumatosis of the upper trunk, multiple pneumatosis and repture of the mid-portion of the small intestine with massive necrosis, and severe bilateral hemorrhagic renal cortical necrosis. Permission for brain autopsy was not obtained.

Case 5. The co-twin had died more than 3 weeks before the birth of the live twin. An obstetric ultra-

Case4.

sound examination conducted at 24 weeks gestation revealed twin gestation with one fetal death and hydroanencephalus of the live fetus. Twin A, the severely macerated stillborn fetus, weighed 146 g, and the placenta revealed a velamentous insertion of the u m b i l i c a l c o r d . T h e membranes h a d a monochorionic-diamniotic configuration, and V-V and A-A anastomoses were seen on the placental sur- face. The findings of autopsy in Twin A revealed no anomalies. At birth, Twin B weighed 680g with Apgar scores of 1 and 1 at 1 and 5 minutes. No external anomalies were seen. He died 1 hour later. The autopsy findings for Twin B included massive splenic infarction, marked congestion of the small intestine mucosa with massive hemorrhage, and mas- sive destruction of the brain, which was occupied by fluid (acquired hydroanencephalus). The brain stem and cerebellum presented normal appearance. The brain weight was 30 g (normal range, 89+24 g). An injection study was conducted at autopsy, the contrast medium was not observed to enter the brain (Fig. 5) . The destroyed brain and normal brain stem and cere- bellum suggested thromboembolic arterial occlusion related to bilateral anterior cerebral arteries.

The mother was transferred to our center because of pregnancy with twins and threatened pre- mature delivery (TPD) at 24 weeks gestation. Mono- chorionic diamniotic placenta with A-A and V-V anastomosis was noted. The fetal surface showed marked dilatation of the veins. No chorioamnionitis

Case6.

282 Neuropathol. 13, 1993

Fig. 5 X-ray view at autopsy. The contrast medium has not entered the brain.

was present. The live fetus was severely macerated. Apgar was 3/5. Soon after birth, respiratory distress was noted. At 1 hour after birth, progressive meta- bolic acidosis was noted. Hypotension persisted. At 5.5 hours, surfactant was administered but was ineffective. Bradycardia developed at 12 hours, and she expired at 25 hours. The autopsy findings includ- ed moderate petechiae and necrosis at the left lower extremity. At postmortem angiography, the cerebral areas stained poorly. Slight serosanguinous pleural effusion and ascites were seen. No cardiac anomalies were seen, but both ventricles were markedly dilated. The liver presented mottled necrotic appearance, and the spleen also presented mottling and hemorrhage. The kidneys were dark and tin-colored, suggesting infarction. The brain was discolored gray. Slight subependymal hemorrhage and congestion of choroid plexus were found, but no definite infarction was detected in the brain. The brain weight was 74g (normal range, 129+37 g).

Case7. The Apgar score was 6/8. Soon after birth, oliguria, cardiac failure and multifocal low density areas in the brain were recognized. Blood exchange transfusion was administered for hyper- kalemia. The male patient died on the 3rd day after birth due to congestive heart failure. At autopsy the lung was moderately firm lung, and its cut surface presented a variegated appearance with anemic and congestive areas. Pleural effusion was seen. The heart showed marked hypertrophy of the right ventricle

and dilated right atrium. Partial closing of the ductus was observed. The liver was dark and congested, but no definite infarction was observed. The surface of the spleen was wrinkled, but the spleen was otherwise normal. The kidneys were symmetrical but abnor- mally small. In a barium injection cardiac study, the contrast medium did not enter the kidneys. Direct injection into the right renal artery was attempted, but only a small amount could be injected. The brain weight was 159 g (normal range, 301+75 8). The brain was destroyed especially in the cerebrum. Multiple infaction was detected. The Purkinje cells were relatively well preserved. The spinal cord lacked anterior horn cells.

The counterpart had died in utero at 29 weeks and 4days, and the twins were delivered at 31 weeks and 5 days. The live twin suffered from chronic renal failure, rickets and severe anemia. Marked microcephalus was observed. The autopsy examina- tion was confined to only the abdominal area. Both kidneys were very small and anemic, and the renal surface was irregular. Normal parenchymal structures were not detected. A few medium-sized cysts were identified. Histological examination revealed numer- ous cysts and dilatation of the tubules. Immature glomeruli were seen in the outer cortex. Focal ne- crosis was seen in the liver. Permission to examine the brain was not obtained.

Case 8.

M. Nakayama : Intrauterine embolism syndrome 283

Discussion

A recently recognized problem is sequelae of a co-twin, whose counterpart has died in utero. Occa- sionally, death may be attributed to placental insufficiency associated with maternal disease. How- ever, the cause of death is usually unclear. In our experience, abnormal insertion of the cord, including velamentous and marginal insertion, is observed more often in cases of single fetal death1.

The reported frequency of demise of one fetus in multiple gestation ranges from 0.5% to 6.8%, with more recent reports indicating higher incidence. The inci- dence of intrauterine death has been observed to be higher when the placenta is monobchorionic than when it is dichorionic2. Vascular anastomosis between the placentae is noted frequently with mono- chorionic placentas. Vascular communication is fre- quently A-A anastomosis, but is sometimes venous. There have been almost no detailed studies of vascular anastomosis of the placentae in cases of in utero demise of one twin. When placental vascularity is common, persistent flow can damage the surviving twin. Death and severe morbidity of the live-born twin are attribut- ed to the presence of multiple infarction in the affected organs. Placental vascular communication is report- ed to be the most important factor affecting the progno- sis of the live-born twin4.

In 1961, Bernirschke reported cases of monochorionic-diamniotic twin gestation with ante- partum death of one twin3. The live-born twin was delivered at 32 weeks, but developed apneic episodes and respiratory distress, as well as muscular rigidity. This neonate died 62 hours after birth, and autopsy revealed bilateral renal cortical necrosis, numerous vessels which had been occluded by thrombi, splenic and brain infarction, and fibrin deposits in cortical brain stem vessels. Benirschke proposed that transfu- sion of thromboplastin-rich blood to the live-born twin via placental anastomosis was the pathogenetic mech an i sm5p6.

While there are some reports that DIC is the main cause of this syndrome, our study of the pattern of brain lesion and other organs indicated infarction and no evidence of DIC was detected7.

Other researchers have documented renal cortical necrosis or encephaloplastic brain lesions (hydranence- phaly, porencephaly, and multicystic ence- phalomalacia) but did not describe the chorionicity of the placenta. Furthermore, while there are some reports describing monochorionic placenta, the vascu- lar pattern of the placenta has not been documented in detai18.9.10.

We reviewed the findings in 22cases of twins, in which one twin had died in utero. The brain and kidneys frequently demonstrated severe infarction. Renal cortical necrosis was usually massive and sym- metrical. The spleen was also frequently damaged by infarction, and the liver sometimes contained necrotic lesions with cirrhotic change, while the lungs were not affected.

In cases in which dichorionic or monochorionic placenta was lacking superficial vascular anastomosis, all of the live-born twins showed favorable outcome. While in all of those with unfavorable outcome, the placenta was monochorionic and superficial vascular anastomosis was observed. Examination of the placental vascular patterns in these cases indicated that the incidence of vein-to-vein and of complex anas- tomosis including the vein was high. These venous dominant patterns were found in almost all of the cases with single demise in atero in which the placenta was monochorionic. The findings that the stillborn fetus frequently failed to show any abnormal findings at autopsy which would have accounted for its death and that the placenta often presented marginal or velamentous insertion suggest that the presence of venous anastomosis is related to the demise of one fetus. Furthermore, venous anastomosis may cause damage to the other fetus. The concept of embolism being the cause of multiple infarction in the live-born fetus is strongly supported by the findings of venous drainage in the placenta, since the thrombus could easily enter the fetus via the umbilical vein. The conventionally used term of intrauterine DIC may be inappropriate, since no definite evidence of DIC was detected clinically or pathologically. These lesions could be caused by thrombus or embolism, and we would recommend that the term “intrauterine embo- lism syndrome in twins” be used.

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References

Nakayama, M. Analysis of perinatal deaths from 269 autopsy cases. in Maeda, K. Okuyama, K. and Takeda, K. ed. Recent advances in perinatology. Excerpta Medica, Amsterdam, 1986, pp. 365-375. Dudley, D.K.M., D’ Alton, M.E. Single fetal death in twin gestation. Seminars in Perinatology. 10 : 65-72, 1986. Johnson, S.F. , Driscoll S.G. Twin placentation and its complications. Seminars in perinatology 10 : 9-13, 1986 Benirschke, K. Twin placenta in perinatal mortality. N Y Stata I Med 61: 1499, 1961. Hanna, J.H., Hill, J.M. Single intrauterine fetal demise in multiple gestation. Obstet Gynecol 63 : 126-130, 1984 D‘Alton, M.E., Newton, E.R., Cetrulo C.L. Intrauterine